In a study published in Nature Communications, Lewis Zhichang Shi, M.D., Ph.D., and University of Alabama at Birmingham colleagues show, for the first time, how HIF1α in T cells is key for induction of interferon gamma, or IFN-γ, in that hypoxic environment. The cytokine IFN-γ is known to be essential to induce the tumor-killing capacity of T cells. Additionally, an alternative metabolism called glycolysis, which is able to produce energy in human cells when no oxygen is present, is similarly known to be required for IFN-γ induction in T cells.

“Intriguingly, under normal oxygen levels in the body, called normoxia, IFN-g induction and glycolysis in T cells are not mediated by HIF1α, a primary regulator of glycolysis, but by its widely regarded downstream target LDHa, as reported in an early study by another group,” said Shi, a professor in the UAB Department of Radiation Oncology. “However, it has been unknown, under hypoxia, whether and how HIF1α regulates IFN-γ induction and glycolysis in T cells.”

The UAB researchers found that HIF1α-glycolysis is indispensable for IFN-γ induction in hypoxic T cells. HIF1α is a subunit of HIF, or hypoxia-inducible factor, that is known to play a crucial role in orchestrating cellular responses to hypoxia.

Shi and colleagues showed this key role for HIF1α in hypoxia by combining genetic mouse models, metabolic flux analysis using ¹³C-labeled glucose tracing assays and a Seahorse analyzer, as well as pharmacological approaches.

In both human and mouse T cells that were activated under hypoxia, they found that the deletion of HIF1α from the T cells prevented the metabolic reprogramming shift from catabolic metabolism to anabolic metabolism, of which anaerobic glycolysis is a major component; the deletion also suppressed the induction of IFN-γ. Additionally, pharmacologic inhibition of T cell glycolysis under hypoxia prevented induction of IFN-γ. Conversely, stabilization of HIF1α by knocking out a negative regulator of HIF1α increased IFN-γ under hypoxic conditions.

With regard to defense against cancer, the researchers found that hypoxic T cells deleted for HIF1α were less able to kill tumor cells in vitro. In vivo, tumor-bearing mice that had the HIF1α-deleted in T cells did not respond to ICB therapy.

The researchers then showed a way to overcome that resistance to ICB therapy. Elucidation of the mechanistic function of the HIF1α deletion showed that loss of HIF1α greatly diminished glycolytic activity in hypoxic T cells, resulting in depleted intracellular acetyl-CoA and attenuated activation-induced cell death, or AICD. Restoration of intracellular acetyl-CoA by supplementing growth media with acetate reengaged AICD and rescued IFN-γ production for hypoxic Hif1α-deletion T cells.

Shi and colleagues then demonstrated, in living mice, that acetate supplementation was an effective strategy to bypass ICB resistance in tumor-bearing mice with specific deletion of HIF1α in T cells. When Hif1α-deletion tumor-bearing mice were given acetate supplementation followed by combination ICB therapy, the mice had significant improvement in ICB therapy, as seen by potent suppression of tumor growth and greatly reduced tumor weights.

“TILs and tumor cells utilize the same metabolic pathways for their growth and function, and co-live in the metabolically harsh tumor-microenvironments characterized by hypoxia and poor nutrition, placing them in a fierce metabolic tug-of-war,” Shi said. “How to tilt this metabolic battle to favor TILs would be key, and we showed that acetate supplementation restored IFN-γ production in Hif1α-deletion-TILs and overcame ICB resistance derived from HIF1α loss in T cells.”

“Our study, together with an early report by others, compellingly shows that the impaired HIF1α function in T cells is a major T cell-intrinsic mechanism of therapeutic resistance to ICBs, like anti-CTLA-4 and anti-PD-1/L1,” Shi said.

Co-authors with Shi in the study, “HIF1α-regulated glycolysis promotes activation-induced cell death and IFN-γ induction in hypoxic T cells,” are Hongxing Shen, Oluwagbemiga A. Ojo, Haitao Ding, Chuan Xing, Abdelrahman Yassin, Vivian Y. Shi, Zach Lewis, Ewa Podgorska and James A. Bonner, UAB Department of Radiation Oncology; Logan J. Mullen, University of Alaska Fairbanks, Fairbanks, Alaska; M. Iqbal Hossain and Shaida A. Andrabi, UAB Department of Pharmacology and Toxicology; and Maciek R. Antoniewicz, University of Michigan, Ann Arbor, Michigan.

Support came from UAB; the O’Neal Comprehensive Cancer Center at UAB; National Institutes of Health grants CA230475-01A1, CA25972101A1 and CA279849-01A1; V Foundation Scholar Award V2018-023; Department of Defense-Congressionally Directed Medical Research Programs grant ME210108; and Cancer Research Institute CLIP Grant CRI4342.

At UAB Radiation Oncology and Pharmacology and Toxicology are departments in the Marnix E. Heersink School of Medicine. Shi is a scientist in the O’Neal Comprehensive Cancer Center and holds the Koikos-Petelos-Jones-Bragg ROAR Endowed Professorship for Cancer Research.

The study, which was published Dec. 13 in the print edition of the journal Patterns and featured on the journal’s cover, describes a computer program named PlacentaVision that can analyze a simple photograph of the placenta to detect abnormalities associated with infection and neonatal sepsis, a life-threatening condition that affects millions of newborns globally.

“Placenta is one of the most common specimens that we see in the lab,” said study co-author Dr. Jeffery Goldstein, director of perinatal pathology and an associate professor of pathology at Northwestern University Feinberg School of Medicine. “When the neonatal intensive care unit is treating a sick kid, even a few minutes can make a difference in medical decision making. With a diagnosis from these photographs, we can have an answer days earlier than we would in our normal process.”

Northwestern provided the largest set of images for the study, and Goldstein led the development and troubleshooting of the algorithms.

Alison D. Gernand, contact principal investigator on the project, conceived the original idea for this tool through her global health work, particularly with pregnancies where women deliver in their homes due to lack of health care resources.

“Discarding the placenta without examination is a common but often overlooked problem,” said Gernand, associate professor in the Penn State College of Health and Human Development (HHD) Department of Nutritional Sciences. “It is a missed opportunity to identify concerns and provide early intervention that can reduce complications and improve outcomes for both the mother and the baby.”

Why early examination of the placenta matters

The placenta plays a vital role in the health of both the pregnant individual and baby during pregnancy, yet it is often not thoroughly examined at birth, especially in areas with limited medical resources.

“This research could save lives and improve health outcomes,” said Yimu Pan, a doctoral candidate in the informatics program from the College of Information Sciences and Technology (IST) and lead author on the study. “It could make placental examination more accessible, benefitting research and care for future pregnancies, especially for mothers and babies at higher risk of complications.”

Early identification of placental infection through tools like PlacentaVision might enable clinicians to take prompt actions, such as administering antibiotics to the mother or baby and closely monitoring the newborn for signs of infection, the scientists said.

PlacentaVision is intended for use across a range of medical demographics, according to the researchers.

“In low-resource areas — places where hospitals don’t have pathology labs or specialists — this tool could help doctors quickly spot issues like infections from a placenta,” Pan said. “In well-equipped hospitals, the tool may eventually help doctors determine which placentas need further, detailed examination, making the process more efficient and ensuring the most important cases are prioritized.”

“Before such a tool can be deployed globally, core technical obstacles we faced were to make the model flexible enough to handle various diagnoses related to the placenta and to ensure that the tool can be robust enough to handle various delivery conditions, including variation in lighting conditions, imaging quality and clinical settings” said James Z. Wang, distinguished professor in the College of IST at Penn State and one of the principal investigators on the study. “Our AI tool needs to maintain accuracy even when many training images come from a well-equipped urban hospital. Ensuring that PlacentaVision can handle a wide range of real-world conditions was essential.”

How the tool learned how to analyze pictures of placentas

The researchers used cross-modal contrastive learning, an AI method for aligning and understanding relationship between different types of data — in this case, visual (images) and textual (pathological reports) — to teach a computer program how to analyze pictures of placentas. They gathered a large, diverse dataset of placental images and pathological reports spanning a 12-year period, studied how these images relate to health outcomes and built a model that could make predictions based on new images. The team also developed various image alteration strategies to simulate different photo-taking conditions so the model’s resilience can be evaluated properly.

The result was PlacentaCLIP+, a robust machine-learning model that can analyze photos of placentas to detect health risks with high accuracy. It was validated cross-nationally to confirm consistent performance across populations.

According to the researchers, PlacentaVision is designed to be easy to use, potentially working through a smartphone app or integrated into medical record software so doctors can get quick answers after delivery.

Next step: A user-friendly app for medical staff

“Our next steps include developing a user-friendly mobile app that can be used by medical professionals — with minimal training — in clinics or hospitals with low resources,” Pan said. “The user-friendly app would allow doctors and nurses to photograph placentas and get immediate feedback and improve care.”

The researchers plan to make the tool even smarter by including more types of placental features and adding clinical data to improve predictions while also contributing to research on long-term health. They’ll also test the tool in different hospitals to ensure it works in a variety of settings.

“This tool has the potential to transform how placentas are examined after birth, especially in parts of the world where these exams are rarely done,” Gernand said. “This innovation promises greater accessibility in both low- and high-resource settings. With further refinement, it has the potential to transform neonatal and maternal care by enabling early, personalized interventions that prevent severe health outcomes and improve the lives of mothers and infants worldwide.”

This research was supported by the National Institutes of Health National Institute of Biomedical Imaging and Bioengineering (grant R01EB030130). The team used supercomputing resources from the National Science Foundation-funded Advanced Cyberinfrastructure Coordination Ecosystem: Services & Support (ACCESS) program.

The jet coming out of the center of M87 is seven orders of magnitude — tens of millions of times — larger than the event horizon, or surface of the black hole itself. The bright burst of high-energy emission was well above the energies typically detected by radio telescopes from the black hole region. The flare lasted about three days and probably emerged from a region less than three light-days in size, or a little under 15 billion miles.

A gamma ray is a packet of electromagnetic energy, also known as a photon. Gamma rays have the most energy of any wavelength in the electromagnetic spectrum and are produced by the hottest and most energetic environments in the universe, such as regions around black holes. The photons in M87’s gamma ray flare have energy levels up to a few teraelectronvolts. Teraelectronvolts are used to measure the energy in subatomic particles and are equivalent to the energy of a mosquito in motion. This is a huge amount of energy for particles that are many trillion times smaller than a mosquito. Photons with several teraelectronvolts of energy are vastly more energetic than the photons that make up visible light.

As matter falls toward a black hole, it forms an accretion disk where particles are accelerated due to the loss of gravitational potential energy. Some are even redirected away from the black hole’s poles as a powerful outflow, called “jets,” driven by intense magnetic fields. This process is irregular, which often causes a rapid energy outburst called a “flare.” However, gamma rays cannot penetrate Earth’s atmosphere. Nearly 70 years ago, physicists discovered that gamma rays can be detected from the ground by observing the secondary radiation generated when they strike the atmosphere.

“We still don’t fully understand how particles are accelerated near the black hole or within the jet,” said Weidong Jin, a postdoctoral researcher at UCLA and a corresponding author of a paper describing the findings published by an international team of authors in Astronomy & Astrophysics. “These particles are so energetic, they’re traveling near the speed of light, and we want to understand where and how they gain such energy. Our study presents the most comprehensive spectral data ever collected for this galaxy, along with modeling to shed light on these processes.”

Jin contributed to analysis of the highest energy part of the dataset, called the very-high-energy gamma rays, which was collected by VERITAS — a ground-based gamma-ray instrument operating at the Fred Lawrence Whipple Observatory in southern Arizona. UCLA played a major role in the construction of VERITAS — short for Very Energetic Radiation Imaging Telescope Array System — participating in the development of the electronics to read out the telescope sensors and in the development of computer software to analyze the telescope data and to simulate the telescope performance. This analysis helped detect the flare, as indicated by large luminosity changes that are a significant departure from the baseline variability.

More than two dozen high-profile ground- and space-based observational facilities, including NASA’s Fermi-LAT, Hubble Space Telescope, NuSTAR, Chandra and Swift telescopes, together with the world’s three largest imaging atmospheric Cherenkov telescope arrays (VERITAS, H.E.S.S. and MAGIC) joined this second EHT and multi-wavelength campaign in 2018. These observatories are sensitive to X-ray photons as well as high-energy and very-high-energy gamma-rays, respectively.

One of the key datasets used in this study is called spectral energy distribution.

“The spectrum describes how energy from astronomical sources, like M87, is distributed across different wavelengths of light,” Jin said. “It’s like breaking the light into a rainbow and measuring how much energy is present in each color. This analysis helps us uncover the different processes that drive the acceleration of high-energy particles in the jet of the supermassive black hole.”

Further analysis by the paper’s authors found a significant variation in the position and angle of the ring, also called the event horizon, and the jet position. This suggests a physical relationship between the particles and the event horizon, at different size scales, influences the jet’s position.

“One of the most striking features of M87’s black hole is a bipolar jet extending thousands of light years from the core,” Jin said. “This study provided a unique opportunity to investigate the origin of the very-high-energy gamma-ray emission during the flare, and to identify the location where the particles causing the flare are being accelerated. Our findings could help resolve a long-standing debate about the origins of cosmic rays detected on Earth.”

Cancer immunotherapy has revolutionised treatment for patients, whereby the body’s own immune system is harnessed to destroy cancer cells.

Typically, several molecules restrain the ability of T cells to target cancer cells and developing approaches to limit this restraining effect can lead to improved effectiveness of cancer immunotherapy.

Research published in Science Immunology has determined the structure of how an inhibitory molecule, LAG3, interacts with its main ligand and provides a new targeted approach to improving the effectiveness of immunotherapy for certain forms of cancer.

The publication is the first to show the crystal structure of a human LAG-3/HLA-II complex and provides a better foundation for development of blocking LAG-3 therapeutics.

Led by Professor Jamie Rossjohn at Monash University’s Biomedicine Discovery Institute (BDI), in Melbourne, Australia, in collaboration with Immutep, this research resolves how the human LAG-3 receptor binds to HLA II molecules.

First author Dr Jan Petersen said: “The way the PD-1 and CTLA-4 immune checkpoint molecules bind to their respective ligands has been resolved for many years.

“However, the resolution of the interface between another important checkpoint molecule, LAG-3, and its main ligands, HLA-II molecules, has remained elusive.

“Solved using data collected at the Australian Synchrotron, a structure of a LAG-3/HLA-II complex provides a structural foundation to harness rationally for future development of antibodies and small molecule therapeutics designed to block LAG-3 activity.”

Dr Frédéric Triebel, Immutep’s CSO, added: “These findings add to the strong foundation of our work with Professor Rossjohn and his team to develop a deeper understanding of the structure and function of the LAG-3 immune control mechanism, particularly as it relates to our anti-LAG-3 small molecule program.”

The struggle of our cells

Imagine trying to fit two meters of rope into a space much smaller than the tip of a needle — that’s the challenge every cell in your body faces when packing its DNA into its tiny nucleus. To achieve this, nature employs ingenious strategies, like twisting the DNA into coils of coils, so-called ‘supercoils’ (see pictures for a visualisation) and wrapping it around special proteins for compact storage.

Small DNA loops regulate chromosome functions

However, compaction isn’t enough. Cells also need to regulate the chromosome structure to enable its function. For example, when genetic information needs to be accessed, the DNA is locally read off. In particular when it’s time for a cell to divide, the DNA must first unpack, duplicate, and then properly separate into two new cells. Specialised protein machines called SMC complexes (Structural Maintenance of Chromosomes) play a critical role in these processes. Just a few years ago, scientists at Delft and other places discovered that these SMC proteins are molecular motors that make long loops in our DNA, and that these loops are the key regulators of chromosome function.

A new twist

In the lab of Cees Dekker at TU Delft, postdocs Richard Janissen and Roman Bath now provide clues that help to crack this puzzle. They deloped a new way to use ‘magnetic tweezers’ by which they could watch individual SMC proteins make looping steps in DNA. Importantly, they were also able to resolve if the SMC protein would change the twist in the DNA. And strikingly, the team found that it did: the human SMC protein cohesin does indeed not only pull DNA into a loop, but also twists the DNA in a left-handed way by 0.6 turns in each step of creating the loop.

A glimpse into the evolution of SMC proteins

What’s more, the team found that this twisting action isn’t unique to humans. Similar SMC proteins in yeast behave the same way. Strikingly, all the various types of SMC proteins from human and yeast add the same amount of twist — they turn DNA 0.6 times at every at every DNA loop extrusion step. This shows that the DNA extrusion and twisting mechanisms stayed the same for very long times during evolution. No matter whether DNA is looped in humans, yeast, or any other cell — nature employs the same strategy.

Essential clues

These new findings will provide essential clues for resolving the molecular mechanism of this new type of motor. Additionally, they make clear that DNA looping also affects the supercoiling state of our chromosomes, which directly affects processes like gene expression. Finally, these SMC proteins are related to various diseases such as Cornelia de Lange Syndrome, and a better understanding of these processes is vital for tracking down the molecular origins of these serious illnesses.

The air around us contains a powerful solution for making agriculture more sustainable. Researchers at Stanford University and King Fahd University of Petroleum and Minerals in Saudi Arabia have developed a prototype device that can produce ammonia — a key fertilizer ingredient — using wind energy to draw air through a mesh. The approach they developed, if perfected, might eliminate the need for a century-old method that produces ammonia by combining nitrogen and hydrogen at high pressures and temperatures. The older method consumes 2% of global energy and contributes 1% of annual carbon dioxide emissions from its reliance on natural gas.

The study, published Dec. 13 in Science Advances, involved the first on-site — rather than in a lab — demonstration of the technology. The researchers envision someday integrating the device into irrigation systems, enabling farmers to generate fertilizer directly from the air.

“This breakthrough allows us to harness the nitrogen in our air and produce ammonia sustainably,” said study senior author Richard Zare, the Marguerite Blake Wilbur Professor in Natural Science in the Stanford School of Humanities and Sciences. “It’s a significant step toward a decentralized and eco-friendly approach to agriculture.”

A cleaner alternative

In preparation for designing their device, the researchers studied how different environmental factors — like humidity, wind speed, salt levels, and acidity — affect ammonia production. They also looked at how the size of water droplets, the concentration of the solution, and the contact of water with materials that do not dissolve in water impact the process. Lastly, they tested the best mix of iron oxide and an acid polymer with fluorine and sulfur to determine the ideal conditions for producing ammonia and understand how these catalyst materials interact with water droplets.

The Stanford team’s process makes ammonia cleanly and inexpensively and utilizes the surrounding air to get nitrogen and hydrogen from water vapor. By passing air through a mesh coated with catalysts to facilitate the necessary reaction, the researchers produced enough ammonia with a sufficiently high concentration to serve as a hydroponic fertilizer in greenhouse settings. Unlike traditional methods, the new technique operates at room temperature and standard atmospheric pressure, requiring no external voltage source to be attached to the mesh. Farmers could run the portable device onsite, eliminating the need to purchase and ship fertilizer from a manufacturer.

“This approach significantly reduces the carbon footprint of ammonia production,” said study lead author Xiaowei Song, a chemistry research scientist at Stanford.

In laboratory experiments, the team demonstrated further potential by recycling water through a spraying system, achieving ammonia concentrations sufficient to fertilize plants grown in a greenhouse after just two hours. By incorporating a filter made from a microporous stone material, this approach could produce enough ammonia to support broader agricultural applications.

A future without fossil fuels

The device is two to three years away from being market-ready, according to study co-author Chanbasha Basheer of King Fahd University of Petroleum and Minerals. In the meantime, the researchers plan to use increasingly large mesh systems to produce more ammonia. “There is a lot of room to develop this,” Basheer said.

Ammonia’s importance extends beyond fertilizers. As a clean energy carrier, it can store and transport renewable energy more efficiently than hydrogen gas due to its higher energy density. The innovation positions ammonia as a linchpin in decarbonizing industries like shipping and power generation.

“Green ammonia represents a new frontier in sustainability,” Zare said. “This method, if it can be scaled up economically, could drastically reduce our reliance on fossil fuels across multiple sectors.”

The study was funded by the U.S. Air Force Office of Scientific Research and King Fahd University of Petroleum and Minerals.

The team used sound wave, known as seismic, data to reveal Ice Age landforms buried beneath almost 1 km of mud in the North Sea. The results, reported in the journal Science Advances, suggest that the landforms were produced about 1 million years ago, when an ice sheet centred over Norway extended towards the British Isles.

This is important because the timing of this ice advance corresponds to a period of global cooling called the Mid-Pleistocene Transition.

Glacial landforms reveal how past ice sheets responded to changes in climate, which can help to make better predictions about how today’s ice sheets will respond to climate warming. A challenge is that glacial landforms are often buried beneath thick layers of sediment, preventing their identification.

Dr Christine Batchelor, Senior Lecturer in Physical Geography, Newcastle University, played a key role in the research by helping to map and interpret the landforms. “To fully understand the linkages between ice sheets and climate, we need to study how past ice sheets responded to long-term changes in climate,” said Dr Batchelor. “Using modern seismic data, our results suggests that ice sheets in northwest Europe expanded significantly in response to climate cooling about 1 million years ago.”

Dr Dag Ottesen from the Geological Survey of Norway, the paper’s lead author, said: “This study was made possible by the availability of 3D seismic data from the North Sea, which allowed us to examine the buried landforms in striking detail.”

3D seismic technology was developed to assess sediment suitability to host oil and gas or renewable infrastructures. However, this same data can be used to study buried landforms produced by glacial processes.

The mapped landscape includes streamlined features that were carved beneath the former ice sheet and ridges that record the imprint of the ice sheet as it started to retreat. Despite their ancient age, the landforms have striking resemblance to similar features produced by ice sheets much more recently.

The buried landforms provide new knowledge about the mechanisms by which ice sheets retreat. In order for such subdued landforms to remain unmodified, the former ice sheet must have retreated rapidly by lift-off and floatation of its frontal margin.

In addition to glacial landforms, the researchers also found elongated furrows incised into the former seabed, which they interpreted to have been produced by strong ocean currents. These landforms are even more deeply buried than the glacial landforms, showing that they were produced prior to the advance of the ice sheet.

“With our high-resolution data, we can see that the shape and size of the furrows is consistent with an origin as ocean current furrows,” said Dr Ottesen. “This differs from previous interpretations of these features as glacial landforms, re-writing our understanding of North Sea glacial history.”

By providing a new level of detail about the buried landforms, the findings shed light into the evolution of the North Sea in our recent geological past. The study shows that the North Sea was characterised by strong ocean currents prior to about 1 million years ago, after which it became more directly influenced by ice sheets.

The research team acknowledge that a limitation of the study is a lack of data about the precise age of the landforms.

“A wealth of seismic data are now available for the North Sea,” said Dr Batchelor. “The next step is to acquire long sediment cores that can allow researchers to better understand the timing of glacial events.”

Other co-authors are Helge Løseth at Equinor ASA, Trondheim and Harald Brunstad at Aker BP ASA, Trondheim.