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Suicide increased among younger Black, Hispanic and Native American people, and declined among whites and older people, the C.D.C. reported.A two-year decline in yearly suicides ended in 2021, as suicide rates rose among younger Americans and people of color, according to a new report from the Centers for Disease Control and Prevention.For decades, suicide rates among Black and Hispanic Americans were comparatively low, around a third the rate recorded among white Americans. But a gradual shift is underway, as suicide rates rise in populations most affected by the pandemic.Between 2018 and 2021, the suicide rate among Black people increased by 19.2 percent, from 7.3 to 8.7 per 100,000. The swiftest rise took place among some of the youngest Black people, those ages 10 to 24. The suicide rate in that group rose by 36.6 percent, from 8.2 to 11.2 per 100,000.Among people ages 25 to 44, suicide rates rose 5 percent overall, and even more significantly among Black, Hispanic, multiracial and American Indian or Alaska Native people. The suicide rate remained highest among Native American and Alaska Native people, increasing by 26 percent, from 22.3 to 28.1 per 100,000, in that period.The only racial group that saw a decrease in suicide rates across age cohorts was non-Hispanic white people. That population saw a decline of 3.9 percent, from 18.1 to 17.4 per 100,000. Suicide deaths in the white population numbered 36,681, more than three-quarters of the total number.Tips for Parents to Help Their Struggling TeensCard 1 of 6Are you concerned for your teen?

Researchers have found that the movement of glaciers in Greenland is more complex than previously thought, with deformation in regions of warmer ice containing small amounts of water accounting for motion that had often been assumed to be caused by sliding where the ice meets the bedrock beneath.
The international team of researchers, led by the University of Cambridge, used computer modelling techniques based off earlier fibre-optic measurements from the Greenland Ice Sheet to build a more detailed picture of the behaviour of the world’s second-largest ice sheet.
Their results, reported in the journal Science Advances, could be used to develop more accurate predictions of how the Greenland Ice Sheet will continue to move in response to climate change.
Mass loss from the Greenland Ice Sheet has increased sixfold since the 1980s and is now the single largest contributor to global sea-level rise. Around half of this mass loss is from surface meltwater runoff, while the other half is driven by discharge of ice directly into the ocean by fast-flowing glaciers that reach the sea.
The RESPONDER project, funded by the European Research Council, is exploring the dynamics of the Greenland Ice Sheet using a combination of physical measurements and computer modelling.
The current research builds on earlier observations reported by the RESPONDER team in 2021 using fibre-optic cables. In that work, the team found that the temperature of ice sheets does not vary as a smooth gradient, but is far more heterogeneous, with areas of highly localised deformation warming the ice further.

The borehole measurements also showed that the ice at the base contains small amounts — up to roughly two percent — of water. In some parts of the ice sheet, this mixed ice-water layer, called temperate ice, was around eight metres thick, but in other parts it was up to 70 metres thick.
“The addition of even tiny amounts of water softens the ice considerably, transforming it into a unique material with substantially altered mechanical characteristics,” said first author Dr Robert Law, who completed the work while based at Cambridge’s Scott Polar Research Institute and is now based at the University of Bergen. “We wanted to know why the thickness of this layer varied so much, because if we don’t fully understand it, our models of ice sheet behaviour won’t fully capture the physical processes occurring in nature.”
“The textbook view of glacier motion is that it occurs with a neat partitioning of basal sliding and internal deformation, and that both are well understood,” said co-author and RESPONDER project leader Professor Poul Christoffersen, who is based at SPRI. “But that’s not what we observed when we looked carefully in boreholes with new techniques. With less detailed observations in the past, it was difficult to get a really good picture of how the ice sheet moves and even more challenging to replicate it with computer models.”
Law, Christoffersen and their colleagues from the UK, US, Switzerland and France developed a model based on their earlier borehole measurements that can account for all of the new observations.
Importantly, they accounted for natural variations in the landscape at the base of the ice, which, in Greenland, is full of rocky hills, basins and deep fjords. The researchers found that as a glacier moves over a large obstacle or hill, there is a deformation and heating effect which sometimes extends several hundred metres from the ice sheet base. Previously, this effect was omitted in models.

“The stress on the ice base is highest at the tops of these hills, which leads to more basal sliding,” said Law. “But so far most models have not accounted for all of these variations in the landscape.”
By incorporating these variations, the model developed by the researchers showed that a variable layer of temperate ice forms as the glacier moves over the landscape, whether the glacier itself is fast- or slow-moving. The thickness of this temperate ice layer agrees with the earlier borehole measurements, but diverges significantly from standard modelling methods used to predict sea level rise from ice sheets.
“Because of this hilly landscape, the ice can go from sliding across its base almost entirely to hardly sliding at all, over short distances of just a few kilometres,” said Law. “This directly influences the thermal structure — if you’ve got less basal sliding then you’ve got more internal deformation and heating, which can lead to the layer of temperate ice getting thicker, altering the mechanical properties of the ice over a broad area. This temperate basal ice layer can actually act like a deformation bridge between hills, facilitating the fast motion of the much colder ice directly above it.”
The researchers hope to use this improved understanding to build more accurate descriptions of ice motion for the ice sheet models used in predicting future sea level rise.
The research was funded in part by the European Union and the Natural Environment Research Council (NERC), part of UK Research and Innovation (UKRI).

New adoptive T cell therapies — in which T cells, the immune system’s natural hunters patrolling the body for foreign adversaries, are retrieved from cancer-riddled patients, super-charged and amplified outside the body, and then infused back into the same patient — are changing the prospects of cancer patients. Since 2017, when CAR (chimeric antigen receptor)-T cells were green-lighted as the first modified therapeutic cells by the Federal Drug Administration (FDA) to treat leukemia, five similar products have since been approved and more than 20,000 people have been treated with this game-changing immunotherapy.
CAR-T cells are engineered to carry synthetic membrane-spanning receptor molecules that use their outside-facing portion to bind to antigens on cancer cells, which their inside-facing portion responds to by switching on a powerful tumor cell-destroying program. However, not all patients respond equally well to CAR-T cell therapies, and cancer immunologists have been trying to figure out what makes them work well or fail. Despite a budding understanding of differences between cancer patients’ T cells and healthy individuals’ T cells, these insights have not been taken into account in CAR-T cell manufacturing processes. All processes use a similar type of stimulation with T-cell specific agonists and general immune-stimulating cytokines to create infusible CAR-T cell products, irrespective of variations in the original T cells’ phenotype.
Now, a collaboration between bioengineers at the Wyss Institute for Biologically Inspired Engineering at Harvard University and Harvard John A. Paulson School of Engineering and Applied Sciences (SEAS) led by David Mooney, Ph.D. and cancer-immunologists at the Dana-Farber Cancer Institute (DFCI) led by Catherine Wu, M.D., Ph.D. has demonstrated that personalizing CAR-T cell stimulation during manufacturing can significantly enhance the consistency and potency of the resulting CAR-T cell products. By using artificial antigen-presenting cell mimicking scaffolds (APC-ms), the team was able to fine-tune the levels of T cell stimulation to match the phenotype of T cells obtained from leukemia patients, and significantly enhanced their ex vivo and in vivo tumor-clearing abilities. The findings are published in Nature Communications.
“We show that CAR-T cell products made from T cells derived from cancer patients are generally less functional than CAR-T cells products derived from healthy individuals,” said Founding Wyss Core Faculty member Mooney. “Matching the CAR-T cell antigen-stimulation dose to the phenotype of patients’ T cells using a precisely controllable biomaterials approach that closely mimics natural antigen presentation can significantly improve their function. This approach could further personalize CAR-T cell therapy and remove an existing inadequacy from current T cell manufacturing.” Mooney also is Robert P. Pinkas Family Professor of Bioengineering at SEAS, and a lead of the NIH-funded Immunomaterials to Improve Immunotherapy (i3) Center coordinated at the Wyss Institute. This project was conceived at the Center, and Wu is one of its Principal Investigators.
Cutting the keys for personalized CAR-T therapies
The team investigated the phenotypes of T cells that they isolated from samples obtained from patients suffering from acute lymphoblastic leukemia (ALL) and chronic lymphoblastic leukemia (CLL), as well as from healthy donors. Next, they utilized APC-ms to provide the T cells with different doses of anti-CD3/anti-CD28 antigen stimulation and thus created a CAR-T cell library. All CAR-T cell products contained in the library were then probed again for functional differences, including their ability to kill cancer cells in vitro. The researchers directly compared their approach with one that is commonly used in CAR-T cell manufacturing, which presents the same antigens on rigid magnetic beads (Dynabeads) to T cells.

A key finding was that cancer patients’ T cells were much more easily over-stimulated at antigen doses commonly used during CAR-T cell manufacturing than “healthy” T cells. This made them lose their functionality, or become more “exhausted” as immunologists say, and decreased their ability to proliferate. CAR-T cells not only need to be transformed into a functional state but also amplified by millions to be able to eliminate tumor cells and metastasis in the entire body.
“By exploring a precise, narrow range of stimulation doses made possible with APC-ms, we show that there is something like a personalized ‘sweet spot’ for patient-derived T cells that maximizes functionality and amplification, which is, on average, lower than the usual doses,” said first-author David Zhang, who is a graduate student on Mooney’s team. “The APC-ms approach functions much more naturally than Dynabeads, because highly controllable levels of T-cell signals are embedded into a lipid bilayer, which allows the CAR-T cells to push and pull at them as just as T cells usually do across the ‘immunological synapse’ between them and antigen-presenting cells when T cell stimulation is at its best.”
From in vitro studies to cell manufacturing
While the team did not observe any significant differences between CAR-T cells created from ALL and CLL patient samples, overall their approach generated more cells with high cytotoxic potential toward tumor cells, a more balanced ratio between cytotoxic CD8+ T cells and CD4+ T cells that support their function, and more memory T cells that themselves are not cytotoxic but can be activated in later responses. In a mouse in vivo study, infused CAR-T cell products created with different levels of stimulation also exhibited significantly different abilities to control CD19-expressing Burkitt’s lymphoma, with cells again stimulated at lower than usual levels during manufacturing showing the strongest potential.
“We constructed a proof-of-concept model that is based on the quantifiable relationship between the phenotype of a T cell blood sample and its CAR-T cell products, and that outputs an optimal T cell stimulation dose for personalized CAR-T cell production,” said Wu. “Given that T cell samples are always fingerprinted for important markers at the beginning of the cell manufacturing process, similar strategies could be devised to further personalize the therapy using the APC-ms approach.” Wu is the Lavine Family Chair, Preventative Cancer Therapies at DFCI, and Professor of Medicine at Harvard Medical School.
“Dave Mooney’s team in the Wyss’ Immunomaterials platform is pushing the envelope of CAR-T cell and other immunotherapies using entirely new engineering and materials-based approaches. Hopefully, this will eventually enable us to also mobilize the immune system against recalcitrant solid tumors for which no therapies exist yet. It’s also a great example of where less is more,” said Wyss Founding Director Donald Ingber, M.D., Ph.D., who is also the Judah Folkman Professor of Vascular Biology at HMS and Boston Children’s Hospital, and Hansjörg Wyss Professor of Bioinspired Engineering at the Harvard John A. Paulson School of Engineering and Applied Sciences.
Additional authors on the study are Wyss and SEAS researchers Kwasi Adu-Berchie, Siddharth Iyer, Yutong Liu, and Joshua Brockman; DFCI researcher Nicoletta Cieri, and Donna Neuberg, Sc.D., a data scientist at the DFCI and member of the i3 Center. The study was funded by the Wyss Institute at Harvard University, the Food and Drug Administration (under award #5R01FD006589), the National Cancer Institute of the NIH (under award #U54CA244726), as well as a fellowship from the Canadian Institutes of Health Research.

Regulatory T cells ensure that immune responses happen in a controlled way. But eating too much salt weakens these cells’ energy supply, thus rendering them dysfunctional for a while. This may have implications for autoimmunity, an international team — including Dominik Müller — reports in Cell Metabolism.
Eating too much salt, which is common in many Western societies, is not only bad for our blood pressure and cardiovascular system — it could also adversely impact the immune system. An international research team, coordinated by scientists at the VIB Center for Inflammation Research and Hasselt University in Belgium as well as the Max Delbrück Center in Germany, is now reporting in “Cell Metabolism” that salt can disrupt key immune regulators called regulatory T cells by impairing their energy metabolism. The findings may provide new avenues for exploring the development of autoimmune and cardiovascular diseases.
A few years ago, research by teams led by Professor Dominik Müller at the Max Delbrück Center for Molecular Medicine and the Experimental and Clinical Research Center, a joint institution of Charité — Universitätsmedizin Berlin and Max Delbrück Center (ECRC) in Berlin, Germany and Professor Markus Kleinewietfeld at the VIB Center for Inflammation Research and Hasselt University in Belgium, as well as by colleagues of theirs, revealed that too much salt in our diet can negatively affect the metabolism and energy balance in certain types of innate immune cells called monocytes and macrophages and stop them from working properly. They further showed that salt triggers malfunctions in the mitochondria, the power plants of our cells. Inspired by these findings, the research groups wondered whether excessive salt intake might also create a similar problem in adaptive immune cells like regulatory T cells.
Important immune regulators
Regulatory T cells, also known as Tregs, are an essential part of the adaptive immune system. They are responsible for maintaining the balance between normal function and unwanted excessive inflammation. Tregs are sometimes referred to as the “immune police” because they keep bad guys like autoreactive immune cells at bay and ensure that immune responses happen in a controlled way without harming the host organism.
Scientists believe that the deregulation of Tregs is linked to the development of autoimmune diseases like multiple sclerosis. Recent research has identified problems in mitochondrial function of Tregs from patients with autoimmunity, yet the contributing factors remain elusive.
“Considering our previous findings of salt affecting mitochondrial function of monocytes and macrophages as well as the new observations on mitochondria in Tregs from autoimmune patients, we were wondering if sodium might elicit similar issues in Tregs of healthy volunteers,” says Müller, who co-heads the Hypertension-Mediated End-Organ Damage Lab at the Max Delbrück Center and the ECRC.
Previous research has also shown that excess salt could impact Treg function by inducing an autoimmune-like phenotype. In other words, too much salt makes the Treg cells look like those involved in autoimmune conditions. However, exactly how sodium impairs Treg function had not yet been uncovered.
Salt interferes with mitochondrial function of Tregs
The new international study led by Kleinewietfeld and Müller and first-authored by Dr. Beatriz Côrte-Real and Dr. Ibrahim Hamad — both of whom work at the VIB Center for Inflammation Research and Hasselt University in Belgium — has now discovered that sodium disrupts Treg function by altering cellular metabolism through interference with mitochondrial energy generation. This mitochondrial problem seems to be the initial step in how salt modifies Treg function, leading to changes in gene expression that showed similarities to those of dysfunctional Tregs in autoimmune conditions.
Even a short-term disruption of mitochondrial function had long-lasting consequences for the fitness and immune-regulating capacity of Tregs in various experimental models. The new findings suggest that sodium may be a factor that could contribute to Treg dysfunction, potentially playing a role in different diseases, although this needs to be confirmed in further studies.
“The better understanding of factors and underlying molecular mechanisms contributing to Treg dysfunction in autoimmunity is an important question in the field. Since Tregs also play a role in diseases such as cancer or cardiovascular disease, the further exploration of such sodium-elicited effects may offer novel strategies for altering Treg function in different types of diseases,” says Kleinewietfeld, who heads the VIB Laboratory for Translational Immunomodulation. “However, future studies are needed to understand the molecular mechanisms in more detail and to clarify their potential relationship to disease.”

Terahertz spectroscopy maps spontaneous formation of protein-rich droplets that may lead to neurodegenerative diseases.
Using a new method “Terahertz (THz) calorimetry,” a research team from the Cluster of Excellence Ruhr Explores Solvation (RESOLV) in Bochum was successful in shedding new light on the spontaneous phase separation into a protein-rich and a protein-poor phase in a solution. It is assumed that the protein-rich droplets promote the formation of neurotoxic protein aggregates — a hot spot for neurodegenerative diseases. The researchers, led by Professor Martina Havenith, Chair of Physical Chemistry II at Ruhr University Bochum, report in the Journal of Physical Chemistry Letters published online on 6 February 2023.
Molecular level and time resolution in the picosecond range
The study is part of the “THz calorimetry” project, which received a European Research Council (ERC) Advanced Grant. “The visionary idea in the project was to combine two powerful techniques in Physical Chemistry — laser spectroscopy and calorimetry,” explains the grantee, Martina Havenith.
Calorimetry measures quantities fundamental to chemical and biochemical reactions, such as heat capacity, enthalpy, and entropy. Based on well-known substance-specific parameters, it is possible to predict whether, for example, a reaction will occur spontaneously without any external input of energy or whether equilibrium conditions dominate. Calorimetric measurements take place in a macroscopic container. The amount of heat required for a temperature change or a chemical or biochemical reaction is measured. “The limitation of this method is its limited time resolution and the amount of sample required,” says Martina Havenith.
The goal of the ERC project was to overcome these limitations. This required a new approach to measure calorimetric quantities for the smallest samples with a time resolution of picoseconds, or one-millionth of one-millionth of a second at the molecular level. “However, we can not, in principle, achieve time and spatial resolution on this scale reach with these traditional concepts of heat measurements,” the researcher explains. “This required a different revolutionary approach that intrinsically offers a different access.”
Water plays a crucial role
The research group showed that spectroscopic fingerprints of water could be measured by their absorption in the THz range, which is linearly correlated with calorimetric quantities. This allows the researchers to track these fundamental calorimetric quantities in real time using spectroscopic and ultrafast laser spectroscopic methods, even for complex systems during a process or reaction.
In their current work, inspired by their collaboration with the research groups of Professor Konstanze Winklhofer and Professor Jörg Tatzelt at Ruhr University Bochum, they used this method for the first time to study a hot topic in Biomedical research: They investigated liquid-liquid phase separation, the spontaneous phase separation into a protein-rich and a protein-poor liquid phase.
“Using THz calorimetry, we can map the formation of these protein-rich droplets on a molecular level. Not only the proteins themselves but the water also plays a crucial role,” Martina Havenith reports. “We can now follow on-line any changes in the water during the formation process with the THz camera. Based on the derived calorimetric quantities, we can give accurate predictions about the formation of phase separated droplets and the dependency on external parameters such as temperature.”

Scientists from NIH’s National Human Genome Research Institute (NHGRI) and Undiagnosed Diseases Program (UDP) identified three children with the condition, two siblings and an unrelated child. The three children all had issues with motor coordination and speech, and one child had abnormalities in the cerebellum, the part of the brain involved in complex movement among other functions. Additionally, the children all had mutations in both copies of the ATG4D gene.
ATG4D aids in the cellular housekeeping process called autophagy, which cells use to break down and recycle damaged proteins and other defective pieces of the cell to stay healthy. Autophagy is a fundamental process used by cells throughout the body, but neurons are particularly dependent on autophagy for survival. However, little is known about how ATG4D contributes to healthy neurons.
The first inclination of ATG4D’s effects on brain health came from a 2015 study in which researchers identified a genetic neurological disease among Lagotto Romagnolo dogs, an Italian breed known for their fluffy coats and truffle-hunting abilities. The affected dogs had abnormal behavior, atrophy of the cerebellum, issues with motor coordination and eye movement and ATG4D mutations.
While this 2015 study invigorated research interest in ATG4D’s role in the brain, scientists had yet to connect ATG4D to any neurological disease in humans.
“Among genetic diseases, we’ve solved many of the lower hanging fruits,” said May Christine Malicdan, M.D., Ph.D., NHGRI staff scientist and senior author of the study. “Now, we’re reaching for the higher fruits — genes like ATG4D that are more difficult to analyze — and we have the genomic and cellular tools to do so.”
Computational analyses predicted that the three children’s ATG4D mutations would produce dysfunctional proteins. However, three other genes in the human genome serve very similar roles to ATG4D, and in some cells, these other genes may compensate for a loss of ATG4D.

While all cells in the body share the same genome, some genes are more important for certain cells. When the researchers studied the children’s ATG4D mutations in skin cells, the variants did not affect the cells’ recycling process, but this may not be true in the brain.
“The brain is so complex, and neurons have very specialized functions. To fit those functions, different neurons use different genes, so changes in redundant genes can have major impacts in the brain,” said Malicdan.
To simulate cells that rely more heavily on ATG4D, the researchers deleted the similar genes in cells grown in the laboratory and then inserted the children’s ATG4D mutations. The researchers determined the cells with the children’s ATG4D mutations could not carry out the necessary steps for autophagy, indicating that the children’s symptoms are likely caused by insufficient cellular recycling.
Still, much about ATG4D remains unknown. “We have only a bird’s eye view of many important cellular processes like autophagy,” said Malicdan. A rare disease that involves changes in one gene can help tease apart how that gene acts in a broadly important cellular process.
Other components of autophagy are involved in common neurological disorders, such as Alzheimer’s disease. Knowledge of this rare neurological disorder could lead to new avenues of research about ATG4D’s involvement in more common conditions.
“That’s the million-dollar question in rare disease research,” said Malicdan. “Rare diseases can help us understand biological pathways, so we can better understand how those pathways contribute to other rare and common conditions.”
NIH researchers and clinicians continue to work with the children in this study, and the researchers are aiming to identify more patients. Treatments are many steps away, but by learning more about ATG4D and autophagy, researchers may be able to develop new treatments for this condition and others involving autophagy pathways.