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ATP release deficiency through astrocytic connexin 43 in the dorsal hippocampus promotes depressive- and anxiety-like behaviors

New in JNeurosci from Wang et al: Impaired ATP release in the dorsal hippocampus of male mice may lead to depressive-and anxiety-like behavior. Connexin 43 may be a key molecular player in this mechanism.

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Depression is a common psychiatric disorder, and increasing evidence implicates the dysregulation of extracellular ATP and hippocampal dysfunction in its pathophysiology. However, whether ATP release is involved in depression and mechanisms underlying this involvement remain unclear. Moreover, the basis for the comorbidity of depression and anxiety disorders remains unclear. In our study, we observed reduced connexin 43 (Cx43) and extracellular ATP levels in the dorsal hippocampus but not ventral hippocampus of susceptible adult male mice exposed to chronic social defeat stress. Conditional knockout of astrocytic Cx43 or its specific knockdown in dorsal hippocampal astrocytes led to depressive-and anxiety-like behaviors, whereas neuronal knockout of Cx43 had no effect on these behaviors. These deficits were accompanied by decreased extracellular ATP levels, while supplementation with exogenous ATPγS reversed these behavioral deficits. We further identified Cx43 as a critical regulator of ATP release and a modulator of astrocytic network connectivity and morphology. Notably, overexpression of Cx43 combined with the inhibition of ATP-degrading enzymes in the dorsal hippocampus restored ATP levels and ameliorated behavioral deficits. Taken together, our results demonstrate that deficiency of ATP release from dorsal hippocampal astrocytes leads to depressive-and anxiety-like behaviors, primarily through Cx43. These findings shed new light on the mechanisms by which ATP regulates depression and anxiety pathogenesis and the role of dorsal hippocampus in depression and anxiety, providing potential therapeutic targets for treating these comorbid disorders.

Significance statement This study provides the first direct evidence of a causal relationship between astrocytic Cx43 in the dorsal hippocampus and depressive-like behaviors. It highlights the crucial role of ATP release in the comorbidity of depression and anxiety. Astrocyte-specific knockout or knockdown of Cx43 in the dorsal hippocampus resulted in reduced extracellular ATP levels and emotional disturbances. Conversely, restoring Cx43 expression combined with inhibition of ATP degradation rescued both ATP levels and behavioral deficits in susceptible mice. These findings underscore the central role of astrocytic Cx43-mediated ATP release in the pathophysiology of depression and highlight promising therapeutic strategies for the treatment of comorbid depression and anxiety.

‘Zombie’ cells spark inflammation in severe fatty liver disease, Mayo Clinic researchers find

Now online! Melanoma cells escape immune surveillance by releasing MHC-antigen-loaded large EVs, known as melanosomes, that directly engage and impair CD8+ T cell receptors.

Now online! Melanoma cells and melanosomes had distinct MHC class I ligandome profiles (Figure 4 G), but a substantial proportion of the melanosome-derived peptide repertoire overlapped with that of the parent cells (83.8%), implying derivation from the total cellular ligandome (Figure 4 G). Pathway enrichment analysis of the immunopeptidome landscape revealed a positive correlation between pathways enriched in cells and their corresponding melanosomes, with substantial overlaps in functional categories such as class I MHC-mediated antigen processing and presentation, DNA repair, and cell cycle regulation (Figures 4 H and 4I). Given the observed MHC class I-dependent, peptide-specific suppression of CD8+ T cell activity by melanosomes, we hypothesized that melanosomes present immunogenic peptides. Indeed, we have identified 25 tumor-associated antigens (TAAs) in melanosome samples (Figure 4 J) with high-confidence peptide identifications (Figure 4 K). These TAAs are predicted to bind a variety of HLA alleles with high affinity. Strikingly, the majority of these peptides were also detected in the corresponding melanoma cell samples (Figure 4 J). Notably, melanosomes exhibited a statistically significant enrichment in TAA presentation compared with melanoma cells, regardless of IFNγ treatment (Figure 4 L).

Finally, we used whole-exome sequencing to generate a custom proteomic database for proteogenomic analysis of neopeptides/neoantigens. This approach identified three mutation-derived neoantigens within the human melanosome immunopeptidome, two of which were also present in the cellular MHC class I repertoire (Figures 4 M and 4N). Importantly, we analyzed the murine B16F10 cells and secreted melanosome immunopeptidomic data, which recapitulated most of our findings in human cells (Figures S4 A–S4J). Together, these findings suggest that melanosomes, by carrying immunogenic peptides, including TAAs and neoantigens, compete with melanoma cells for CD8+ T cell recognition, thereby contributing to their immunomodulatory effects.

Robotic arm successfully learns 1,000 manipulation tasks in one day

Over the past decades, roboticists have introduced a wide range of systems that can effectively tackle some real-world problems. Most of these robots, however, often perform poorly on tasks that they were not trained on, particularly those that entail manipulating previously unseen objects or handling objects that were encountered before in new ways.

Researchers at the Robot Learning Lab at Imperial College London recently developed a new imitation learning approach that could allow robots to successfully learn new tasks faster and without requiring substantial training data. Using this method, which was introduced in a paper published in Science Robotics, they were able to train a robotic arm to complete 1,000 different tasks in a single day.

“The research was initially inspired by our prior work on trajectory transfer, where we introduced a method that proved robust and efficient for teaching robots single tasks,” Kamil Dreczkowski and Pietro Vitiello, co-authors of the paper, told Tech Xplore.

Physicists push superconducting diodes to high temperatures

For the first time, researchers in China have demonstrated a high-temperature superconducting diode effect, which allows a supercurrent to flow in both directions. Published in Nature Physics, the team’s result could help address the noisy signals that pose a fundamental challenge in quantum computing.

A diode is a device that shows an asymmetric electrical response, allowing current to flow more easily in one direction than the other. Until recently, diode behavior had only been observed in conventional, non-superconducting electrical systems—but in 2020, a team of researchers in Japan became the first to demonstrate the diode effect in a superconductor. Ever since, this effect has gained increasing attention for its potential in practical quantum computing.

“However, most of the reported superconducting diodes work at low temperatures around 10 Kelvin, and often require an external magnetic field,” explains Ding Zhang at Tsinghua University and the Beijing Academy of Quantum Information Sciences, who led the research. “The diode efficiency is also low for many superconducting diodes.”

Subtle twist in materials prompts surprising electromagnetic behavior

Materials react differently to electric and magnetic fields, and these reactions are known as electromagnetic responses. In many solid materials, unusual electromagnetic responses have been known to only emerge when specific symmetries are broken.

Researchers at Rutgers University, Pohang University of Science and Technology, National Taiwan University and University of Michigan recently observed new electromagnetic effects in ferro-rotational materials, which they reported in a paper in Nature Physics. These are solid materials in which individual crystals collectively rotate, and form ordered rotational domains, without breaking spatial inversion (I) or time-reversal (T) symmetry.

“Twisting is ubiquitous in nature, appearing in DNA structures, climbing vines, and even in quartz crystals that exhibit piezoelectricity. Such twisting is typically three-dimensional and is described by chirality, characterized by left-or right-handedness,” Sang-Wook Cheong, senior author of the paper told Phys.org.

Shortest light pulse ever created captures ultrafast electron dynamics

Electrons determine everything: how chemical reactions unfold, how materials conduct electricity, how biological molecules transfer energy, and how quantum technologies operate. But electron dynamics happens on attosecond timescales—far too fast for conventional measurement tools.

Researchers have now generated a 19.2-attosecond soft X-ray pulse, which effectively creates a camera capable of capturing these elusive dynamics in real time with unprecedented detail, enabling the observation of processes never observed before. Dr. Fernando Ardana-Lamas, Dr. Seth L. Cousin, Juliette Lignieres, and ICREA Prof. Jens Biegert, at ICFO, has published this new record in Ultrafast Science. At just 19.2 attoseconds long, it is the shortest and brightest soft X-ray pulse ever produced, giving rise to the fastest “camera” in existence.

Flashes of light in the soft X-ray spectral range provide fingerprinting identification, allowing scientists to track how electrons reorganize around specific atoms during reactions or phase transitions. Generating an isolated pulse this short, required innovations in high-harmonic generation, advanced laser engineering, and attosecond metrology. Together, these developments allow researchers to observe electron dynamics, which define material properties, at their natural timescales.

Conventional entanglement can have thousands of hidden topologies in high dimensions

Researchers from the University of the Witwatersrand in South Africa, in collaboration with Huzhou University, discovered that the entanglement workhorse of most quantum optics laboratories can have hidden topologies, reporting the highest ever observed in any system: 48 dimensions with over 17,000 topological signatures, an enormous alphabet for encoding robust quantum information.

Most quantum optics laboratories produce entangled photons by a process of spontaneous parametric downconversion (SPDC), which naturally produces entanglement in “space,” the spatial degrees of freedom of light. Now the team have found that hidden in this space is a world of high-dimensional topologies, offering new paradigms for encoding information and making quantum information immune to noise. The topology was shown using the orbital angular momentum (OAM) of light, from two dimensional to very high dimensions.

Reporting in Nature Communications, the team showed that if one measures the OAM of two entangled photons it can be shown to have a topology: an underlying feature of the entanglement itself. Since OAM can take on an infinite number of possibilities, so too can the topology.

Color-superconducting quark matter may explain stability of massive neutron stars

Describing matter under extreme conditions, such as those found inside neutron stars, remains an unsolved problem. The density of such matter is equivalent to compressing around 100,000 Eiffel Towers into a single cubic centimeter. In particular, the properties of so-called quark matter—which consists of the universe’s fundamental building blocks, the quarks, and may exist in extremely dense regions—play a central role.

Researchers from TU Darmstadt and Goethe University Frankfurt have studied this matter and its thermodynamic properties. Their findings are published in the journal Physical Review Letters.

Theoretical studies suggest that quarks at very low temperatures enter a so-called color-superconducting state, which fundamentally alters the nature of matter. This state is analogous to the transition of an electron gas into an electrical superconductor—except that, instead of electrons, quarks pair up and create an energy gap in their excitation spectrum.

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