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A vision of chromosome organization

The DNA of eukaryotic organisms is packaged by histone proteins into chromatin. The structural organization of chromatin is tied to its function. Loosely packed, more transcriptionally active regions of chromatin are known as euchromatin, whereas highly condensed, less transcriptionally active regions are known as heterochromatin.

Despite advances in the study of chromatin structure over the past 100 years, a biochemical understanding of how basic structural motifs beget higher-order chromatin organization remains lacking.

In a new Science study, researchers present an approach that enables imaging and analysis of the structure of chromatin condensates in situ, which moves the field much closer toward defining the structural chromatin motifs that underpin its nuclear functions.

Learn more in a new Science Perspective.

Cryogenic electron tomography of condensed chromatin enables multiscale analysis of its structure.

Kaite Zhang and Vijay Ramani Authors Info & Affiliations

Continue reading “A vision of chromosome organization” | >

Non-opioid analgesic binding sites on glycine transporter 2

Glycine is a major inhibitory neurotransmitter that reduces nerve activity, helping to regulate pain signals, motor control and sensory processing. Glycine transporter 2 (GlyT2) is a key regulator of glycinergic neurotransmission because it removes glycine from the synaptic clefts. When GlyT2 is inhibited, glycine reuptake is reduced, allowing synaptic glycine levels to rise and enhance inhibitory signaling. Because of its ability to modulate glycinergic transmission, GlyT2 is an attractive therapeutic target for neuropathic pain. It is particularly attractive because it suggests new means of non-opioid pain management.

In a new study published in PNAS, researchers reported high-resolution cryo-EM structures of GlyT2 in three major conformational states. These structures illuminate the transporter’s molecular mechanisms and provide critical insights into how analgesic compounds are recognized.

The researchers identified a previously unknown third sodium-binding site (Na3) on GlyT2. Whereas other neurotransmitter transporters use two Na ⁺ ions and one Cl ⁻ ion, the additional binding site demonstrates that GlyT2 uses three Na ⁺ ions and one Cl ⁻ ion to transport glycine per cycle. This additional sodium ion supplies the extra energetic drive required for glycine transport and offers new understanding of Na ⁺ /Cl ⁻-coupled substrate binding and conformational changes, supporting GlyT2’s specialized physiological function.

The researchers also uncovered a distinctive allosteric binding pocket that accommodates lipid-based inhibitors such as oleoyl-D-lysine, a derivative of the endogenous lipid N-arachidonyl glycine. Structural and biochemical analyzes revealed features that determine the inhibitory potency of this class of lipid molecules, providing a foundation for rational design of improved lipid-based GlyT2 analgesics.

Additionally, the researchers resolved structures of GlyT2 bound to several small-molecule inhibitors, including ALX1393, opiranserin, and ORG25543. These structures reveal distinct competitive and allosteric inhibition mechanisms and identify key residues responsible for selectivity between GlyT1 and GlyT2.

Abstract: A widely held hypothesis posits that ER stress drives cell death in thyroid disease

Here, Peter Arvan & team generate a mouse model lacking thyroglobulin, finding stimulated thyroid hormone synthesis machinery drives thyrocyte cell death independent of ER stress:

The figure shows limited ER diameter in thyroid tissue from Tg-KO untreated mice.

Address correspondence to: Peter Arvan, Division of Metabolism, Endocrinology & Diabetes, University of Michigan, Brehm Tower rm 5,112, 1000 Wall Street, Ann Arbor, Michigan 48,105, USA. Phone: 734.936.5505; Email: [email protected].

Unveiling the Role of Graphene in Enhancing the Mechanical Properties of Electrodeposited Ni Composites

Graphene holds significant promise as an ideal reinforcing phase. However, its tendency to irreversibly aggregate and its unclear impact on electrodeposition mechanisms have hindered the full exploitation of its advantages for enhancing material mechanical properties. In this study, we produced a graphene/Ni composite reinforced with reduced graphene oxide (rGO) via a simple, scalable, and cost-effective electrodeposition approach. The incorporation of graphene not only raised the cathodic polarization potential but also enhanced the transport of ions. As a result, the presence of rGO significantly influenced the grain size, grain distribution, and the proportion of growth twins-3(111). Compared with Ni, the graphene/Ni composite exhibited improvements of 14.8% in strength and 16.8% in fracture elongation.

Performance Improvements In UE5.7 Over UE5.4

A new video from MxBenchmarkPC demonstrates the performance gains in Unreal Engine 5.7 by comparing it side by side with Unreal Engine 5.4 using the recently released Venice tech demo by Scans Factory.

The test was conducted at 4K and 1440p with Nanite and hardware ray tracing with Lumen, using Ultra settings on an RTX 5,080 paired with an Intel Core i7-14700F.

“GPU performance is improved by up to 25% in UE5.7 (depending on a scene), and the 5.7 version is now better utilizing GPU resources, hence the GPU power draw is now higher,” commented MxBenchmarkPC. “UE5.7 offers a significant up to 35% CPU performance boost (depending on the scene) and more stable frametimes with less hitches across all scenes.”

Molecular basis of vesicular monoamine transport and neurological drug interactions

Ye et al. reveal how VMAT2 loads monoamine neurotransmitters into storage vesicles and interacts with neurological drugs, facilitated by the structural flexibility of the transporter. Amphetamine directly triggers monoamine release to induce psychostimulation, likely by bypassing the regular transport cycle. These insights elucidate psychostimulant action and inform therapeutic strategies.

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.

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