Forskningsradar

Science Journals

Peer-reviewade publikationer — 50304 artiklar

eLife 2026-05-15
Drug-induced changes in connectivity to midbrain dopamine cells revealed by rabies monosynaptic tracing
Addictive drugs cause long-lasting changes in connectivity from inputs onto ventral tegmental area dopamine cells (VTA<sup>DA</sup>) that contribute to drug-induced behavioral adaptations. However, it is not known which inputs are altered. Here, we used a rabies virus (RABV)-based mapping strategy to quantify RABV-labeled inputs to VTA cells after a single exposure to one of a variety of misused drugs – cocaine, amphetamine, methamphetamine, morphine, and nicotine – and compared the relative global input labeling across conditions. We observed that all tested addictive drugs elicited similar input changes onto VTA<sup>DA</sup> cells, in particular onto DA cells projecting to the lateral shell of the nucleus accumbens and amygdala. In addition, repeated administration of ketamine/xylazine to induce anesthesia induces a change in inputs to VTA<sup>DA</sup> cells that is similar to but different from those elicited by a single exposure to addictive drugs, suggesting that caution should be taken when using ketamine/xylazine-based anesthesia in rodents when assessing motivated behaviors. Furthermore, comparison of viral tracing data to an atlas of gene expression in the adult mouse brain showed that the basal expression patterns of several gene classes, especially calcium channels, were highly correlated with the extent of both addictive drug- or ketamine/xylazine-induced changes in RABV-labeled inputs to VTA<sup>DA</sup> cells. Reducing expression levels of the voltage-gated calcium channel <i>Cacna1e</i> in cells in the nucleus accumbens lateral shell reduced RABV-mediated input labeling of these cells into VTA<sup>DA</sup> cells. These results directly link genes controlling cellular excitability and the extent of input labeling by RABV.
eLife 2026-05-15
The role of ATP synthase subunit e (ATP5I) in mediating the metabolic and antiproliferative effects of metformin in cancer cells
Here, we identify the subunit e of F₁F₀-ATP synthase (ATP5I) as a target of metformin, a first-in-class antidiabetic biguanide. ATP5I maintains the stability of F₁F₀-ATP synthase dimers, which is crucial for shaping cristae morphology. We demonstrate that ATP5I interacts with a biguanide analogue in vitro, and disabling its expression by CRISPR–Cas9 in pancreatic cancer cells leads to the same phenotype as biguanide-treated cells, including mitochondrial morphology alterations, reduction of the NAD<sup>+</sup>/NADH ratio, inhibition of oxidative phosphorylation (OXPHOS), rescue of respiration by uncouplers, and a compensatory increase in glycolysis. Notably, metformin disrupts F₁F₀-ATP synthase oligomerization, leading to the accumulation of vestigial assembly intermediates in pancreatic and osteosarcoma cancer cells, a phenotype also observed upon ATP5I inactivation in pancreatic cancer cells. Moreover, ATP5I knockout (KO) cells exhibit resistance to the antiproliferative effects of biguanides, but reintroduction of ATP5I rescues the metabolic and antiproliferative effects of metformin and phenformin. Finally, a genome-wide CRISPR screening in NALM-6 lymphoma cells revealed that metformin-treated cells exhibit genetic interaction profiles similar to those observed with the F₁F₀-ATP synthase inhibitor oligomycin, but not with the complex I inhibitor rotenone. This provides unbiased support for the relevance of the newly proposed target.
eLife 2026-05-15
Bilateral equalization of synaptic output in olfactory glomeruli of <i>Xenopus</i> tadpoles
Odorants stimulate olfactory sensory neurons (OSNs) to create a bilateral sensory map defined by a set of glomeruli present in the left and right olfactory bulbs. Using <i>Xenopus tropicalis</i> tadpoles, we challenged the notion that glomerular activation is exclusively determined ipsilaterally. Glomerular responses evoked by unilateral stimulation were potentiated following transection of the contralateral olfactory nerve. The gain of function was observed as early as 2 hr after injury and faded away with a time constant of 4 days. Potentiation was mediated by the presence of larger and faster calcium transients driving glutamate release from OSN axon terminals. The cause was the reduction of the tonic presynaptic inhibition exerted by dopamine D<sub>2</sub> receptors. Inflammatory mediators generated by injury were not involved. These findings reveal the presence of a bilateral modulation of glomerular output driven by dopamine that compensates for imbalances in the number of operative OSNs present in the two olfactory epithelia. Considering that the constant turnover of OSNs is an evolutionarily conserved feature of the olfactory system and determines the innervation of glomeruli, the compensatory mechanism described here may represent a general property of the vertebrate olfactory system to establish an odor map.
eLife 2026-05-15
Stranded short nascent strand sequencing reveals the topology of DNA replication origins in <i>Trypanosoma brucei</i>
The universal features that define genomic regions acting as replication origins remain unclear. In this study, we mapped a set of origins in <i>Trypanosoma brucei</i> using stranded short nascent strand sequencing methods. Our results showed that DNA replication predominantly initiates in intergenic regions between poly(dA)- and poly(dT)-enriched sequences. G4 structures were detected in the vicinity of some origins and were embedded in poly(dA)-enriched sequences in a strand-specific manner: G4s on the plus strand were located upstream while those on the minus strand were located downstream of the centre. The origins' centres were found to be areas of low nucleosome occupancy, surrounded by regions of high nucleosome occupancy. Furthermore, our results demonstrate that 90% of replication origins overlap with a minor proportion of the previously reported RNA: DNA hybrids. These findings shed new light on the sequence and structural features that define the topology of replication origins in <i>T. brucei</i>. To further characterise replication dynamics at the single-molecule level, we employed DNA combing analysis.
PLOS Biology 2026-05-14
Structural basis for hemoglobin scavenging by CD163 reveals mechanism of ligand promiscuity
<p>by Richard X. Zhou, Matthew K. Higgins</p> The scavenger receptor CD163 detoxifies free hemoglobin released on erythrocyte lysis to prevent oxidative damage. The best understood route for hemoglobin detoxification involves the formation of haptoglobin-hemoglobin complexes that bind CD163 and are internalized into macrophages, resulting in hemoglobin degradation. However, during conditions such as sickle cell anemia or malaria, haptoglobin is depleted. CD163 can then act as a lower-affinity receptor for free hemoglobin. Previous studies revealed that CD163 forms a multimeric "base," which presents "arms" that form a binding site for haptoglobin-hemoglobin. In this study, we use cryogenic electron microscopy to reveal how human CD163 binds hemoglobin tetramers in a process that, unlike haptoglobin-hemoglobin uptake, requires a full trimeric CD163 assembly to achieve sufficient binding. We reveal how flexibility at the calcium-mediated base, combined with a hinge between receptor domains 2 and 3, allows the arms to wrap around diverse ligands. This brings together multiple small binding surfaces from different domains to form cradles for different ligands. These adaptations allow the scavenger receptor to be promiscuous, protecting us from oxidative damage caused by hemoglobin release in various pathological conditions.
PLOS Biology 2026-05-14
Encoding performance of cortical neurons critically depends on their morphological and neurophysiological properties
<p>by Omer Revah, Fred Wolf, Michael J. Gutnick, Andreas Neef</p> Sixty years after the concept of population coding in neuronal networks was introduced, we still lack a comprehensive understanding of its performance limits and the role of neuronal physiology. Here, we use dynamic gain analysis in a general model of population coding and demonstrate that disparate parameters of neurons and populations determine how accurately they can encode information. These are cell number, cell size, and the correlation time of the background noise. We experimentally test and confirm these predictions on neurons of excitatory populations in the mouse barrel cortex. Surprisingly, dendrite size and background correlations are precisely matched with the number of neurons in layer 4, such that even a single thalamocortical spike at the input is reliably reflected in the population output. However, this encoding performance can be modulated by the channels that mediate M-current, suggesting that coding in layer 4 may vary as a function of brain state.
PLOS Biology 2026-05-14
Beyond survival: Redefining successful aging in the era of medical complexity
<p>by Karin Modig, Marcus Ebeling</p> A common misconception is that increasing longevity reflects slower aging. Instead, most longevity gain comes from medical advances that allow survival with disease, rather than changes to the biology of aging itself, challenging how we study aging and health. Modern medicine has transformed not only how long we live, but also how we age, with more people surviving to old age with chronic disease. This Perspective examines how aging, health, and care should be redefined to reflect these increasingly complex later lives.