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Biology subjects

Braun, L. M.

Publications and source records attributed to Braun, L. M..

3 recordsLinked to original sources

A common structure in recurrent networks supports neural sequence generation locally and in downstream neurons

Neural sequences, characterized by neurons or groups of neurons that fire one after the other, have been observed in multiple brain regions, across species, and are known to underlie a diversity of brain functions. To flexibly support behaviour and cognition, neural sequences exhibit much variability in properties like their temporal width, baseline, and peak firing rate. Despite this variability and the central role that sequences play in supporting brain function, a framework that explains how flexible sequences are generated and dynamically maintained within a circuit is still missing. Here we go beyond traditional approaches that investigate a one-to-one relationship between network connectivity and specific sequential dynamics. Instead, we train recurrent neural network models to generate a repertoire of sequential dynamics and characterize the obtained connectivity matrices. We found that different connectivity matrices can generate the same neural sequence, yet all connectivity matrices that generate a specific sequence share a common connectivity profile, defined here as the average weight between pairs of neurons as a function of their distance in the sequence ordering. It is the connectivity profile, as opposed to the connectivity matrix, that serves as a fingerprint of the sequential dynamics and shapes the network response to perturbations of the neural activity. Our model predictions were consistent with results obtained from experimental data recorded across brain regions and across species. Finally, we demonstrated that neural sequences can facilitate and constrain the formation of a large repertoire of sequences in downstream brain regions, with the potential of acting as scaffolds for a wide range of computations. Altogether, our results explain how network connectivity can generate a diversity of neural sequences across circuits and how those sequences can be flexibly adapted. Our framework reveals sequences as a common algorithm to support brain function across brain regions and species.

neuroscience↗

Cooperative siderophore use stabilizes a protective leaf microbiome

Plant-associated microbial communities provide crucial protection against pathogens. Specialized metabolites play key roles in plant-microbe and microbe-microbe interactions and, ultimately, in plant health; however, the molecular mechanisms underlying their plant-protecting properties remain largely unknown. Nutrient deficiency (e.g., iron) on leaf surfaces creates intense competition among microbes, driving both antagonism and cooperation. Using a gnotobiotic Arabidopsis thaliana model and a synthetic leaf microbial community, we show that community stability and plant protection depend on cooperative siderophore exchange between the basidiomycete yeast Rhodotorula kratochvilovae and commensal Pseudomonas species. Removal of Pseudomonas caused a strong shift in the community metabolome and accumulation of the yeast siderophore rhodotorulic acid (RA). RA selectively promoted the growth of commensal Pseudomonas via TonB-dependent transporters, which are absent in pathogenic Pseudomonas strains. Inactivation of these transporter genes abolished RA uptake, destabilized the synthetic community, and eliminated protection against Pseudomonas syringae infection. RA and Rhodotorula also induced host iron-deficiency and jasmonate-related defense metabolites, linking microbial cooperation to plant stress responses. These findings reveal that microbial siderophore exchange acts as a key mechanism that maintains stability in the phyllosphere microbiome. Rather than solely promoting competition, iron-binding compounds can serve as cooperative currencies that align microbial fitness with host protection.

microbiology↗

Oncogenic PTPN11/SHP2 drives immune escape in juvenile myelomonocytic leukemia (JMML) through activation of ectonucleotidase/adenosine signaling

Juvenile myelomonocytic leukemia (JMML) is a myelodysplastic/myeloproliferative neoplasm of early childhood driven by RAS pathway mutations. Allogeneic hematopoietic stem cell transplantation (HSCT) is the therapy of choice for most patients. However, relapse rate is high, in patients with adverse features, frequently noted in PTPN11-mutated JMML, or in patients without evidence of graft-versus-host disease (GvHD). Here we set out to understand the mechanisms associated with oncogenic PTPN11 immune escape. Analyzing primary PTPN11-mutated JMML samples and MxCre;Ptpn11D61Y/+ mice, we observed elevated expression of immune checkpoint molecules, including ectonucleotidases CD39 and CD73 - key mediators of the adenosine pathway - on monocytic and granulocytic leukemic cells. Stimulation with GM-CSF, a central mediator of JMML pathogenesis, induced ectonucleotidases expression on granulocytes and monocytes. In contrast, MEK inhibition downstream of Ptpn11D61Y/+ reduced ectonucleotidases expression. Functionally, Ptpn11D61Y/+-mutated myeloid cells suppressed activation and proliferation of wild-type (WT) T lymphocytes, an effect recapitulated by adenosine and reversed by pharmacological CD39 inhibition with POM-1. In vivo, POM-1 treatment of MxCre;Ptpn11D61Y/+mice presenting with myeloproliferation reduced spleen size and partially restored immune responsiveness. Moreover, POM-1 induced apoptosis in murine Ptpn11D61Y/+ myeloid cells, highlighting a dual therapeutic benefit of CD39 inhibition in JMML. Together, these findings suggest that targeting the adenosine pathway may represent an immunomodulatory approach to enhance T cell-mediated control of JMML, particularly in the context of HSCT and relapse prevention.

cancer biology↗