Interactive extraction of diverse vocal units from a planar embedding without the need for prior sound segmentation.

Annotating and proofreading data sets of complex natural behaviors such as vocalizations are tedious tasks because instances of a given behavior need to be correctly segmented from background noise and must be classified with minimal false positive error rate. Low-dimensional embeddings have proven very useful for this task because they can provide a visual overview of a data set in which distinct behaviors appear in different clusters. However, low-dimensional embeddings introduce errors because they fail to preserve distances; and embeddings represent only objects of fixed dimensionality, which conflicts with vocalizations that have variable dimensions stemming from their variable durations. To mitigate these issues, we introduce a semi-supervised, analytical method for simultaneous segmentation and clustering of vocalizations. We define a given vocalization type by specifying pairs of high-density regions in the embedding plane of sound spectrograms, one region associated with vocalization onsets and the other with offsets. We demonstrate our two-neighborhood (2N) extraction method on the task of clustering adult zebra finch vocalizations embedded with UMAP. We show that 2N extraction allows the identification of short and long vocal renditions from continuous data streams without initially committing to a particular segmentation of the data. Also, 2N extraction achieves much lower false positive error rate than comparable approaches based on a single defining region. Along with our method, we present a graphical user interface (GUI) for visualizing and annotating data.

Positional information encoded in the dynamic differences between neighboring oscillators during vertebrate segmentation.

A central problem in developmental biology is to understand how cells interpret their positional information to give rise to spatial patterns, such as the process of periodic segmentation of the vertebrate embryo into somites. For decades, somite formation has been interpreted according to the clock-and-wavefront model. In this conceptual framework, molecular oscillators set the frequency of somite formation while the positional information is encoded in signaling gradients. Recent experiments using ex vivo explants have challenged this interpretation, suggesting that positional information is encoded in the properties of the oscillators, independent of long-range modulations such as signaling gradients. Here, we propose that positional information is encoded in the difference in the levels of neighboring oscillators. The differences gradually increase because both the amplitude and the period of the oscillators increase with time. When this difference exceeds a certain threshold, the segmentation program starts. Using this framework, we quantitatively fit experimental data from in vivo and ex vivo mouse segmentation, and propose mechanisms of somite scaling. Our results suggest a novel mechanism of spatial pattern formation based on the local interactions between dynamic molecular oscillators.

Bitopertin, a selective oral GLYT1 inhibitor, improves anemia in a mouse model of ß-thalassemia.

Anemia of ß-thalassemia is caused by ineffective erythropoiesis and reduced red cell survival. Several lines of evidence indicate that iron/heme restriction is a potential therapeutic strategy for the disease. Glycine is a key initial substrate for heme and globin synthesis. We provide evidence that bitopertin, a glycine transport inhibitor administered orally, improves anemia, reduces hemolysis, diminishes ineffective erythropoiesis, and increases red cell survival in a mouse model of ß-thalassemia (Hbbth3/+ mice). Bitopertin ameliorates erythroid oxidant damage, as indicated by a reduction in membrane-associated free α-globin chain aggregates, in reactive oxygen species cellular content, in membrane-bound hemichromes, and in heme-regulated inhibitor activation and eIF2α phosphorylation. The improvement of ß-thalassemic ineffective erythropoiesis is associated with diminished mTOR activation and Rab5, Lamp1, and p62 accumulation, indicating an improved autophagy. Bitopertin also upregulates liver hepcidin and diminishes liver iron overload. The hematologic improvements achieved by bitopertin are blunted by the concomitant administration of the iron chelator deferiprone, suggesting that an excessive restriction of iron availability might negate the beneficial effects of bitopertin. These data provide important and clinically relevant insights into glycine restriction and reduced heme synthesis strategies for the treatment of ß-thalassemia.

Travelling waves in somitogenesis: Collective cellular properties emerge from time-delayed juxtacrine oscillation coupling.

The sculpturing of the vertebrate body plan into segments begins with the sequential formation of somites in the presomitic mesoderm (PSM). The rhythmicity of this process is controlled by travelling waves of gene expression. These kinetic waves emerge from coupled cellular oscillators and sweep across the PSM. In zebrafish, the oscillations are driven by autorepression of her genes and are synchronized via Notch signalling. Mathematical modelling has played an important role in explaining how collective properties emerge from the molecular interactions. Increasingly more quantitative experimental data permits the validation of those mathematical models, yet leads to increasingly more complex model formulations that hamper an intuitive understanding of the underlying mechanisms. Here, we review previous efforts, and design a mechanistic model of the her1 oscillator, which represents the experimentally viable her7;hes6 double mutant. This genetically simplified system is ideally suited to conceptually recapitulate oscillatory entrainment and travelling wave formation, and to highlight open questions. It shows that three key parameters, the autorepression delay, the juxtacrine coupling delay, and the coupling strength, are sufficient to understand the emergence of the collective period, the collective amplitude, and the synchronization of neighbouring Her1 oscillators. Moreover, two spatiotemporal time delay gradients, in the autorepression and in the juxtacrine signalling, are required to explain the collective oscillatory dynamics and synchrony of PSM cells. The highlighted developmental principles likely apply more generally to other developmental processes, including neurogenesis and angiogenesis.