Biology subjects

Stigliani, A.

Publications and source records attributed to Stigliani, A..

6 recordsLinked to original sources

bioRxiv2023

Pulmonary maternal immune activation does not extend through the placenta but leads to fetal metabolic adaptation

Maternal immune system activation (MIA) during pregnancy can disrupt the fetal environment, causing postnatal susceptibility to disorders. How the placenta and the fetus respond to acute MIA over time is unknown. Here, we characterized the response to acute maternal pulmonary inflammation across time in maternal and fetal organs using multi-omics. Unlike maternal organs which mounted strong innate immune responses, the placenta upregulated tissue-integrity genes, likely to prevent fetal exposure to infections, and downregulated growth-associated genes. Subsequently, the placenta upregulated biosynthesis and endoplasmic reticulum stress genes in order to return to homeostasis. These responses likely protected the fetus, since we observed no immune response in fetal liver. Instead, likely due to nutrient depletion, the fetal liver displayed metabolic adaptations, including increases in lipids containing docosahexaenoic acid, crucial for fetal brain development. Our study shows, for the first time, the integrated temporal response to pulmonary MIA across maternal and fetal organs.

genomics↗

bioRxiv2023

Adaptation to an acid microenvironment promotes pancreatic cancer organoid growth and drug resistance in a p53-dependent manner

The harsh environments in poorly perfused tumor regions have been proposed to select for traits that may drive cancer aggressiveness. Here, we tested the hypothesis that tumor acidosis interacts with driver mutations to exacerbate cancer hallmarks, including drug resistance, in pancreatic cancer. We gradually adapted mouse organoids from normal pancreatic duct (mN) and early PDAC (mP, with KRAS G12V mutation and +/- p53 knockout), from pH 7.4 (physiological level) to 6.7, representing acidic tumor niches. Acid adaptation rewired organoid transcriptional activity, increased viability and, strikingly, increased Gemcitabine- and Erlotinib resistance. Importantly, this response only occurred in organoids expressing wild-type p53 and was most pronounced when acid-adapted cells were returned to physiological pH (mimicking increased perfusion or invasion). While the acid adaptation transcriptional change was overall not highly similar to that induced by drug adaptation of the organoids, acid adaptation induced expression of cytidine deaminase (Cda) and ribonucleotide reductase regulatory subunit M2 (Rrm2), both associated with Gemcitabine resistance, and inhibition of these proteins partially restored Gemcitabine sensitivity. Thus, adaptation to the acidic tumor microenvironment increases drug resistance even after cells leave this niche, and this is in part dependent on acid-adaptation-induced transcriptional upregulation of Cda and Rrm2.

cancer biology↗

bioRxiv2021

The LEAFY floral regulator displays pioneer transcription factor properties

Pioneer transcription factors (TFs) are a special category of TFs with the capacity to bind to closed chromatin regions in which DNA is wrapped around histones and often highly methylated. Subsequently, they are able to modify the chromatin state to initiate gene expression. In plants, LEAFY (LFY) is a master floral regulator and has been suggested to act as a pioneer TF in Arabidopsis. Here, we demonstrate that LFY is able to bind both methylated and non-methylated DNA using a combination of in vitro genome-wide binding experiments and structural modeling. Comparisons between regions bound by LFY in vivo and chromatin accessibility data suggest that LFY binds a subset of regions occupied by nucleosomes. We confirm that LFY is able to bind nucleosomal DNA in vitro using reconstituted nucleosomes. Finally, we show that constitutive LFY expression in seedling tissues is sufficient to induce chromatin accessibility in the LFY direct target genes, APETALA1 and AGAMOUS. Taken together, our study suggests that LFY possesses key pioneer TF features that contribute to launch the floral gene expression program.

plant biology↗

bioRxiv2018

Differential Sustained and Transient Temporal Processing Across Visual Streams

How do high-level visual regions process the temporal aspects of our visual experience? While the temporal sensitivity of early visual cortex has been studied with fMRI in humans, temporal processing in high-level visual cortex is largely unknown. By modeling neural responses with millisecond precision in separate sustained and transient channels, and introducing a flexible encoding framework that captures differences in neural temporal integration time windows and response nonlinearities, we predict fMRI responses across visual cortex for stimuli ranging from 33 ms to 20 s. Using this innovative approach, we discovered that lateral category-selective regions respond to visual transients associated with stimulus onsets and offsets but not sustained visual information. Thus, lateral category-selective regions compute moment-tomoment visual transitions, but not stable features of the visual input. In contrast, ventral category-selective regions respond to both sustained and transient components of the visual input. Responses to sustained stimuli exhibit adaptation, whereas responses to transient stimuli are surprisingly larger for stimulus offsets than onsets. This large offset transient response may reflect a memory trace of the stimulus when it is no longer visible, whereas the onset transient response may reflect rapid processing of new items. Together, these findings reveal previously unconsidered, fundamental temporal mechanisms that distinguish visual streams in the human brain. Importantly, our results underscore the promise of modeling brain responses with millisecond precision to understand the underlying neural computations.\n\nAUTHOR SUMMARYHow does the brain encode the timing of our visual experience? Using functional magnetic resonance imaging (fMRI) and a temporal encoding model with millisecond resolution, we discovered that visual regions in the lateral and ventral processing streams fundamentally differ in their temporal processing of the visual input. Regions in lateral temporal cortex process visual transients associated with stimulus onsets and offsets but not the unchanging aspects of the visual input. That is, they compute moment-to-moment changes in the visual input. In contrast, regions in ventral temporal cortex process both stable and transient components, with the former exhibiting adaptation. Surprisingly, in these ventral regions responses to stimulus offsets were larger than onsets. We suggest that the former may reflect a memory trace of the stimulus, when it is no longer visible, and the latter may reflect rapid processing of new items at stimulus onset. Together, these findings (i) reveal a fundamental temporal mechanism that distinguishes visual streams and (ii) highlight both the importance and utility of modeling brain responses with millisecond precision to understand the temporal dynamics of neural computations in the human brain.

neuroscience↗

bioRxiv2018

Capturing auxin response factors syntax using DNA binding models

Auxin is a key hormone performing a wealth of functions throughout the plant life cycle. It acts largely by regulating genes at the transcriptional level through a family of transcription factors (TF) called auxin response factors (ARF). Even if all ARF monomers analysed so far bind a similar DNA sequence, there is evidence that ARFs differ in their target genomic regions and regulated genes. Here we use position weight matrices (PWM) to model ARF DNA binding specificity based on published DNA affinity purification sequencing (DAP-seq) data. We find that the genome binding of two ARFs (ARF2 and ARF5/Monopteros/MP) differ largely because these two factors have different preferred ARF binding site (ARFbs) arrangements (orientation and spacing). We illustrate why PWMs are more versatile to reliably identify ARFbs than the widely used consensus sequences and demonstrate their power with biochemical experiments on the regulatory regions of the IAA19 model gene. Finally, we combined gene regulation by auxin with ARF-bound regions and identified specific ARFbs configurations that are over-represented in auxin up-regulated genes, thus deciphering the ARFbs syntax functional for regulation. This provides a general method to exploit the potential of genome-wide DNA binding assays and decode gene regulation.

plant biology↗

bioRxiv2017

An encoding model of temporal processing in human visual cortex

ABSTRACTHow is temporal information processed in human visual cortex? Visual input is relayed to V1 through segregated transient and sustained channels in the retina and LGN. However, there is intense debate as to how transient and sustained channels contribute to visual processing beyond V1. Using a 2 temporal-channel encoding model we can predict fMRI responses to time-varying stimuli ranging from milliseconds to seconds. The transient channel dominates responses in the periphery of early visual cortex and lateral occipito-temporal regions. However, both sustained and transient channels drive responses in central early visual cortex and ventral occipito-temporal regions. Together these finding resolve an outstanding debate and lay the foundation for a complete temporal model of neural processing in visual cortex. Importantly, this encoding approach can be applied with fMRI to decipher neural computations in millisecond resolution in any part of the brain, which has vast implications for understanding neural processing.

neuroscience↗