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Biology subjects

Wang, C. L.

Publications and source records attributed to Wang, C. L..

6 recordsLinked to original sources

AI-Discovered Cognitive Models Reveal Novel Insights into Human and Animal Learning

Scientific models are widely used across the natural sciences as an interface between scientific theories and empirical data [1]. Such models play a key role, for example, in the study of human and animal learning, where they express algorithmic hypotheses and relate them to psychology and neuroscience data [2, 3]. These models are traditionally handcrafted by expert researchers based on existing theory or new insights. Such handcrafted models, however, are now known to fall short of capturing the full richness of behavior, even in their narrow domains [4-7]. An alternative data-driven approach has emerged, seeking to discover new insights by fitting and interpreting flexible models [8-11]. However, these tools require substantial human effort to derive insight from data, and it has been unclear how to discover new ideas from data efficiently. Here, we present DataDIVER, a general approach for automatically discovering computational models from data, and demonstrate that these models surface novel mechanistic insights into human and animal learning. Our approach delivers models that take the form of short computer programs, which are optimized both to fit data well and to be simple. These programs explicitly connect with existing theoretical frameworks and are readily understandable by human scientists. They can also be used to make novel predictions, some of which we show are borne out in re-analysis of existing data. General-purpose tools for surfacing new ideas from data, especially in combination with the large datasets that are increasingly available in many fields, stand to dramatically accelerate scientific discovery.

animal behavior and cognition↗

Endothelial PHD2 deficiency induces apoptosis resistance and inflammation via AKT activation and AIP1 loss independent of HIF2α

BACKGROUNDIn hypoxic and pseudohypoxic rodent models of pulmonary arterial hypertension (PAH), hypoxia-inducible factor (HIF) inhibition reduces disease severity. However, HIF activation alone, due to genetic alterations or use of inhibitors of prolyl hydroxylase domain (PHD) enzymes, has not been definitively shown to cause PAH in humans, indicating the involvement of other mechanisms. METHODSPseudohypoxia was investigated in primary human lung endothelial cells by silencing PHD2, and in Tie2-Cre/Phd2 knockout mice, a rodent model of PAH. Lung vascular endothelial cells from PAH patients, and lung tissue from both SU5416/hypoxia PAH rats and PAH patients, were examined for validation. RESULTSPHD2 silencing or inhibition, while activating HIF2, induces apoptosis-resistance, hypo-proliferation, and IFN/STAT activation in endothelial cells, independent of HIF signaling. Mechanistically, PHD2 deficiency activates AKT and ERK, inhibits JNK, and reduces AIP1 (ASK1-interacting protein 1), all independent of HIF2. Like PHD2, AIP1 silencing affects these same kinase pathways and produces a similar dysfunctional endothelial cell phenotype, which can be partially reversed by AKT inhibition. These findings are corroborated in lung tissues of rodent PAH models and pulmonary vascular endothelial cells and tissues from PAH patients. CONCLUSIONSPHD2 deficiency in lung vascular endothelial cells induces an apoptosis-resistant, inflammatory, and hypo-proliferative phenotype. AKT activation and AIP1 loss, but not HIF signaling, drive these aberrant phenotypic changes. Our study suggests that HIF blockade alone may not suffice for PAH therapy; targeting PHD2, AKT, and AIP1 has the potential for developing more effective treatment. GRAPHIC ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=110 SRC="FIGDIR/small/578286v1_ufig1.gif" ALT="Figure 1"> View larger version (38K): org.highwire.dtl.DTLVardef@1fd0a0borg.highwire.dtl.DTLVardef@19e6ba9org.highwire.dtl.DTLVardef@1ae2827org.highwire.dtl.DTLVardef@ce31ec_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIPHD2 silencing in human lung vascular endothelial cells suppresses apoptosis, inhibits proliferation, and activates STAT signaling, effects that persist despite HIF2 inhibition or knockdown. C_LIO_LIPHD2 silencing activates AKT and ERK, inhibits JNK, and decreases AIP1, all independently of HIF2 C_LIO_LILike PHD2, AIP1 silencing led to similar alterations in kinase signaling and endothelial cell phenotypes, which are partially reversed by ATK inhibition. C_LIO_LIThese in vitro findings align with observations in lung vascular endothelial cells and tissues from rodent models of PAH as well as PAH patients. C_LI

cell biology↗

Microglia mediate contact-independent neuronal pruning via secreted Neuraminidase-3 associated with extracellular vesicles

Neurons communicate with each other through electrochemical transmission at synapses. Microglia, the resident immune cells of the central nervous system, can prune these synapses through a variety of contact-dependent and -independent means. Microglial secretion of active sialidase enzymes upon exposure to inflammatory stimuli is one unexplored mechanism of pruning. Recent work from our lab showed that treatment of neurons with bacterial sialidases disrupts neuronal network connectivity. Here, we find that activated microglia secrete Neuraminidase-3 (Neu3) associated with fusogenic extracellular vesicles. Furthermore, we show Neu3 mediates contact-independent pruning of neurons and subsequent disruption of neuronal networks through neuronal glycocalyx remodeling. We observe that NEU3 is transcriptionally upregulated upon exposure to inflammatory stimuli, and that a genetic knock-out of NEU3 abrogates the sialidase activity of inflammatory microglial secretions. Moreover, we demonstrate that Neu3 is associated with a subpopulation of extracellular vesicles, possibly exosomes, that are secreted by microglia upon inflammatory insult. Finally, we demonstrate that Neu3 is both necessary and sufficient to both desialylate neurons and decrease neuronal network connectivity. These results implicate Neu3 in remodeling of the glycocalyx leading to aberrant network-level activity of neurons, with implications in neuroinflammatory diseases such as Parkinsons disease and Alzheimers disease. Graphical AbstractNeuroinflammation induces secretion of the sialidase Neu3 via extracellular vesicles from microglia that prune neuronal synapses and disrupt neuronal communication. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=75 SRC="FIGDIR/small/554214v2_ufig1.gif" ALT="Figure 1"> View larger version (24K): org.highwire.dtl.DTLVardef@6842a0org.highwire.dtl.DTLVardef@ee3976org.highwire.dtl.DTLVardef@1fe7ec3org.highwire.dtl.DTLVardef@1345507_HPS_FORMAT_FIGEXP M_FIG C_FIG

biochemistry↗

Multiset correlation and factor analysis enables exploration of multi-omic data

Multi-omics datasets are becoming more common, necessitating better integration methods to realize their revolutionary potential. Here, we introduce Multi-set Correlation and Factor Analysis, an unsupervised integration method that enables fast inference of shared and private factors in multi-modal data. Applied to 614 ancestry-diverse participant samples across five omics types, MCFA infers a shared space that captures clinically relevant molecular processes.

genomics↗

Analyzing Nested Experimental Designs - A User-Friendly Resampling Method to Determine Experimental Significance

We report Hierarch, a Python package to perform hypothesis tests and compute confidence intervals on hierarchical experimental designs. Using a combination of permutation resampling and bootstrap aggregation, Hierarch can be used to perform hypothesis tests that maintain nominal Type I error rates and generate confidence intervals that maintain the nominal coverage probability without making distributional assumptions about the dataset of interest. Hierarch makes use of the Numba JIT compiler to reduce p-value computation times to under one second for typical datasets in biomedical research. Hierarch also enables researchers to construct user-defined resampling plans that take advantage of Hierarchs Numba-accelerated functions. Hierarch is freely available as a Python package at https://github.com/rishi-kulkarni/hierarch.

neuroscience↗

Subthreshold Voltage Analysis Demonstrates Neuronal Cell-Surface Sialic Acids Modulate Excitability and Network Integration

All neurons are covered in a thick layer of carbohydrates called glycans. Glycans are modified during neurological processes and are thought to play a role in neuronal communication. We develop a voltage imaging platform for analyzing functional connectivity changes using simultaneous voltage recordings in small populations of neurons. We validate this platform using a culture model of development as well as with several pharmacological interventions. Using this platform, we show that ablation of SNA-binding glycans results in loss of functional connectivity in mouse hippocampal neurons, while ablation of MAL II binding glycans minimally perturbs functional connectivity. Altogether, our data reveal that subpopulations of glycans play different roles in maintenance of electrophysiology and provide a platform for modeling changes in functional connectivity with simultaneous voltage recordings.

neuroscience↗