Improving Multi-Task Generalization via Regularizing Spurious Correlation

Multi-Task Learning (MTL) is a powerful learning paradigm to improve generalization performance via knowledge sharing. However, existing studies find that MTL could sometimes hurt generalization, especially when two tasks are less correlated. One possible reason that hurts generalization is spurious correlation, i.e., some knowledge is spurious and not causally related to task labels, but the model could mistakenly utilize them and thus fail when such correlation changes. In MTL setup, there exist several unique challenges of spurious correlation. First, the risk of having non-causal knowledge is higher, as the shared MTL model needs to encode all knowledge from different tasks, and causal knowledge for one task could be potentially spurious to the other. Second, the confounder between task labels brings in a different type of spurious correlation to MTL. We theoretically prove that MTL is more prone to taking non-causal knowledge from other tasks than single-task learning, and thus generalize worse. To solve this problem, we propose Multi-Task Causal Representation Learning framework, aiming to represent multi-task knowledge via disentangled neural modules, and learn which module is causally related to each task via MTL-specific invariant regularization. Experiments show that it could enhance MTL model's performance by 5.5% on average over Multi-MNIST, MovieLens, Taskonomy, CityScape, and NYUv2, via alleviating spurious correlation problem.Comment: Published on NeurIPS 202

p53 Regulates Progenitor Cell Quiescence and Differentiation in the Airway

SummaryMechanisms that regulate progenitor cell quiescence and differentiation in slowly replacing tissues are not fully understood. Here, we demonstrate that the tumor suppressor p53 regulates both proliferation and differentiation of progenitors in the airway epithelium. p53 loss decreased ciliated cell differentiation and increased the self-renewal and proliferative capacity of club progenitors, increasing epithelial cell density. p53-deficient progenitors generated a pseudostratified epithelium containing basal-like cells in vitro and putative bronchioalveolar stem cells in vivo. Conversely, an additional copy of p53 increased quiescence and ciliated cell differentiation, highlighting the importance of tight regulation of p53 levels. Using single-cell RNA sequencing, we found that loss of p53 altered the molecular phenotype of progenitors and differentially modulated cell-cycle regulatory genes. Together, these findings reveal that p53 is an essential regulator of progenitor cell behavior, which shapes our understanding of stem cell quiescence during homeostasis and in cancer development

Tunable Surface Wrinkling on Shape Memory Polymers with Application in Smart Micromirror

Surfaces with tunable topological features enable important applications, such as optical devices, precision metrology, adhesion, and&nbsp; wetting. In this study, we demonstrate a facile method to fabricate and control the surface morphologies by combining thin film wrinkling&nbsp; and thermal expansion. This approach utilizes self-assembled surface wrinkling induced by shape recovery of shape memory polymers and&nbsp; localized thermal expansion caused by Joule heating. Recovering the prestrain in the SMP substrate induces global wrinkling of the thin film&nbsp; on the substrate. Joule heating in the SMP by a heating wire embedded in the substrate induces thermal expansion of the substrate in a&nbsp; localized area, which leads to disappearance of the wrinkling pattern. This effect is reversed when heating is stopped, leading to reversible&nbsp; and repeatable tuning of the surface morphology in a controllable localized surface region. With metal coating, the SMP surface&nbsp; can be switched from specular to diffuse reflectance with respond to external Joule heating. Finally, we demonstrate a smart micromirror&nbsp; device with its diffuse reflectance tunable between 13.5% to 81.9% in visible light region. This approach provides a method to modulate&nbsp; surface diffusivity by controlling its surface morphologies, with potential applications in optical display and optical microelectromechanical (MEMS) devices.</p

Fatty acid 2-hydroxylation inhibits tumor growth and increases sensitivity to cisplatin in gastric cancer

Background: Most gastric cancers are diagnosed at an advanced or metastatic stage with poor prognosis and survival rate. Fatty acid 2-hydroxylase (FA2H) with high expression in stomach generates chiral (R)-2-hydroxy FAs ((R)-2-OHFAs) and regulates glucose utilization which is important for cell proliferation and invasiveness. We hypothesized that FA2H impacts gastric tumor growth and could represent a novel target to improve gastric cancer therapy. Methods: FA2H level in 117 human gastric tumors and its association with tumor growth, metastasis and overall survival were examined. Its roles and potential mechanisms in regulating tumor growth were studied by genetic and pharmacological manipulation of gastric cancer cells in vitro and in vivo. Findings: FA2H level was lower in gastric tumor tissues as compared to surrounding tissues and associated with clinicopathologic status of patients, which were confirmed by analyses of multiple published datasets. FA2H depletion decreased tumor chemosensitivity, partially due to inhibition of AMPK and activation of the mTOR/S6K1/Gli1 pathway. Conversely, FA2H overexpression or treatment with (R)-2-OHFAs had the opposite effects. In line with these in vitro observations, FA2H knockdown promoted tumor growth with increased level of tumor Gli1 in vivo. Moreover, (R)-2-OHFA treatment significantly decreased Gli1 level in gastric tumors and enhanced tumor chemosensitivity to cisplatin, while alleviating the chemotherapy-induced weight loss in mice. Interpretation: Our results demonstrate that FA2H plays an important role in regulating Hh signaling and gastric tumor growth and suggest that (R)-2-OHFAs could be effective as nontoxic wide-spectrum drugs to promote chemosensitivity. Fund: Grants of NSF, NIH, and PAPD. Keywords: Fatty acid 2-hydroxylation, Gastric cancer, Lipid metabolism, mTOR, Chemotherapy, Hedgehog pathwa

Integrative single-cell transcriptomic investigation unveils long non-coding RNAs associated with localized cellular inflammation in psoriasis

Psoriasis is a complex, chronic autoimmune disorder predominantly affecting the skin. Accumulating evidence underscores the critical role of localized cellular inflammation in the development and persistence of psoriatic skin lesions, involving cell types such as keratinocytes, mesenchymal cells, and Schwann cells. However, the underlying mechanisms remain largely unexplored. Long non-coding RNAs (lncRNAs), known to regulate gene expression across various cellular processes, have been particularly implicated in immune regulation. We utilized our neural-network learning pipeline to integrate 106,675 cells from healthy human skin and 79,887 cells from psoriatic human skin. This formed the most extensive cell transcriptomic atlas of human psoriatic skin to date. The robustness of our reclassified cell-types, representing full-layer zonation in human skin, was affirmed through neural-network learning-based cross-validation. We then developed a publicly available website to present this integrated dataset. We carried out analysis for differentially expressed lncRNAs, co-regulated gene patterns, and GO-bioprocess enrichment, enabling us to pinpoint lncRNAs that modulate localized cellular inflammation in psoriasis at the single-cell level. Subsequent experimental validation with skin cell lines and primary cells from psoriatic skin confirmed these lncRNAs’ functional role in localized cellular inflammation. Our study provides a comprehensive cell transcriptomic atlas of full-layer human skin in both healthy and psoriatic conditions, unveiling a new regulatory mechanism that governs localized cellular inflammation in psoriasis and highlights the therapeutic potential of lncRNAs in this disease’s management