FoSR: First-order spectral rewiring for addressing oversquashing in GNNs

Graph neural networks (GNNs) are able to leverage the structure of graph data by passing messages along the edges of the graph. While this allows GNNs to learn features depending on the graph structure, for certain graph topologies it leads to inefficient information propagation and a problem known as oversquashing. This has recently been linked with the curvature and spectral gap of the graph. On the other hand, adding edges to the message-passing graph can lead to increasingly similar node representations and a problem known as oversmoothing. We propose a computationally efficient algorithm that prevents oversquashing by systematically adding edges to the graph based on spectral expansion. We combine this with a relational architecture, which lets the GNN preserve the original graph structure and provably prevents oversmoothing. We find experimentally that our algorithm outperforms existing graph rewiring methods in several graph classification tasks.Comment: 21 pages, accepted to ICLR 202

NEU Insights and Development of Potential Therapeutics for Pulmonary Fibrosis

Fibrosing diseases involve the formation of inappropriate scar tissue, but what drives fibrosis is unclear. Idiopathic pulmonary fibrosis involves the formation of excess scar tissue in the lungs. Sialidases (also called neuraminidases) are enzymes that desialylate glycoconjugates by cleaving terminal sialic acids from the glycoconjugates. Our lab previously found that a sialylated serum glycoprotein called serum amyloid P (SAP) inhibits fibrosis, and that sialidases attenuate SAP function. Mammals have four different sialidases, NEU1 – 4. In this dissertation, I show that extensive desialylation of glycoconjugates and upregulation of the sialidase NEU3 is observed in the fibrotic lesions in human and mouse lungs. NEU3 is upregulated in the bronchoalveolar lavage (BAL) fluid of the fibrotic mouse lungs in bleomycin-induced pulmonary fibrosis mouse model studies. Fibrosis-associated signals such as transforming growth factor-β1 (TGF-β1) and interleukin (IL)-6 upregulate NEU3 in a variety of human lung cells. Conversely, recombinant human NEU3 upregulates extracellular accumulation of active TGF-β1 and upregulates IL-6 in human peripheral blood mononuclear cells (PBMC). NEU3 also desialylates the human latency associated glyco-peptide (LAP) protein, which holds TGF-β1 in an inactive state, releasing active TGF-β1. Compared to wild-type mice, mice lacking NEU3 have significantly less bleomycin-induced pulmonary fibrosis, reduced TGF-β1 staining in the lungs after bleomycin-assault, and reduced protein, cells, and IL-6 levels in the lung fluid, providing genetic evidence for the role of NEU3 in pulmonary fibrosis in mice. Two small molecule sialidase inhibitors, DANA and oseltamivir (Tamiflu), work well on viral and mouse sialidases, but relatively poorly on human sialidases. In the bleomycin-induced pulmonary fibrosis mouse model, daily intraperitoneal injections of either DANA or oseltamivir at 10 mg / kg, starting at day 10 after bleomycin insult, strongly attenuated pulmonary fibrosis at day 21. The currently studied NEU3 inhibitors have relatively poor efficacies; thus, we designed a new class of small molecule NEU3 inhibitors. Some of our designed inhibitors have nanomolar IC50 values for the inhibition of recombinant human NEU3 releasing active TGF-β1 from the recombinant human latent TGF-β1, and inhibition of the NUE3-induced accumulation of IL-6 in human PBMC. One of our small molecule inhibitors given as daily 0.1 mg/kg injections, and two inhibitors as daily 1 mg/ kg injections, starting at day 10 after bleomycin insult, strongly attenuated pulmonary fibrosis at day 21 in the bleomycin-induced fibrosis mouse model. All of these results suggest that a NEU3-to-fibrosis-to-NEU3 positive feedback loop helps to potentiate pulmonary fibrosis. NEU3 could be a suitable target to develop treatments for lung fibrosis and our NEU3 inhibitors might be effective as therapeutics for fibrosing diseases

Sum index and difference index of graphs

Let $G$ be a nonempty simple graph with a vertex set $V(G)$ and an edge set $E(G)$. For every injective vertex labeling $f:V(G)\to\mathbb{Z}$, there are two induced edge labelings, namely $f^+:E(G)\to\mathbb{Z}$ defined by $f^+(uv)=f(u)+f(v)$, and $f^-:E(G)\to\mathbb{Z}$ defined by $f^-(uv)=|f(u)-f(v)|$. The sum index and the difference index are the minimum cardinalities of the ranges of $f^+$ and $f^-$, respectively. We provide upper and lower bounds on the sum index and difference index, and determine the sum index and difference index of various families of graphs. We also provide an interesting conjecture relating the sum index and the difference index of graphs

Hedgehog Signaling Regulates the Survival of Gastric Cancer Cells by Regulating the Expression of Bcl-2

Gastric cancer is the second most common cause of cancer deaths worldwide. The underlying molecular mechanisms of its carcinogenesis are relatively poorly characterized. Hedgehog (Hh) signaling, which is critical for development of various organs including the gastrointestinal tract, has been associated with gastric cancer. The present study was undertaken to reveal the underlying mechanism by which Hh signaling controls gastric cancer cell proliferation. Treatment of gastric cancer cells with cyclopamine, a specific inhibitor of Hh signaling pathway, reduced proliferation and induced apoptosis of gastric cancer cells. Cyclopamine treatment induced cytochrome c release from mitochondria and cleavage of caspase 9. Moreover, Bcl-2 expression was significantly reduced by cyclopamine treatment. These results suggest that Hh signaling regulates the survival of gastric cancer cells by regulating the expression of Bcl-2

Highly Scalable, Wearable Surface‐Enhanced Raman Spectroscopy

The last two decades have witnessed a dramatic growth of wearable sensor technology, mainly represented by flexible, stretchable, on-skin electronic sensors that provide rich information of the wearer's health conditions and surroundings. A recent breakthrough in the field is the development of wearable chemical sensors based on surface-enhanced Raman spectroscopy (SERS) that can detect molecular fingerprints universally, sensitively, and noninvasively. However, while their sensing properties are excellent, these sensors are not scalable for widespread use beyond small-scale human health monitoring due to their cumbersome fabrication process and limited multifunctional sensing capabilities. Here, a highly scalable, wearable SERS sensor is demonstrated based on an easy-to-fabricate, low-cost, ultrathin, flexible, stretchable, adhesive, and biointegratable gold nanomesh. It can be fabricated in any shape and worn on virtually any surface for label-free, large-scale, in situ sensing of diverse analytes from low to high concentrations (10–106 × 10−9 m). To show the practical utility of the wearable SERS sensor, the sensor is tested for the detection of sweat biomarkers, drugs of abuse, and microplastics. This wearable SERS sensor represents a significant step toward the generalizability and practicality of wearable sensing technology

Activation of the Hedgehog pathway in pilocytic astrocytomas

Pilocytic astrocytoma is commonly viewed as a benign lesion. However, disease onset is most prevalent in the first two decades of life, and children are often left with residual or recurrent disease and significant morbidity. The Hedgehog (Hh) pathway regulates the growth of higher WHO grade gliomas, and in this study, we have evaluated the activation and operational status of this regulatory pathway in pilocytic astrocytomas. Expression levels of the Hh pathway transcriptional target PTCH were elevated in 45% of tumor specimens analyzed (ages 1–22 years) and correlated inversely with patient age. Evaluation of a tissue array revealed oligodendroglioma-like features, pilomyxoid features, infiltration, and necrosis more commonly in specimens from younger patients (below the median patient age of 10 years). Immunohistochemical staining for the Hh pathway components PTCH and GLI1 and the proliferation marker Ki67 demonstrated that patients diagnosed before the age of 10 had higher staining indices than those diagnosed after the age of 10. A significant correlation between Ki67 and PTCH and GLI1 staining indices was measured, and 86% of Ki67-positive cells also expressed PTCH. The operational status of the Hh pathway was confirmed in primary cell culture and could be modulated in a manner consistent with a ligand-dependent mechanism. Taken together, these findings suggest that Hh pathway activation is common in pediatric pilocytic astrocytomas and may be associated with younger age at diagnosis and tumor growth

Drosophila Boi limits Hedgehog levels to suppress follicle stem cell proliferation

The Boi receptor regulates stem cell function by sequestering the diffusible hedgehog ligand

Prostate cancer and Hedgehog signalling pathway

[Abstract] The Hedgehog (Hh) family of intercellular signalling proteins have come to be recognised as key mediators in many fundamental processes in embryonic development. Their activities are central to the growth, patterning and morphogenesis of many different regions within the bodies of vertebrates. In some contexts, Hh signals act as morphogens in the dose-dependent induction of distinct cell fates within a target field, in others as mitogens in the regulation of cell proliferation or as inducing factors controlling the form of a developing organ. These diverse functions of Hh proteins raise many intriguing questions about their mode of action. Various studies have now demonstrated the function of Hh signalling in the control of cell proliferation, especially for stem cells and stem-like progenitors. Abnormal activation of the Hh pathway has been demonstrated in a variety of human tumours. Hh pathway activity in these tumours is required for cancer cell proliferation and tumour growth. Recent studies have uncovered the role for Hh signalling in advanced prostate cancer and demonstrated that autocrine signalling by tumour cells is required for proliferation, viability and invasive behaviour. Thus, Hh signalling represents a novel pathway in prostate cancer that offers opportunities for prognostic biomarker development, drug targeting and therapeutic response monitoring

Self-Renewal of Acute Lymphocytic Leukemia Cells Is Limited by the Hedgehog Pathway Inhibitors Cyclopamine and IPI-926

Conserved embryonic signaling pathways such as Hedgehog (Hh), Wingless and Notch have been implicated in the pathogenesis of several malignancies. Recent data suggests that Hh signaling plays a role in normal B-cell development, and we hypothesized that Hh signaling may be important in precursor B-cell acute lymphocytic leukemia (B-ALL). We found that the expression of Hh pathway components was common in human B-ALL cell lines and clinical samples. Moreover, pathway activity could be modulated by Hh ligand or several pathway inhibitors including cyclopamine and the novel SMOOTHENED (SMO) inhibitor IPI-926. The inhibition of pathway activity primarily impacted highly clonogenic B-ALL cells expressing aldehyde dehydrogenase (ALDH) by limiting their self-renewal potential both in vitro and in vivo. These data demonstrate that Hh pathway activation is common in B-ALL and represents a novel therapeutic target regulating self-renewal and persistence of the malignant clone