Latent Complex Research Articles

Galectin 3-binding protein (LGALS3BP) depletion attenuates hepatic fibrosis by reducing transforming growth factor-β1 (TGF-β1) availability and inhibits hepatocarcinogenesis.

Increased Galectin 3-binding protein (LGALS3BP) serum levels have been used to assess hepatic fibrosis stages and the severity of hepatocellular carcinoma (HCC). Considering the crucial role of transforming growth factor-β1 (TGF-β1) in the emergence of these diseases, the present study tested the hypothesis that LGALS3BP regulates the TGF-β1 signaling pathway. The expression levels of LGALS3BP and TGFB1 were analyzed in patients with metabolic dysfunction-associated steatohepatitis (MASH) and HCC. Multiple omics techniques, such as RNA-sequencing, transposase-accessible chromatin-sequencing assay, and liquid chromatography-tandem mass spectrometry proteomics, were used to identify the regulatory mechanisms for the LGALS3BP-TGF-β1 axis. The effects of altered TGF-β1 signaling by LGALS3BP were investigated in conditional LGALS3BP-knockin and LGALS3BP-knockout mice. In patients with MASH and HCC, the levels of LGALS3BP and TGFB1 exhibited positive correlations. Stimulation of LGALS3BP by the inflammatory cytokine interferon α in HCC cells or ectopic overexpression of LGALS3BP in hepatocytes promoted the expression levels of TGFB1. Aggravated fibrosis was observed in the livers of hepatocyte-specific LGALS3BP-knockin mice, with increased TGFB1 levels. LGALS3BP directly bound to and assembled integrin αV, an integral mediator required for releasing active TGF-β1 from extracellular latent complex with the rearranged F-actin cytoskeleton. The released TGF-β1 activated JunB transcription factor, which in turn promoted the TGF-β1 positive feedback loop. LGALS3BP deletion in the hepatocytes downregulated TGF-β1 signaling and CCl4 induced fibrosis. Moreover, LGALS3BP depletion hindered hepatocarcinogenesis by limiting the availability of fibrogenic TGF-β1. LGALS3BP plays a crucial role in hepatic fibrosis and carcinogenesis by controlling the TGF-β1 signaling pathway, making it a promising therapeutic target in TGF-β1-related diseases.

Dynamic allostery drives autocrine and paracrine TGF-β signaling

TGF-β, essential for development and immunity, is expressed as a latent complex (L-TGF-β) non-covalently associated with its prodomain and presented on immune cell surfaces by covalent association with GARP. Binding to integrin αvβ8 activates L-TGF-β1/GARP. The dogma is that mature TGF-β must physically dissociate from L-TGF-β1 for signaling to occur. Our previous studies discovered that αvβ8-mediated TGF-β autocrine signaling can occur without TGF-β1 release from its latent form. Here, we show that mice engineered to express TGF-β1 that cannot release from L-TGF-β1 survive without early lethal tissue inflammation, unlike those with TGF-β1 deficiency. Combining cryogenic electron microscopy with cell-based assays, we reveal a dynamic allosteric mechanism of autocrine TGF-β1 signaling without release where αvβ8 binding redistributes the intrinsic flexibility of L-TGF-β1 to expose TGF-β1 to its receptors. Dynamic allostery explains the TGF-β3 latency/activation mechanism and why TGF-β3 functions distinctly from TGF-β1, suggesting that it broadly applies to other flexible cell surface receptor/ligand systems.

Targeting alternative splicing of fibronectin in human renal proximal tubule epithelial cells with antisense oligonucleotides to reduce EDA+ fibronectin production and block an autocrine loop that drives renal fibrosis

TGFβ1 is a powerful regulator of fibrosis; secreted in a latent form, it becomes active after release from the latent complex. During tissue fibrosis, the EDA + isoform of cellular fibronectin is overexpressed. In pulmonary fibrosis it has been proposed that the fibronectin splice variant including an EDA domain (FN EDA+) activates latent TGFβ. Our work investigates the potential of blocking the ‘splicing in’ of EDA with antisense oligonucleotides to inhibit TGFβ1-induced EDA + fibronectin and to prevent the cascade of events initiated by TGFβ1 in human renal proximal tubule cells (PTEC).Human primary PTEC were treated with TGFβ1 for 48 h, medium removed and the cells transfected with RNase H-independent antisense oligonucleotides (ASO) designed to block EDA exon inclusion (ASO5). The efficacy of ASO to block EDA exon inclusion was assessed by EDA + fibronectin RNA and protein expression; the expression of TGFβ, αSMA (α smooth muscle actin), MMP2 (matrix metalloproteinse-2), MMP9 (matrix metalloproteinse-9), Collagen I, K Cadherin and connexin 43 was analysed.Targeting antisense oligonucleotides designed to block EDA exon inclusion in fibronectin pre mRNA were effective in reducing the amount of TGFβ1 -induced cellular EDA + fibronectin RNA and secreted EDA + fibronectin protein (assessed by western immunoblotting and immunocytochemistry) in human proximal tubule cells in an in vitro cell culture model. The effect was selective for EDA + exon with no effect on EDB + fibronectin RNA and total fibronectin mRNA.Exogenous TGFβ1 induced endogenous TGFβ, αSMA, MMP2, MMP9 and Col I mRNA. TGFβ1 treatment for 48h reduced the expression of K-Cadherin and increased the expression of connexin-43. These TGFβ1-induced pro-fibrotic changes were attenuated by ASO5 treatment. 48 h after the removal of exogenous TGFβ, further increases in αSMA, MMP2, MMP9 was observed; ASO5 significantly inhibited this subsequent increase. ASO5 treatment also significantly inhibited ability of the cell culture medium harvested at the end of the experiment (96h) to stimulate SMAD3 reporter cells. The role of endogenous TGFβ1 was confirmed by the use of a TGFβ receptor inhibitor.Our results demonstrate a critical role of FN EDA+ in a cycle of TGFβ driven pro-fibrotic responses in human PTEC and blocking its production with ASO technology offers a potential therapy to interrupt this vicious circle and hence limit the progression of renal fibrosis.

An antibody that inhibits TGF-β1 release from latent extracellular matrix complexes attenuates the progression of renal fibrosis.

Inhibitors of the transforming growth factor-β (TGF-β) pathway are potentially promising antifibrotic therapies, but nonselective simultaneous inhibition of all three TGF-β homologs has safety liabilities. TGF-β1 is noncovalently bound to a latency-associated peptide that is, in turn, covalently bound to different presenting molecules within large latent complexes. The latent TGF-β-binding proteins (LTBPs) present TGF-β1 in the extracellular matrix, and TGF-β1 is presented on immune cells by two transmembrane proteins, glycoprotein A repetitions predominant (GARP) and leucine-rich repeat protein 33 (LRRC33). Here, we describe LTBP-49247, an antibody that selectively bound to and inhibited the activation of TGF-β1 presented by LTBPs but did not bind to TGF-β1 presented by GARP or LRRC33. Structural studies demonstrated that LTBP-49247 recognized an epitope on LTBP-presented TGF-β1 that is not accessible on GARP- or LRRC33-presented TGF-β1, explaining the antibody's selectivity for LTBP-complexed TGF-β1. In two rodent models of kidney fibrosis of different etiologies, LTBP-49247 attenuated fibrotic progression, indicating the central role of LTBP-presented TGF-β1 in renal fibrosis. In mice, LTBP-49247 did not have the toxic effects associated with less selective TGF-β inhibitors. These results establish the feasibility of selectively targeting LTBP-bound TGF-β1 as an approach for treating fibrosis.

More Velcro for the TGF-β1 straitjacket: A new antibody straps latent TGF-β1 to the matrix.

In this issue of Science Signaling, Jackson et al. present a new antibody strategy to-quite literally-strap transforming growth factor-β1 (TGF-β1) to latent complexes in the extracellular matrix. The antibody has no effect on latent TGF-β1 presented on the surface of immune cells and thus allows targeting of the detrimental effects of TGF-β1 in fibrosis without affecting its beneficial immune-suppressing activities.

Molecular force-induced liberation of transforming growth factor-beta remodels the spleen for ectopic liver regeneration

Ectopic liver regeneration in the spleen is a promising alternative to organ transplantation for treating liver failure. To accommodate transplanted liver cells, the splenic tissue must undergo structural changes to increase extracellular matrix content, demanding a safe and efficient approach for tissue remodelling. We synthesised sulphated hyaluronic acid (sHA) with an affinity for the latent complex of transforming growth factor-β (TGF-β) and cross-linked it into a gel network (sHA-X) via click chemistry. We injected this glycan into the spleens of mice to induce splenic tissue remodelling via supraphysiological activation of endogenous TGF-β. sHA-X efficiently bound to the abundant latent TGF-β in the spleen. It provided the molecular force to liberate the active TGF-β dimers from their latent complex, mimicking the 'bind-and-pull' mechanism required for physiological activation of TGF-β and reshaping the splenic tissue to support liver cell growth. Hepatocytes transplanted into the remodelled spleen developed into liver tissue with sufficient volume to rescue animals with a metabolic liver disorder (Fah-/- transgenic model) or following 90% hepatectomy, with no adverse effects observed and no additional drugs required. Our findings highlight the efficacy and translational potential of using sHA-X to remodel a specific organ by mechanically activating one single cytokine, representing a novel strategy for the design of biomaterials-based therapies for organ regeneration. Cell transplantation may provide a lifeline to millions of patients with end-stage liver diseases, but their severely damaged livers being unable to accommodate the transplanted cells is a crucial hurdle. Herein, we report an approach to restore liver functions in another organ - the spleen - by activating one single growth factor in situ. This approach, based on a chemically designed polysaccharide that can mechanically liberate the active transforming growth factor-β to an unusually high level, promotes the function of abundant allogenic liver cells in the spleen, rescuing animals from lethal models of liver diseases and showing a high potential for clinical translation.

A Self-Healing System for Polydicyclopentadiene Thermosets.

Self-healing offers promise for addressing structural failures, increasing lifespan, and improving durability in polymeric materials. Implementing self-healing in thermoset polymers faces significant manufacturing challenges, especially due to the elevated temperature requirements of thermoset processing. To introduce self-healing into structural thermosets, the self-healing system must be thermally stable and compatible with the thermoset chemistry. This article demonstrates a self-healing microcapsule-based system stable to frontal polymerization (FP), a rapid and energy-efficient manufacturing process with a self-propagating exothermic reaction (≈200 °C). A thermally latent Grubbs-type complex bearing two N-heterocyclic carbene ligands addresses limitations in conventional G2-based self-healing approaches. Under FP's elevated temperatures, the catalyst remains dormant until activated by a Cu(I) co-reagent, ensuring efficient polymerization of the dicyclopentadiene (DCPD) upon damage to the polyDCPD matrix. The two-part microcapsule system consists of one capsule containing the thermally latent Grubbs-type catalyst dissolved in the solvent, and another capsule containing a Cu(I) coagent blended with liquid DCPD monomer. Using the same chemistry for both matrix fabrication and healing results in strong interfaces as demonstrated by lap-shear tests. In an optimized system, the self-healing system restores the mechanical properties of the tough polyDCPD thermoset. Self-healing efficiencies greater than 90% via tapered double cantilever beam tests are observed.

Abstract P2106: Transforming Growth Factor β-dependent Regulation Of Cardiomyocyte Maturation

Transforming growth factor β (TGFβ) is a secreted growth factor that is sequestered to the ECM as a latent complex and released in response to cardiac stress. Once released, TGFβ is required for conversion of quiescent fibroblasts to myofibroblasts that support cardiac repair and fibrosis through production of ECM components. While these functional features of TGFβ are well known, the fibroblast-independent effector functions of TGFβ in the heart are unknown. We hypothesized that TGFβ is a critical ECM-cell cross talk mediator in the heart whereby cardiomyocyte -generated TGFβ communicates with fibroblasts to program the composition and stability of the ECM in a reinforcing feedback network. We found that deletion of TGFβ ligands ( Tgfb1 , Tgfb2 , and Tgfb3 ) from cardiomyocytes with an α-MHC-Cre transgene ( Tgfb123 fl/fl -αMHC-Cre ), but not a fibroblast-specific targeted allele ( Tgfb123 fl/fl -Tcf21-MCM ), results in cardiac dysfunction. These results suggest that cardiomyocytes (CMs) are the predominant source of TGFβ in the heart at baseline and that perhaps celltypes beyond the fibroblast were also involved. Interestingly, fibroblast numbers and ECM deposition are increased in Tgfb123 fl/fl -αMHC-Cre hearts and with acute injury hearts from these mice produce shorter, disorganized collagen fibers. Gene expression profiling of Tgfb123 fl/fl -αMHC-Cre hearts at 6 weeks of age demonstrates defective cardiomyocyte maturation. Indeed, Tgfb123 fl/fl -αMHC-Cre hearts are dysmorphic at neonatal day 1 and cardiomyocytes from these hearts remain in cell cycle for a longer duration with greater levels of mononucleation. However, deleting TGFβ receptors I/II or Smad2/3 from CMs does not recapitulate this phenotype suggesting that TGFβ is not driving CM maturation in an autocrine manner. Instead, these findings indicate that TGFβ functions as a critical cross-talk mediator to fibroblasts to establish proper ECM organization and content that drives CM maturation.

A Video Question Answering Model Based on Knowledge Distillation

Video question answering (QA) is a cross-modal task that requires understanding the video content to answer questions. Current techniques address this challenge by employing stacked modules, such as attention mechanisms and graph convolutional networks. These methods reason about the semantics of video features and their interaction with text-based questions, yielding excellent results. However, these approaches often learn and fuse features representing different aspects of the video separately, neglecting the intra-interaction and overlooking the latent complex correlations between the extracted features. Additionally, the stacking of modules introduces a large number of parameters, making model training more challenging. To address these issues, we propose a novel multimodal knowledge distillation method that leverages the strengths of knowledge distillation for model compression and feature enhancement. Specifically, the fused features in the larger teacher model are distilled into knowledge, which guides the learning of appearance and motion features in the smaller student model. By incorporating cross-modal information in the early stages, the appearance and motion features can discover their related and complementary potential relationships, thus improving the overall model performance. Despite its simplicity, our extensive experiments on the widely used video QA datasets, MSVD-QA and MSRVTT-QA, demonstrate clear performance improvements over prior methods. These results validate the effectiveness of the proposed knowledge distillation approach.

Abstract 6326: Discovery & preclinical evaluation of BPB-101: A novel triple functional bi-specific antibody targeting GARP-TGFβ complex/SLC, free TGF-β and PD-L1

Abstract Background: Recent studies on tumor microenvironment (TME) have been conferred considerable attention, especially the transforming growth factor-β (TGF-β) signal axis and the PD-L1/PD-1 signal axis. TGF-β is a crucial enforcer in promoting tumor cells angiogenesis, plasticity, fibrosis, and in regulating immune homeostasis and tolerance. The TGF-β signaling controls innate and adaptive immunity in TME by inhibiting the activity of natural killer (NK) cells and effector T cells, while promoting the expansion of regulatory T cells (Tregs). Many studies have revealed that free TGF-β mainly released from glycoprotein A repetitions predominant (GARP)-TGFβ complex at the surface of activated Tregs, B, NK, and tumor cells. Existing antibodies or fusion proteins targeting TGF-β cannot simultaneously block the TGF-β releasing and naturalized free TGF-β in TME, thus limiting the anti-tumor effect. Herein, we designed a bi-specific antibody named as BPB-101 with triple functions: specifically target GARP-TGFβ complex and/or small latent complex (SLC), free TGF-β, and PD-L1. BPB-101 can stop tumor expansion and recruitment, and may enhance the immune effector cells to eliminate the tumor. Methods: An anti-GARP mAb was discovered using a hybridoma platform and selected for binding with GARP-TGFβ complex/SLC and free TGF-β. An anti-PD-L1 nAb was screened out by VHH library and optimized in tumor-bearing mice. After humanizing, these two antibodies were successfully assembled to form a unique bi-specific antibody, BPB-101. The binding affinity of BPB-101 to GARP-TGFβ complex/SLC, free TGF-β and PD-L1 was determined by ELISA, FACS and SPR/BLI. Report gene assay was utilized to detect the blocking activity of BPB-101. The TGF-β secretion from activated Tregs was also analyzed. Finally, the anti-tumor efficacy of BPB-101 was assessed with a transgenic mouse model (B6-hLRRC32). To address the biosafety risks, the nonclinical safety profile was also evaluated in cynomolgus monkeys. Results and Conclusion: BPB-101 is a high-affinity antibody aims to reverse immunosuppressive TME by triple-targeting functions. The blocking ability of TGF-β in not only latent form but also free form makes our BPB-101 distinct from M7824, any other existing anti-TGF-β mAbs and anti-GARP mAbs. In a MC38-hPD-L1 tumor-bearing B6-hLRRC32 model, BPB-101 showed significant tumor growth inhibition of 93 % at the dose of 5 mg/kg (p<0.001), showing superior efficacy to monoclonal antibody alone or in combination with anti-PD-L1 nAb. In addition, BPB-101 showed durable responsiveness and a splendid safety profile with manageable adverse events. These striking results support the clinical development potential of our trifunctional agent as a monotherapy and in combination with other immunotherapies. Citation Format: Wenxin Xu, Jieying Xu, Deyu Xu, Hongjie Cheng, Li Zhang, Huan Zheng, Siyuan Ye, Mengshi Jiang, Jiabing Wang, Lieming Ding. Discovery & preclinical evaluation of BPB-101: A novel triple functional bi-specific antibody targeting GARP-TGFβ complex/SLC, free TGF-β and PD-L1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6326.

Latent CSN-CRL complexes are crucial for curcumin-induced apoptosis and recruited during adipogenesis to lipid droplets via small GTPase RAB18

The COP9 signalosome (CSN) and cullin-RING ubiquitin ligases (CRLs) form latent CSN-CRL complexes detectable in cells. We demonstrate that the CSN variants CSNCSN7A and CSNCSN7B preferentially bind to CRL3 or CRL4A and CRL4B, respectively. Interestingly, the interacting protein ubiquitin-specific protease 15 exclusively binds to latent CSNCSN7A-CRL3, while p27KIP attaches to latent CSNCSN7B-CRL4A complex. Inhibition of deneddylation by CSN5i-3 or neddylation by MLN4924 do not impede the formation of latent complexes. Latent CSNCSN7A-CRL3 and latent CSNCSN7B-CRL4A/B particles are essential for specific cellular functions. We found that curcumin-induced cell death requires latent CSNCSN7B-CRL4A. Knockout of CSN7B in HeLa cells leads to resistance against curcumin. Remarkably, the small GTPase RAB18 recruits latent CSNCSN7A-CRL3 complex to lipid droplets (LDs), where CRL3 is activated by neddylation, an essential event for LD formation during adipogenesis. Knockdown of CSN7A or RAB18 or destabilization of latent complexes by cutting off CSN7A C-terminal 201-275 amino acids blocks adipogenesis.

Penalized robust learning for optimal treatment regimes with heterogeneous individualized treatment effects

The growing popularity of personalized medicine motivates people to explore individualized treatment regimes according to heterogeneous characteristics of the patients. For the large-scale data analysis, however, the data are collected at different times and different locations, i.e. subjects are usually from a heterogeneous population, which causes that the optimal treatment regimes also vary for patients across different subgroups. In this paper, we mainly focus on the estimation of optimal treatment regimes for subjects come from a heterogeneous population with high-dimensional data. We first remove the main effects of the covariates for each subgroup to eliminate non-ignorable residual confounding. Based on the centralized outcome, we propose a penalized robust learning that estimates the coefficient matrix of the interactions between covariates and treatment by penalizing pairwise differences of the coefficients of any two subgroups for the same covariate, which can automatically identify the latent complex structure of the coefficient matrix with heterogeneous and homogeneous columns. At the same time, the penalized robust learning can also select the important variables that truly contribute to the individualized treatment decisions with commonly used sparsity structure penalty. Extensive simulation studies show that our proposed method outperforms current popular methods, and it is further illustrated in the real analysis of the Tamoxifen breast cancer data.

Monitoring TGFβ signaling in irradiated tumors.

Transforming growth factor β (TGFβ) is exquisitely regulated under physiological conditions but its activity is highly dysregulated in cancer. All cells make TGFβ and have receptors for the ligand, which is sequestered in the extracellular matrix in a latent form. Ionizing radiation elicits rapid release of TGFβ from these stores, so-called activation, over a wide range of doses and exposures, including low dose (<1Gy) whole-body irradiation, creating an extraordinarily potent signal in the irradiated tissue or tumor. Hence, accurate evaluation of TGFβ activity is complicated because of its ubiquitous distribution as a latent complex. Here we describe conditions for assays that reveal TGFβ activity in situ using either tissue preparations or functional imaging.

ADAMTS6 cleaves the large latent TGFβ complex and increases the mechanotension of cells to activate TGFβ

The ADAMTS superfamily is composed of secreted metalloproteases and structurally related non-catalytic ADAMTS-like proteins. A subset of this superfamily, including ADAMTS6, ADAMTS10 and ADAMTSL2, are involved in elastic fiber assembly and bind to fibrillin and other matrix molecules that regulate the extracellular bioavailability of the potent growth factor TGFβ. Fibrillinopathies, that can also result from mutation of these ADAMTS/L proteins, have been linked to disrupted TGFβ homeostasis. ADAMTS6 and ADAMTS10 are homologous metalloproteases with poorly characterized substrates where ADAMTS10 is thought to process fibrillin-2 and ADAMTS6 latent TGFβ-binding protein (LTBP)-1. In order to understand the contribution of ADAMTS6, and these other members of the ADAMTS/L family, to TGFβ homeostasis, we have analyzed the effects of ADAMTS6, ADAMTS10 and ADAMTSL2 expression on TGFβ activation. We found that their expression increases TGFβ activation in a dose dependent manner, following stimulation with mature TGFβ1. For ADAMTS6, the catalytically active protease is required for effective TGFβ activation, where ADAMTS6 cleaves LTBP3 as well as LTBP1, and binds to the large latent TGFβ complexes of LTBP1 and LTBP3. Furthermore, ADAMTS6 expression increases the mechanotension of cells which results in inactivation of the Hippo Pathway, resulting in an increased translocation of YAP/TAZ complex to the nucleus. Together these findings suggest that when the balance of TGFβ is perturbed ADAMTS6 can influence TGFβ activation via two mechanisms. It directly cleaves the latent TGFβ complexes and also acts indirectly, along with ADAMTS10 and ADAMTSL2, by altering the mechanotension of cells. Together this increases activation of TGFβ from large latent complexes which may contribute to disease pathogenesis.

Latent transforming growth factor β binding protein 3 controls adipogenesis

Transforming growth factor-beta (TGFβ) is released from cells as part of a trimeric latent complex consisting of TGFβ, the TGFβ propeptides, and either a latent TGFβ binding protein (LTBP) or glycoprotein-A repetitions predominant (GARP) protein. LTBP1 and 3 modulate latent TGFβ function with respect to secretion, matrix localization, and activation and, therefore, are vital for the proper function of the cytokine in a number of tissues. TGFβ modulates stem cell differentiation into adipocytes (adipogenesis), but the potential role of LTBPs in this process has not been studied. We observed that 72 h post adipogenesis initiation Ltbp1, 2, and 4 expression levels decrease by 74–84%, whereas Ltbp3 expression levels remain constant during adipogenesis. We found that LTBP3 silencing in C3H/10T1/2 cells reduced adipogenesis, as measured by the percentage of cells with lipid vesicles and the expression of the transcription factor peroxisome proliferator-activated receptor gamma (PPARγ). Lentiviral mediated expression of an Ltbp3 mRNA resistant to siRNA targeting rescued the phenotype, validating siRNA specificity. Knockdown (KD) of Ltbp3 expression in 3T3-L1, M2, and primary bone marrow stromal cells (BMSC) indicated a similar requirement for Ltbp3. Epididymal and inguinal white adipose tissue fat pad weights of Ltbp3−/- mice were reduced by 62% and 57%, respectively, compared to wild-type mice. Inhibition of adipogenic differentiation upon LTBP3 loss is mediated by TGFβ, as TGFβ neutralizing antibody and TGFβ receptor I kinase blockade rescue the LTBP3 KD phenotype. These results indicate that LTBP3 has a TGFβ-dependent function in adipogenesis both in vitro and possibly in vivo. SignificanceUnderstanding the control of mesenchymal stem cell fate is crucial for the potential use of these cells for regenerative medicine.

Learning Latent Multi-Criteria Ratings From User Reviews for Recommendations

Multi-criteria recommender systems have been increasingly useful for helping consumers identify the most relevant items based on different dimensions of user experiences and highlighting their most valued features. Therefore, researchers have proposed various multi-criteria models to improve recommendation performance. However, most of the existing methods utilize only multi-criteria ratings explicitly provided by the users. Note that explicit multi-criteria ratings are sparse and have the problem of missing values. User reviews, on the other hand, contain richer information of user experiences and reveal multi-dimensional user preferences. Therefore, we propose to use latent multi-criteria ratings generated from user reviews, as opposed to explicit multi-criteria ratings, to provide recommendations and capture latent complex heterogeneous user preferences. Specifically, we propose two novel models for the latent multi-criteria rating generation process: the one-stage model LatentMC-1S that utilizes document hashing method to directly compute latent ratings and the two-stage model LatentMC-2S that uses GRU and Gumbel-Softmax for indirect rating generation. Extensive experiments show that the proposed latent multi-criteria rating approaches outperform explicit ratings across different datasets and performance measures. We also show that latent multi-criteria ratings could be used for imputing missing explicit multi-criteria ratings and thus further improving multi-criteria recommender systems.

LB1012 Dermal sheath mechanosignaling activation of TGF-β controls progenitor death during hair follicle regression

Epithelial-mesenchymal crosstalk is vital for balancing expansion and regression of the progenitor cell pool during tissue turnover. In the hair growth cycle, little is known about the mechanisms underlying the regulated cell death during follicle regression that precedes each regeneration and hair re-growth. Here, we discover that the dermal sheath smooth muscle, which lines all follicles, controls progenitor death via transforming growth factor (TGF)-β mechanosignaling. The sheath secretes TGF-β, which is first stored as an inactive, latent complex in the basement membrane extracellular matrix. The sheath then contracts to free TGF-β for essential signaling to progenitors for cell death regulation and regression. Finally, we identify Integrin-alpha-V on the sheath surface as the molecular link for force-mediated TGF-β release. Our study establishes the dermal sheath as a mechanosignaling niche that controls progenitor pool reduction through mechanical force, signal activation and cell-cell communication.

Driver Maneuver Identification with Multi-Representation Learning and Meta Model Update Designs

Driver maneuver identification (DMI), i.e., the task of predicting the driver maneuver classes given sensor measurements (such as IMU sensors from mobile devices), can serve as a key enabler for many ubiquitous driver behavior analysis applications. Despite the prior studies, two major technical challenges remain before an effective DMI system can be deployed: (i) latent complex maneuver behavior feature relations for accuracy enhancement, and (ii) inconsistency and uncertainty in model adaptation given dynamic data collection settings (e.g., given different urban environments, drivers, and mobile devices). To address the aforementioned challenges, we propose MetaDMI, a novel and adaptive driver maneuver identification framework based on multi-representation learning and meta model update, with the case study on the inertial measurement unit (IMU) sensor measurements (i.e., accelerometer and gyroscope). Specifically, we first extract multiple feature representations for each driver maneuver record in the forms of graph, spectral, and time sequence. Next, MetaDMI processes them with a novel multi-representation learning network, extracting complex patterns and feature relations from the driver maneuvers. Finally, to further enhance the adaptivity of our DMI model to external impacts with dynamic data collection, we have designed a regularized meta learning-based training method to regularize the knowledge transfers across the source and target datasets (e.g., across cities/devices, and few-shot initialization) for consistent and robust identification performance. We have conducted extensive experimental studies upon our MetaDMI prototype based on two datasets (one is collected on our own) and shown that our approach outperforms other baseline approaches for DMI in terms of accuracy and adaptivity.

The Role of the Fibronectin Synergy Site for Skin Wound Healing

Skin is constantly exposed to injuries that are repaired with different outcomes, either regeneration or scarring. Scars result from fibrotic processes modulated by cellular physical forces transmitted by integrins. Fibronectin (FN) is a major component in the provisional matrix assembled to repair skin wounds. FN enables cell adhesion binding of α5β1/αIIbβ3 and αv-class integrins to an RGD-motif. An additional linkage for α5/αIIb is the synergy site located in close proximity to the RGD motif. The mutation to impair the FN synergy region (Fn1syn/syn) demonstrated that its absence permits complete development. However, only with the additional engagement to the FN synergy site do cells efficiently resist physical forces. To test how the synergy site-mediated adhesion affects the course of wound healing fibrosis, we used a mouse model of skin injury and in-vitro migration studies with keratinocytes and fibroblasts on FNsyn. The loss of FN synergy site led to normal re-epithelialization caused by two opposing migratory defects of activated keratinocytes and, in the dermis, induced reduced fibrotic responses, with lower contents of myofibroblasts and FN deposition and diminished TGF-β1-mediated cell signalling. We demonstrate that weakened α5β1-mediated traction forces on FNsyn cause reduced TGF-β1 release from its latent complex.

Abstract 1568: PLK activated TGF-β functions as a prognostic biomarker for patients with pancreatic ductal adenocarcinoma

Abstract Introduction: Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer death with a 5-year survival rate of approximately 7%. Transforming growth factor beta (TGF-β) is highly involved in progression and metastasis in multiple cancers including PDAC. TGF-β is highly involved in tumor fibrosis and immune suppression, and several clinical trials are ongoing to evaluate anti-TGF-β therapies for treating patients diagnosed with cancer and for which biomarkers are key for success. TGF-β is produced in a latent complex with latency-associated protein (LAP), which needs to be cleaved by plasma kallikrein (PLK), releasing TGF-β to enable receptor binding and initiating of signaling. We developed a competitive enzyme-linked immunosorbent assay (ELISA) targeting PLK activated TGF-β and measured it in serum from patients with PDAC. Methods: An ELISA based on monoclonal antibodies raised against the C-terminal side of the PLK cleavage site of TGF-β at R’58↓ was developed and validated for quantification of PLK activated TGF-β (L59TGF-β) in serum. To confirm that the ELISA was specifically measuring PLK cleaved TGF-β, L59TGF-β was measured in a TGF-β dilution after incubation with and without kallikrein. L59TGF-β was measured in pretreatment serum samples from patients with PDAC (n=39) and healthy controls (n=20). The prognostic value of L59TGF-β levels was examined with Kaplan-Meier analysis and evaluated for association with overall survival (OS) by multivariate cox regression analysis adjusted for age and cancer stage. Results: L59TGF-β was only detected after incubation with kallikrein, demonstrating that the ELISA specifically detected kallikrein cleaved TGF-β. L59TGF-β was significantly elevated in patients with PDAC compared to healthy controls (p&amp;lt;0.0001). High levels of L59TGF-β (&amp;gt;median) were significantly associated with poor OS (HR: 2.71, 95%CI: 1.23-5.97, p=0.0135) in patients with PDAC, and median OS was 5.5 months (95%CI: 1.50-20.0) compared to 26.3 months (95%CI: 15.3-28.1) for patients with low levels of L59TGF-β. The association between high levels of L59TGF-β and poor OS remained statistically significant after adjusting for age and stage (HR: 2.33, 95%CI: 1.05-5.18, p=0.0372). Conclusion: Quantification of PLK activated TGF-β (L59TGF-β) in serum predicted poor OS for patients with PDAC. The biomarker value of L59TGF-β should be validated and further investigated in a larger cohort to explore the clinical applicability of the biomarker. Citation Format: Rasmus S. Pedersen, Neel I. Nissen, Christina Jensen, Jeppe Thorlacius-Ussing, Majken L. Olesen, Lasse Langholm, Tina M. Jensen, Hadi M. Diab, Lars N. Jørgensen, Morten Karsdal, Nicholas Willumsen. PLK activated TGF-β functions as a prognostic biomarker for patients with pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1568.