Inertial Navigation on Extremely Resource-Constrained Platforms: Methods, Opportunities and Challenges.

Inertial navigation provides a small footprint, low-power, and low-cost pathway for localization in GPS-denied environments on extremely resource-constrained Internet-of-Things (IoT) platforms. Traditionally, application-specific heuristics and physics-based kinematic models are used to mitigate the curse of drift in inertial odometry. These techniques, albeit lightweight, fail to handle domain shifts and environmental non-linearities. Recently, deep neural-inertial sequence learning has shown superior odometric resolution in capturing non-linear motion dynamics without human knowledge over heuristic-based methods. These AI-based techniques are data-hungry, suffer from excessive resource usage, and cannot guarantee following the underlying system physics. This paper highlights the unique methods, opportunities, and challenges in porting real-time AI-enhanced inertial navigation algorithms onto IoT platforms. First, we discuss how platform-aware neural architecture search coupled with ultra-lightweight model backbones can yield neural-inertial odometry models that are 31-134× smaller yet achieve or exceed the localization resolution of state-of-the-art AI-enhanced techniques. The framework can generate models suitable for locating humans, animals, underwater sensors, aerial vehicles, and precision robots. Next, we showcase how techniques from neurosymbolic AI can yield physics-informed and interpretable neural-inertial navigation models. Afterward, we present opportunities for fine-tuning pre-trained odometry models in a new domain with as little as 1 minute of labeled data, while discussing inexpensive data collection and labeling techniques. Finally, we identify several open research challenges that demand careful consideration moving forward.

A novel RIPK1 inhibitor reduces GVHD in mice via a nonimmunosuppressive mechanism that restores intestinal homeostasis.

Intestinal epithelial cells (IECs) are implicated in the propagation of T-cell-mediated inflammatory diseases, including graft-versus-host disease (GVHD), but the underlying mechanism remains poorly defined. Here, we report that IECs require receptor-interacting protein kinase-3 (RIPK3) to drive both gastrointestinal (GI) tract and systemic GVHD after allogeneic hematopoietic stem cell transplantation. Selectively inhibiting RIPK3 in IECs markedly reduces GVHD in murine intestine and liver. IEC RIPK3 cooperates with RIPK1 to trigger mixed lineage kinase domain-like protein-independent production of T-cell-recruiting chemokines and major histocompatibility complex (MHC) class II molecules, which amplify and sustain alloreactive T-cell responses. Alloreactive T-cell-produced interferon gamma enhances this RIPK1/RIPK3 action in IECs through a JAK/STAT1-dependent mechanism, creating a feed-forward inflammatory cascade. RIPK1/RIPK3 forms a complex with JAK1 to promote STAT1 activation in IECs. The RIPK1/RIPK3-mediated inflammatory cascade of alloreactive T-cell responses results in intestinal tissue damage, converting the local inflammation into a systemic syndrome. Human patients with severe GVHD showed highly activated RIPK1 in the colon epithelium. Finally, we discover a selective and potent RIPK1 inhibitor (Zharp1-211) that significantly reduces JAK/STAT1-mediated expression of chemokines and MHC class II molecules in IECs, restores intestinal homeostasis, and arrests GVHD without compromising the graft-versus-leukemia (GVL) effect. Thus, targeting RIPK1/RIPK3 in IECs represents an effective nonimmunosuppressive strategy for GVHD treatment and potentially for other diseases involving GI tract inflammation.

Fabrication, control, and modeling of robots inspired by flagella and cilia.

Flagella and cilia are slender structures that serve important functionalities in the microscopic world through their locomotion induced by fluid and structure interaction. With recent developments in microscopy, fabrication, biology, and modeling capability, robots inspired by the locomotion of these organelles in low Reynolds number flow have been manufactured and tested on the micro-and macro-scale, ranging from medicalin vivomicrobots, microfluidics to macro prototypes. We present a collection of modeling theories, control principles, and fabrication methods for flagellated and ciliary robots.

Interferon-mediated repression of miR-324-5p potentiates necroptosis to facilitate antiviral defense.

Mixed lineage kinase domain-like protein (MLKL) is the terminal effector of necroptosis, a form of regulated necrosis. Optimal activation of necroptosis, which eliminates infected cells, is critical for antiviral host defense. MicroRNAs (miRNAs) regulate the expression of genes involved in various biological and pathological processes. However, the roles of miRNAs in necroptosis-associated host defense remain largely unknown. We screened a library of miRNAs and identified miR-324-5p as the most effective suppressor of necroptosis. MiR-324-5p downregulates human MLKL expression by specifically targeting the 3'UTR in a seed region-independent manner. In response to interferons (IFNs), miR-324-5p is downregulated via the JAK/STAT signaling pathway, which removes the posttranscriptional suppression of MLKL mRNA and facilitates the activation of necroptosis. In influenza A virus (IAV)-infected human primary macrophages, IFNs are induced, leading to the downregulation of miR-324-5p. MiR-324-5p overexpression attenuates IAV-associated necroptosis and enhances viral replication, whereas deletion of miR-324-5p potentiates necroptosis and suppresses viral replication. Hence, miR-324-5p negatively regulates necroptosis by manipulating MLKL expression, and its downregulation by IFNs orchestrates optimal activation of necroptosis in host antiviral defense.

Activating transcription factor 6 regulates cystathionine to increase autophagy and restore memory in Alzheimer' s disease model mice.

Endoplasmic reticulum stress (ER stress) plays a crucial role in the process of Alzheimer's disease (AD). Activating transcription factor 6 (ATF6) is a crucial sensor of ER stress. In AD patients, the homeostasis of the endogenous signal H2S produced by cystathionine γ-lyase (CTH) is in disbalance. However, the role of ATF6 and CTH in AD is rarely reported. Herein, we found that ATF6 and CTH were reduced in AD patients and APP/PS1 mice by immunohistochemistry and western blots. In LN229 and U87 MG cells, knockdown of ATF6 attenuated CTH expression, whereas overexpression of ATF6 resulted in upregulation of CTH. Brain-specific ATF6 knockout mice expressed significantly down-regulated CTH in the hippocampus and cortex compared to wild-type mice. Mechanistically, ATF6 and CTH increased H2S generation and autophagy-related proteins. Further we observed that CTH promoted the sulfhydration of αSNAP. This is probably to be the specific mechanism by which AFT6 promotes autophagy. Through in vivo studies, we found that αSNAP sulfhydration expression was significantly lower in ATF6 knockout mice than in wild-type mice. Decreased ATF6 impaired spatial memory retention, while addition of CTH rescued memory loss. Together, we demonstrate that ATF6 positively regulates the expression of CTH, which is closely related to the rescue of AD. Targeting the ATF6/CTH signal pathway may provide a new strategy for the treatment of AD.

Discovery of a Potent RIPK3 Inhibitor for the Amelioration of Necroptosis-Associated Inflammatory Injury.

Necroptosis is a form of regulated necrosis that requires the activation of receptor-interacting kinase 3 (RIPK3 or RIP3) and its phosphorylation of the substrate MLKL (mixed lineage kinase domain-like protein). Necroptosis has emerged as important cell death involved in the pathogenesis of various diseases including inflammatory diseases, degenerative diseases, and cancer. Here, we discovered a small molecule Zharp-99 as a potent inhibitor of necroptosis through blocking the kinase activity of RIPK3. Zharp-99 efficiently blocks necroptosis induced by ligands of the death receptor and Toll-like receptor as well as viral infection in human, rat and mouse cells. Zharp-99 strongly inhibits cellular activation of RIPK3, and MLKL upon necroptosis stimuli. Zharp-99 directly blocks the kinase activity of RIPK3 without affecting RIPK1 kinase activity at the tested concentration. Importantly, Zharp-99 exerts effective protection against TNF-α induced systemic inflammatory response syndrome in the mouse model. Zharp-99 displays favorable in vitro safety profiles and in vivo pharmacokinetic parameters. Thus, our study demonstrates Zharp-99 as a potent inhibitor of RIPK3 kinase and also highlights its potential for further development of new approaches for treating necroptosis-associated inflammatory disorders.

Activating transcription factor 6 reduces Aß1-42 and restores memory in Alzheimer's disease model mice.

OBJECTIVES: Amyloid plaques are the most important pathological hallmarks of Alzheimer's disease. The deposition of amyloid plaques will cause ER Stress. Activating Transcription Factor 6(ATF6) is a sensor of ER Stress. However, the role of ATF6 in Alzheimer's disease has not been reported yet. METHODS: The levels of ß-site APP-cleaving enzyme 1 (BACE1) and Aß1-42 were detected by Western blot, ELISA and Thioflavin S staining. Y maze and Morris water maze tests were used to detect the learning and memory functions. Dual luciferase assay was used to test the promoter activity of BACE1 and ADAM17. RESULTS: In our study, we found that the expression of ATF6 was reduced in APPswe/PSNdE9 (APP/PS1) Alzheimer's disease model mice compared with wild type mice. Furthermore, in LN229 cell, we found that ATF6 reduced the expression of full length amyloid precursor protein (APP) in protein level. At the same time, the overexpression of ATF6 strikingly reduced the level of Aß1-42. Interestingly, ATF6 also downregulated the promoter activity of BACE1. And some behavioral experiments like Y maze and Morris water maze test indicated that ATF6 could protect retention of spatial memory in APP/PS1 mice. CONCLUSION: Our findings indicated that ATF6 rescued the amyloid pathology by downregulating BACE1. Therefore, we suggest that ATF6 could be a potential hub for targeting treatment of the Alzheimer's disease.