Glycolytic enzyme PFKL governs lipolysis by promoting lipid droplet-mitochondria tethering to enhance ß-oxidation and tumor cell proliferation.

Lipid droplet tethering with mitochondria for fatty acid oxidation is critical for tumor cells to counteract energy stress. However, the underlying mechanism remains unclear. Here, we demonstrate that glucose deprivation induces phosphorylation of the glycolytic enzyme phosphofructokinase, liver type (PFKL), reducing its activity and favoring its interaction with perilipin 2 (PLIN2). On lipid droplets, PFKL acts as a protein kinase and phosphorylates PLIN2 to promote the binding of PLIN2 to carnitine palmitoyltransferase 1A (CPT1A). This results in the tethering of lipid droplets and mitochondria and the recruitment of adipose triglyceride lipase to the lipid droplet-mitochondria tethering regions to engage lipid mobilization. Interfering with this cascade inhibits tumor cell proliferation, promotes apoptosis and blunts liver tumor growth in male mice. These results reveal that energy stress confers a moonlight function to PFKL as a protein kinase to tether lipid droplets with mitochondria and highlight the crucial role of PFKL in the integrated regulation of glycolysis, lipid metabolism and mitochondrial oxidation.

Omnidirectional Virtual Visual Acuity: A User-Centric Visual Clarity Metric for Virtual Reality Head-Mounted Displays and Environments.

Users' perceived image quality of virtual reality head-mounted displays (VR HMDs) is determined by multiple factors, including the HMD's structure, optical system, display and render resolution, and users' visual acuity (VA). Existing metrics such as pixels per degree (PPD) have limitations that prevent accurate comparison of different VR HMDs. One of the main limitations is that not all VR HMD manufacturers released the official PPD or details of their HMDs' optical systems. Without these details, developers and users cannot know the precise PPD or calculate it for a given HMD. The other issue is that the visual clarity varies with the VR environment. Our work has identified a gap in having a feasible metric that can measure the visual clarity of VR HMDs. To address this gap, we present an end-to-end and user-centric visual clarity metric, omnidirectional virtual visual acuity (OVVA), for VR HMDs. OVVA extends the physical visual acuity chart into a virtual format to measure the virtual visual acuity of an HMD's central focal area and its degradation in its noncentral area. OVVA provides a new perspective to measure visual clarity and can serve as an intuitive and accurate reference for VR applications sensitive to visual accuracy. Our results show that OVVA is a simple yet effective metric for comparing VR HMDs and environments.

Design and Evaluation of Controller-based Raycasting Methods for Efficient Alphanumeric and Special Character Entry in Virtual Reality.

Alphanumeric and special characters are essential during text entry. Text entry in virtual reality (VR) is usually performed on a virtual Qwerty keyboard to minimize the need to learn new layouts. As such, entering capitals, symbols, and numbers in VR is often a direct migration from a physical/touchscreen Qwerty keyboard-that is, using the mode-switching keys to switch between different types of characters and symbols. However, there are inherent differences between a keyboard in VR and a physical/touchscreen keyboard, and as such, a direct adaptation of mode-switching via switch keys may not be suitable for VR. The high flexibility afforded by VR opens up more possibilities for entering alphanumeric and special characters using the Qwerty layout. In this work, we designed two controller-based raycasting text entry methods for alphanumeric and special characters input (Layer-ButtonSwitch and Key-ButtonSwitch) and compared them with two other methods (Standard Qwerty Keyboard and Layer-PointSwitch) that were derived from physical and soft Qwerty keyboards. We explored the performance and user preference of these four methods via two user studies (one short-term and one prolonged use), where participants were instructed to input text containing alphanumeric and special characters. Our results show that Layer-ButtonSwitch led to the highest statistically significant performance, followed by Key-ButtonSwitch and Standard Qwerty Keyboard, while Layer-PointSwitch had the slowest speed. With continuous practice, participants' performance using Key-ButtonSwitch reached that of Layer-ButtonSwitch. Further, the results show that the key-level layout used in Key-ButtonSwitch led users to parallel mode switching and character input operations because this layout showed all characters on one layer. We distill three recommendations from th results that can help guide the design of text entry techniques for alphanumeric and special characters in VR.

Fructose-1,6-bisphosphatase 1 suppresses PPARα-mediated gene transcription and non-small-cell lung cancer progression.

Rapidly growing tumors often encounter energy stress, such as glutamine deficiency. However, how normal and tumor cells differentially respond to glutamine deficiency remains largely unclear. Here, we demonstrate that glutamine deprivation activates PERK, which phosphorylates FBP1 at S170 and induces nuclear accumulation of FBP1. Nuclear FBP1 inhibits PPARα-mediated ß-oxidation gene transcription in normal lung epithelial cells. In contrast, highly expressed OGT in non-small cell lung cancer (NSCLC) cells promotes FBP1 O-GlcNAcylation, which abrogates FBP1 phosphorylation and enhances ß-oxidation gene transcription to support cell proliferation under glutamine deficiency. In addition, FBP1 pS170 is negatively correlated with OGT expression in human NSCLC specimens, and low expression of FBP1 pS170 is associated with poor prognosis in NSCLC patients. These findings highlight the differential regulation of FBP1 in normal and NSCLC cells under glutamine deprivation and underscore the potential to target nuclear FBP1 for NSCLC treatment.

Effect of Frame Rate on User Experience, Performance, and Simulator Sickness in Virtual Reality.

The refresh rate of virtual reality (VR) head-mounted displays (HMDs) has been growing rapidly in recent years because of the demand to provide higher frame rate content as it is often linked with a better experience. Today's HMDs come with different refresh rates ranging from 20Hz to 180Hz, which determines the actual maximum frame rate perceived by users' naked eyes. VR users and content developers often face a choice because having high frame rate content and the hardware that supports it comes with higher costs and other trade-offs (such as heavier and bulkier HMDs). Both VR users and developers can choose a suitable frame rate if they are aware of the benefits of different frame rates in user experience, performance, and simulator sickness (SS). To our knowledge, limited research on frame rate in VR HMDs is available. In this paper, we aim to fill this gap and report a study with two VR application scenarios that compared four of the most common and highest frame rates currently available (60, 90, 120, and 180 frames per second (fps)) to explore their effect on users' experience, performance, and SS symptoms. Our results show that 120fps is an important threshold for VR. After 120fps, users tend to feel lower SS symptoms without a significant negative effect on their experience. Higher frame rates (e.g., 120 and 180fps) can ensure better user performance than lower rates. Interestingly, we also found that at 60fps and when users are faced with fast-moving objects, they tend to adopt a strategy to compensate for the lack of visual details by predicting or filling the gaps to try to meet the performance needs. At higher fps, users do not need to follow this compensatory strategy to meet the fast response performance requirements.

In-Device Feedback in Immersive Head-Mounted Displays for Distance Perception During Teleoperation of Unmanned Ground Vehicles.

In recent years, Virtual Reality (VR) Head-Mounted Displays (HMD) have been used to provide an immersive, first-person view in real-time for the remote-control of Unmanned Ground Vehicles (UGV). One critical issue is that it is challenging to perceive the distance of obstacles surrounding the vehicle from 2D views in the HMD, which deteriorates the control of UGV. Conventional distance indicators used in HMD take up screen space which leads clutter on the display and can further reduce situation awareness of the physical environment. To address the issue, in this paper we propose off-screen in-device feedback using vibro-tactile and/or light-visual cues to provide real-time distance information for the remote control of UGV. Results from a study show a significantly better performance with either feedback type, reduced workload and improved usability in a driving task that requires continuous perception of the distance between the UGV and its environmental objects or obstacles. Our findings show a solid case for in-device vibro-tactile and/or light-visual feedback to support remote operation of UGVs that highly relies on distance perception of objects.

Linking the YTH domain to cancer: the importance of YTH family proteins in epigenetics.

N6-methyladenosine (m6A), the most prevalent and reversible modification of mRNA in mammalian cells, has recently been extensively studied in epigenetic regulation. YTH family proteins, whose YTH domain can recognize and bind m6A-containing RNA, are the main "readers" of m6A modification. YTH family proteins perform different functions to determine the metabolic fate of m6A-modified RNA. The crystal structure of the YTH domain has been completely resolved, highlighting the important roles of several conserved residues of the YTH domain in the specific recognition of m6A-modified RNAs. Upstream and downstream targets have been successively revealed in different cancer types and the role of YTH family proteins has been emphasized in m6A research. This review describes the regulation of RNAs by YTH family proteins, the structural features of the YTH domain, and the connections of YTH family proteins with human cancers.

Weighted gene coexpression network analysis identifies hub genes related to KRAS mutant lung adenocarcinoma.

The aim of current study was to use Weighted Gene Coexpression Network Analysis (WGCNA) to identify hub genes related to the incidence and prognosis of KRAS mutant (MT) lung adenocarcinoma (LUAD).We involved 184 stage IIB to IV LUAD samples and 59 normal lung tissue samples from The Cancer Genome Atlas (TCGA) database. The R package "limma" was used to identify differentially expressed genes (DEGs). WGCNA and survival analyses were performed by R packages "WGCNA" and "survival," respectively. The functional analyses were performed by R package "clusterProfiler" and GSEA software. Network construction and MCODE analysis were performed by Cytoscape_v3.6.1.Totally 2590 KRAS MT specific DEGs were found between LUAD and normal lung tissues, and 10 WGCNA modules were identified. Functional analysis of the key module showed the ribosome biogenesis related terms were enriched. We observed the expression of 8 genes were positively correlated to the worse survival of KRAS MT LUAD patients, the 7 of them were validated by Kaplan-Meier plotter database (kmplot.com/) (thymosin Beta 10 [TMSB10], ribosomal Protein S16 [RPS16], mitochondrial ribosomal protein L27 [MRPL27], cytochrome c oxidase subunit 6A1 [COX6A1], HCLS1-associated protein X-1 [HAX1], ribosomal protein L38 [RPL38], and ATP Synthase Membrane Subunit DAPIT [ATP5MD]). The GSEA analysis found mTOR and STK33 pathways were upregulated in KRAS MT LUAD (P < .05, false discovery rate [FDR] < 0.25).In summary, our study firstly used WGCNA to identify hub genes in the development of KRAS MT LUAD. The identified prognostic factors would be potential biomarkers in clinical use. Further molecular studies are required to confirm the mechanism of those genes in KRAS MT LUAD.

ß-catenin represses miR455-3p to stimulate m6A modification of HSF1 mRNA and promote its translation in colorectal cancer.

BACKGROUND: Heat shock transcription factor1 (HSF1) was overexpressed to promote glutaminolysis and activate mTOR in colorectal cancer (CRC). Here, we investigated the mechanism for cancer-specific overexpression of HSF1. METHODS: HSF1 expression was analyzed by chromatin immunoprecipitation, qRT-PCR, immunohistochemistry staining and immunoblotting. HSF1 translation was explored by polysome profiling and nascent protein analysis. Biotin pulldown and m6A RNA immunoprecipitation were applied to investigate RNA/RNA interaction and m6A modification. The relevance of HSF1 to CRC was analyzed in APCmin/+ and APCmin/+ HSF1+/-mice. RESULTS: HSF1 expression and activity were reduced after the inhibition of WNT/ß-catenin signaling by pyrvinium or ß-catenin knockdown, but elevated upon its activation by lithium chloride (LiCl) or ß-catenin overexpression. There are much less upregulated genes in HSF1-KO MEF treated with LiCl when compared with LiCl-treated WT MEF. HSF1 protein expression was positively correlated with ß-catenin expression in cell lines and primary tissues. After ß-catenin depletion, HSF1 mRNA translation was impaired, accompanied by the reduction of its m6A modification and the upregulation of miR455-3p, which can interact with 3'-UTR of HSF1 mRNA to repress its translation. Interestingly, inhibition of miR455-3p rescued ß-catenin depletion-induced reduction of HSF1 m6A modification and METTL3 interaction. Both the size and number of tumors were significantly reduced in APCmin/+ mice when HSF1 was genetically knocked-out or chemically inhibited. CONCLUSIONS: ß-catenin suppresses miR455-3p generation to stimulate m6A modification and subsequent translation of HSF1 mRNA. HSF1 is important for ß-catenin to promote CRC development. Targeting HSF1 could be a potential strategy for the intervention of ß-catenin-driven cancers.

Competing Risk Analyses of Medullary Carcinoma of Breast in Comparison to Infiltrating Ductal Carcinoma.

The aim of current study was to use competing risk model to assess whether medullary carcinoma of the breast (MCB) has a better prognosis than invasive ductal carcinomas of breast cancer (IDC), and to build a competing risk nomogram for predicting the risk of death of MCB. We involved 3,580 MCB patients and 319,566 IDC patients from Surveillance, Epidemiology, and End Results (SEER) database. IDC was found to have a worse BCSS than MCB (Hazard ratio (HR) > 1, p < 0.001). The 5-year cumulative incidences of death (CID) was higher in IDC than MCB (p < 0.001). Larger tumor size, increasing number of positive lymph nodes and unmarried status were found to worsen the BCSS of MCB (HR > 1, p < 0.001). We found no association between ER, PR, radiotherapy or chemotherapy and MCB prognosis (p > 0.05). After a penalized variable selection process, the SH model-based nomogram showed moderate accuracy of prediction by internal validation of discrimination and calibration with 1,000 bootstraps. In summary, MCB patients had a better prognosis than IDC patients. Interestingly, unmarried status in addition to expected risk factors such as larger tumor size and increasing number of positive lymph nodes were found to worsen the BCSS of MCB. We also established a competing risk nomogram as an easy-to-use tool for prognostic estimation of MCB patients.

Metabolic enzyme PDK3 forms a positive feedback loop with transcription factor HSF1 to drive chemoresistance.

Background & Aims: Dysregulation of metabolism plays an important role in the development and progression of cancers, while the underlying mechanisms remain largely unknown. This study aims to explore the regulation and relevance of glycolysis in chemoresistance of gastric cancer. Methods: Biochemical differences between chemoresistant and chemosensitive cancer cells were determined by metabolism profiling, microarray gene expression, PCR or western blotting. Cancer cell growth in vitro or in vivo were analyzed by viability, apoptosis and nude mice assay. Immunoprecipation was used to explore the interaction of proteins with other proteins or DNAs. Results: By metabolic and gene expression profiling, we found that pyruvate dehydrogenase kinase 3 (PDK3) was highly expressed to promote glycolysis in chemoresistant cancer cells. Its genetic or chemical inhibition reverted chemoresistance in vitro and in vivo. It was transcriptionally regulated by transcription factor HSF1 (Heat shock factor 1). Interestingly, PDK3 can localize in the nucleus and interact with HSF1 to disrupt its phosphorylation by GSK3ß. Since HSF1 was subjected to FBXW7-catalyzed polyubiquitination in a phosphorylation-dependent manner, PDK3 prevented HSF1 from proteasomal degradation. Thus, metabolic enzyme PDK3 and transcription factor HSF1 forms a positive feedback loop to promote glycolysis. As a result, inhibition of HSF1 impaired enhanced glycolysis and reverted chemoresistance both in vitro and in vivo. Conclusions: PDK3 forms a positive feedback loop with HSF1 to drive glycolysis in chemoresistance. Targeting this mitonuclear communication may represent a novel approach to overcome chemoresistance.