Targeting cargo to an unconventional secretory system within megakaryocytes allows the release of transgenic proteins from platelets.

BACKGROUND: Platelets are essential for hemostasis and thrombosis and play vital roles during metastatic cancer progression and infection. Hallmarks of platelet function are activation, cytoskeletal rearrangements, and the degranulation of their cellular contents upon stimulation. While α-granules and dense granules are the most studied platelet secretory granules, the dense tubular system (DTS) also functions as a secretory system for vascular thiol isomerases. However, how DTS cargo is packaged and transported from megakaryocytes (MKs) to platelets is poorly understood. OBJECTIVES: To underpin the mechanisms responsible for DTS cargo transport and leverage those for therapeutic protein packaging into platelets. METHODS: A retroviral expression system combined with immunofluorescence confocal microscopy was employed to track protein DTS cargo protein disulfide isomerase fused to enhanced green fluorescent protein (eGFP-PDI) during platelet production. Murine bone marrow transplantation models were used to determine the release of therapeutic proteins from platelets. RESULTS: We demonstrated that the endoplasmic reticulum retrieval motif Lys-Asp-Glu-Leu (KDEL) located at the C-terminus of protein disulfide isomerase was essential for the regular transport of eGFP-PDI-containing granules. eGFP-PDIΔKDEL, in which the retrieval signal was deleted, was aberrantly packaged, and its expression was upregulated within clathrin-coated endosomes. Finally, we found that ectopic transgenic proteins, such as tissue factor pathway inhibitor and interleukin 2, can be packaged into MKs and proplatelets by adding a KDEL retrieval sequence. CONCLUSION: Our data corroborate the DTS as a noncanonical secretory system in platelets and demonstrate that in vitro-generated MKs and platelets may be used as a delivery system for transgenic proteins during cellular therapy.

Sulfiredoxin-1 accelerates erastin-induced ferroptosis in HT-22 hippocampal neurons by driving heme Oxygenase-1 activation.

Ferroptosis, a recently identified non-apoptotic form of cell death, is strongly associated with neurological diseases and has emerged as a potential therapeutic target. Nevertheless, the fundamental mechanisms are still predominantly unidentified. In the current investigation, sulfiredoxin-1 (SRXN1) has been identified as a crucial regulator that enhances the susceptibility to ferroptosis in HT-22 mouse hippocampal cells treated with erastin. Utilizing TMT-based proteomics, a significant increase in SRXN1 expression was observed in erastin-exposed HT-22 cells. Efficient amelioration of erastin-induced ferroptosis was achieved via the knockdown of SRXN1, which resulted in the reduction of intracellular Fe2+ levels and reactive oxygen species (ROS) in HT-22 cells. Notably, the activation of Heme Oxygenase-1 (HO-1) was found to be crucial for inducing SRXN1 expression in HT-22 cells upon treatment with erastin. SRXN1 increased intracellular ROS and Fe2+ levels by activating HO-1 expression, which promoted erastin-induced ferroptosis in HT-22 cells. Inhibiting SRXN1 or HO-1 alleviated erastin-induced autophagy in HT-22 cells. Additionally, upregulation of SRXN1 or HO-1 increased the susceptibility of HT-22 cells to ferroptosis, a process that was counteracted by the autophagy inhibitor 3-Methyladenine (3-MA). These results indicate that SRXN1 is a key regulator of ferroptosis, activating the HO-1 protein through cellular redox regulation, ferrous iron accumulation, and autophagy in HT-22 cells. These findings elucidate a novel molecular mechanism of erastin-induced ferroptosis sensitivity and suggest that SRXN1-HO-1-autophagy-dependent ferroptosis serves as a promising treatment approach for neurodegenerative diseases.

Understanding the relationship between sequences and kinetics of DNA strand displacements.

Precisely modulating the kinetics of toehold-mediated DNA strand displacements (TMSD) is essential for its application in DNA nanotechnology. The sequence in the toehold region significantly influences the kinetics of TMSD. However, due to the large sample space resulting from various arrangements of base sequences and the resulted complex secondary structures, such a correlation is not intuitive. Herein, machine learning was employed to reveal the relationship between the kinetics of TMSD and the toehold sequence as well as the correlated secondary structure of invader strands. Key factors that influence the rate constant of TMSD were identified, such as the number of free hydrogen bonding sites in the invader, the number of free bases in the toehold, and the number of hydrogen bonds in intermediates. Moreover, a predictive model was constructed, which successfully achieved semi-quantitative prediction of rate constants of TMSD even with subtle distinctions in toehold sequence.

AudioGest: Gesture-based Interaction for Virtual Reality using Audio Devices.

Current virtual reality (VR) system takes gesture interaction based on camera, handle and touch screen as one of the mainstream interaction methods, which can provide accurate gesture input for it. However, limited by application forms and the volume of devices, these methods cannot extend the interaction area to such surfaces as walls and tables. To address the above challenge, we propose AudioGest, a portable, plug-and-play system that detects the audio signal generated by finger tapping and sliding on the surface through a set of microphone devices without extensive calibration. First, an audio synthesis-recognition pipeline based on micro-contact dynamics simulation is constructed to generate modal audio synthesis from different materials and physical properties. Then the accuracy and effectiveness of the synthetic audio are verified by mixing the synthetic audio with real audio proportionally as the training sets. Finally, a series of desktop office applications are developed to demonstrate the application potential of AudioGest's scalability and versatility in VR scenarios.

Multi-Label Action Anticipation for Real-World Videos With Scene Understanding.

With human action anticipation becoming an essential tool for many practical applications, there has been an increasing trend in developing more accurate anticipation models in recent years. Most of the existing methods target standard action anticipation datasets, in which they could produce promising results by learning action-level contextual patterns. However, the over-simplified scenarios of standard datasets often do not hold in reality, which hinders them from being applied to real-world applications. To address this, we propose a scene-graph-based novel model SEAD that learns the action anticipation at the high semantic level rather than focusing on the action level. The proposed model is composed of two main modules, 1) the scene prediction module, which predicts future scene graphs using a grammar dictionary, and 2) the action anticipation module, which is responsible for predicting future actions with an LSTM network by taking as input the observed and predicted scene graphs. We evaluate our model on two real-world video datasets (Charades and Home Action Genome) as well as a standard action anticipation dataset (CAD-120) to verify its efficacy. The experimental results show that SEAD is able to outperform existing methods by large margins on the two real-world datasets and can also yield stable predictions on the standard dataset at the same time. In particular, our proposed model surpasses the state-of-the-art methods with mean average precision improvements consistently higher than 65% on the Charades dataset and an average improvement of 40.6% on the Home Action Genome dataset.

Designer high-density lipoprotein particles enhance endothelial barrier function and suppress inflammation.

High-density lipoprotein (HDL) nanoparticles promote endothelial cell (EC) function and suppress inflammation, but their utility in treating EC dysfunction has not been fully explored. Here, we describe a fusion protein named ApoA1-ApoM (A1M) consisting of apolipoprotein A1 (ApoA1), the principal structural protein of HDL that forms lipid nanoparticles, and ApoM, a chaperone for the bioactive lipid sphingosine 1-phosphate (S1P). A1M forms HDL-like particles, binds to S1P, and is signaling competent. Molecular dynamics simulations showed that the S1P-bound ApoM moiety in A1M efficiently activated EC surface receptors. Treatment of human umbilical vein ECs with A1M-S1P stimulated barrier function either alone or cooperatively with other barrier-enhancing molecules, including the stable prostacyclin analog iloprost, and suppressed cytokine-induced inflammation. A1M-S1P injection into mice during sterile inflammation suppressed neutrophil influx and inflammatory mediator secretion. Moreover, systemic A1M administration led to a sustained increase in circulating HDL-bound S1P and suppressed inflammation in a murine model of LPS-induced endotoxemia. We propose that A1M administration may enhance vascular endothelial barrier function, suppress cytokine storm, and promote resilience of the vascular endothelium.

Diverse Motion In-betweening from Sparse Keyframes with Dual Posture Stitching.

In-betweening is a technique for generating transitions given start and target character states. The majority of existing works require multiple (often ≥ 10) frames as input, which are not always available. In addition, they produce results that lack diversity, which may not fulfill artists' requirements. Addressing these gaps, our work deals with a focused yet challenging problem: generating diverse and high-quality transitions given exactly two frames (only the start and target frames). To cope with this challenging scenario, we propose a bi-directional motion generation and stitching scheme which generates forward and backward transitions from the start and target frames with two adversarial autoregressive networks, respectively, and stitches them midway between the start and target frames. In contrast to stitching at the start or target frames, where the ground truth cannot be altered, there is no strict midway ground truth. Thus, our method can capitalize on this flexibility and generate high-quality and diverse transitions simultaneously. Specifically, we employ conditional variational autoencoders (CVAEs) to implement our autoregressive networks and propose a novel stitching loss to stitch the bi-directional generated motions around the midway point.

Alterations of microbiota and metabolites in the feces of calves with diarrhea associated with rotavirus and coronavirus infections.

The changes in the composition of intestinal microbiota and metabolites have been linked to digestive disorders in calves, especially neonatal calf diarrhea. Bovine rotavirus (BRV) and bovine coronavirus (BCoV) are known to be the primary culprits behind neonatal calf diarrhea. In this study, we analyzed changes in the fecal microbiota and metabolites of calves with neonatal diarrhea associated with BRV and BCoV infection using high-throughput 16S rRNA sequencing and metabolomics technology. The microbial diversity in the feces of calves infected with BRV and BCoV with diarrhea decreased significantly, and the composition changed significantly. The significant increase of Fusobacterium and the reductions of some bacteria genera, including Faecalibacterium, Bifidobacterium, Ruminococcus, Subdoligranulum, Parabacteroides, Collinsella, and Olsenella, etc., were closely related to diarrhea associated with BRV and BCoV infection. Metabolites in the feces of BRV and BCoV-infected calves with diarrhea were significantly changed. Phosphatidylcholine [PC; 16:1(9 Z)/16:1(9 Z)], lysophosphatidylethanolamine (LysoPE; 0:0/22:0), lysophosphatidylcholine (LysoPC; P-16:0) and LysoPE (0:0/18:0) were significantly higher in the feces of BRV-infected calves with diarrhea. In contrast, some others, such as desthiobiotin, were significantly lower. BRV infection affects glycerophospholipid metabolism and biotin metabolism in calves. Two differential metabolites were significantly increased, and 67 differential metabolites were significantly reduced in the feces of BCoV-infected calves with diarrhea. Seven significantly reduced metabolites, including deoxythymidylic acid (DTMP), dihydrobiopterin, dihydroneopterin triphosphate, cortexolone, cortisol, pantetheine, and pregnenolone sulfate, were enriched in the folate biosynthesis, pantothenate and CoA biosynthesis, pyrimidine metabolism, and steroid hormone biosynthesis pathway. The decrease in these metabolites was closely associated with increased harmful bacteria and reduced commensal bacteria. The content of short-chain fatty acids (SCFAs) such as acetic acid and propionic acid in the feces of BRV and BCoV-infected calves with diarrhea was lower than that of healthy calves, which was associated with the depletion of SCFAs-producing bacteria such as Parabacteroides, Fournierella, and Collinsella. The present study showed that BRV and BCoV infections changed the composition of the calf fecal microbiota and were associated with changes in fecal metabolites. This study lays the foundation for further revealing the roles of intestinal microbiota in neonatal calf diarrhea associated with BRV and BCoV infection.

ATP2B3 Inhibition Alleviates Erastin-Induced Ferroptosis in HT-22 Cells through the P62-KEAP1-NRF2-HO-1 Pathway.

Ferroptosis participates in the occurrence and development of neurological disorders. Modulating ferroptosis may have therapeutic potential in nervous system diseases. Therefore, TMTbased proteomic analysis in HT-22 cells was performed to identify erastin-induced differentially expressed proteins. The calcium-transporting ATP2B3 (ATP2B3) was screened as a target protein. ATP2B3 knockdown markedly alleviated the erastin-induced decrease in cell viability and elevated ROS (p < 0.01) and reversed the up-regulation of oxidative stress-related proteins polyubiquitin-binding protein p62 (P62), nuclear factor erythroid 2-related factor2 (NRF2), heme oxygenase-1 (HO-1), and NAD(P)H quinone oxidoreductase-1 (NQO1) protein expression (p < 0.05 or p < 0.01) and the down-regulation of Kelch-like ECH-associated protein 1(KEAP1) protein expression (p < 0.01). Moreover, NRF2 knockdown, P62 inhibition, or KEAP1 overexpression rescued the erastin-induced decrease in cell viability (p < 0.05) and increase in ROS production (p < 0.01) in HT-22 cells, while simultaneous overexpression of NRF2 and P62 and knockdown of KEAP1 partially offset the relief effect of ATP2B3 inhibition. In addition, knockdown of ATP2B3, NRF2, and P62 and overexpression of KEAP1 significantly down-regulated erastin-induced high expression of the HO-1 protein, while HO-1 overexpression reversed the alleviating effects of ATP2B3 inhibition on the erastin-induced decrease in cell viability (p < 0.01) and increase in ROS production (p < 0.01) in HT-22 cells. Taken together, ATP2B3 inhibition mediates the alleviation of erastin-induced ferroptosis in HT-22 cells through the P62-KEAP1-NRF2-HO-1 pathway.

Chronic Corticosterone Exposure Suppresses Copper Transport through GR-Mediated Intestinal CTR1 Pathway in Mice.

Numerous studies have discovered that chronic stress induces metabolic disorders by affecting iron and zinc metabolism, but the relationship between chronic stress and copper metabolism remains unclear. Here, we explore the influence of chronic corticosterone (CORT) exposure on copper metabolism and its regulatory mechanism in mice. Mice were treated with 100 µg/mL CORT in drinking water for a 4-week trial. We found that CORT treatment resulted in a significant decrease in plasma copper level, plasma ceruloplasmin activity, plasma and liver Cu/Zn-SOD activity, hepatic copper content, and liver metallothionein content in mice. CORT treatment led to the reduction in duodenal expression of copper transporter 1 (CTR1), duodenal cytochrome b (DCYTB), and ATPase copper-transporting alpha (ATP7A) at the mRNA and protein level in mice. CORT treatment activated nuclear glucocorticoid receptor (GR) and down-regulated CRT1 expression in Caco-2 cells, whereas these phenotypes were reversible by an antagonist of GR, RU486. Chromatin immunoprecipitation analysis revealed that GR bound to the Ctr1 promoter in Caco-2 cells. Transient transfection assays in Caco-2 cells demonstrated that the Ctr1 promoter was responsive to the CORT-activated glucocorticoid receptor, whereas mutation/deletion of the glucocorticoid receptor element (GRE) markedly impaired activation of the Ctr1 promoter. In addition, CORT-induced downregulation of Ctr1 promoter activity was markedly attenuated in Caco-2 cells when RU486 was added. These findings present a novel molecular target for CORT that down-regulates intestinal CTR1 expression via GR-mediated trans-repression in mice.

DNA 5mC and RNA m6A modification successively facilitates the initiation and perpetuation stages of HSC activation in liver fibrosis progression.

Hepatic stellate cells (HSC) are key effector cells in liver fibrosis. Upon stimulation, the quiescent HSC undergoes complex morphological and functional changes to transdifferentiate into activated collagen-producing myofibroblasts. DNA/RNA methylations (5mC/m6A) are both implicated to participate in hepatic fibrosis, yet their respective roles and specific targets in HSC activation remain elusive. Here, we demonstrate that 5mC is indispensable for the initiation stage of HSC activation (myofibroblast transdifferentiation), whereas m6A is essential for the perpetuation stage of HSC activation (excessive ECM production). Mechanistically, DNA 5mC hypermethylation on the promoter of SOCS3 and PPARγ genes leads to STAT3-mediated metabolic reprogramming and lipid loss in the initiation stage. RNA m6A hypermethylation on the transcripts of major collagen genes enhances the mRNA stability in a YTHDF1-dependent manner, which contributes to massive ECM production. Vitamin A-coupled YTHDF1 siRNA alleviates CCl4-induced liver fibrosis in mice through HSC-specific inhibition of collagen production. HIF-1α, which is transactivated by STAT3, serves as a bridge linking the initiation and the perpetuation stages through transactivating YTHDF1. These findings indicate successive roles of DNA 5mC and RNA m6A modification in the progression of HSC activation, which provides new drug targets for epigenetic therapy of liver fibrosis.

Histone Deacetylase 1 Expression and Regulatory Network in Lung Adenocarcinoma Based on Data Mining and Implications for Targeted Treatment.

Background and Aims: Histone deacetylase 1 (HDAC1) codes a protein that is a component of the histone deacetylase complex. The abnormal expression of HDAC1 is strongly correlated with cell proliferation, differentiation, transcription, and translation. Through continuous screening of genes associated with changes in lung adenocarcinoma (LUAD), gene networks are formed to explore tumor pathogenesis and new therapeutic targets. Methods: We evaluated HDAC1 gene survival analysis and its expression of LUAD using relevant websites and databases (TCGA and GEO databases). Through data mining, we determined the frequency and type of HDAC1 mutation, obtained the relevant heat map of the gene interaction network, completed the analysis of gene ontology and function enrichment, and understood the pharmaceutic of HDAC1. Results: We found that HDAC1 expression was associated with the prognosis of patients with LUAD. In gene expression analysis, HDAC1 was highly expressed in LUAD, and the HDAC1 interaction gene network (MARCKSL, eIF3I) was closely related to cellular gene expression. Functional network analysis shows that the expression of HDAC1 is related to the monitoring point of the G1-S phase of the cell cycle and the activation of the Notch signaling pathway (CSL transcription factor), which is involved in the process of cell proliferation and differentiation and gene expression associated with new therapeutic targets. Conclusion: Our data revealed the expression and potential regulatory factors of HDAC1 in LUAD of data mining, which laid a foundation for the study of the occurrence, development, and treatment of HDAC1 in LUAD.

Genomic instability drives tumorigenesis and metastasis and its implications for cancer therapy.

Genetic instability can be caused by external factors and may also be associated with intracellular damage. At the same time, there is a large body of research investigating the mechanisms by which genetic instability occurs and demonstrating the relationship between genomic stability and tumors. Nowadays, tumorigenesis development is one of the hottest research areas. It is a vital factor affecting tumor treatment. Mechanisms of genomic stability and tumorigenesis development are relatively complex. Researchers have been working on these aspects of research. To explore the research progress of genomic stability and tumorigenesis, development, and treatment, the authors searched PubMed with the keywords "genome instability" "chromosome instability" "DNA damage" "tumor spread" and "cancer treatment". This extracts the information relevant to this study. Results: This review introduces genomic stability, drivers of tumor development, tumor cell characteristics, tumor metastasis, and tumor treatment. Among them, immunotherapy is more important in tumor treatment, which can effectively inhibit tumor metastasis and kill tumor cells. Breakthroughs in tumorigenesis development studies and discoveries in tumor metastasis will provide new therapeutic techniques. New tumor treatment methods can effectively prevent tumor metastasis and improve the cure rate of tumors.

Chronic Psychological Stress Disrupts Iron Metabolism and Enhances Hepatic Mitochondrial Function in Mice.

To explore the changes in iron metabolism and mitochondrial function exposed to chronic psychological stress, seventy-five male mice aged 5 ~ 6 weeks were randomly sorted into 2 groups: control group and chronic psychological stress group. Mice were conducted by communication box to induce psychological stress for 21 consecutive days. The results showed that chronic psychological stress led to a significant reduction in average daily gain (P < 0.01) and the final weight (P < 0.05). Chronic psychological stress greatly increased plasma and duodenal iron level (P < 0.05), whereas markedly decreased hepatic iron content in mice (P < 0.05). Increasing expression of duodenal DCYTB and FPN (P < 0.05) was observed in mice exposed to chronic psychological stress. Moreover, chronic psychological stress greatly enhanced hepatic TFR1, FTL, and FPN protein expression (P < 0.05) in mice. Additionally, chronic psychological stress enhanced the levels of hepatic NADH, NAD + , ATP, mtDNA content, mtDNA-encoded genes, and the activity of mitochondrial complex I and II (P < 0.05). Taken together, chronic psychological stress impairs growth, disrupts iron metabolism, and enhances hepatic mitochondrial function in mice. These results will provide new insights for understanding the mechanisms of iron metabolism and mitochondrial function during chronic psychological stress.

Effects of Curcumin on the Egg Quality and Hepatic Lipid Metabolism of Laying Hens.

Curcumin, the major active compound of turmeric, has shown potential benefits for poultry health and production in various studies. However, its specific role in enhancing the egg quality and liver health of laying hens, as well as its underlying mechanisms, have yet to be determined. Here, a total of 600 Su Qin No.1 Laying hens, aged 55 weeks and with similar laying rates, were randomly placed into five groups, with 10 replicates of 12 hens each. Curcumin doses of 0, 100, 200, 400, and 800 mg/kg were added to the basal diet to form the experimental groups. After an 8-week feeding period, no significant changes were observed in the production performance of laying hens due to curcumin supplementation. However, additional tests revealed that a 200 mg/kg curcumin supplementation improved albumen height, yolk color, Haugh unit, and eggshell thickness, while reducing the thin albumen's weight and proportion. This was accompanied by a significant down-regulation of the mRNA expression level of the Prolactin Receptor (Prlr) in the oviduct magnum. Furthermore, the number of hepatic lipid droplets and the hepatic triglyceride (TG) content, as well as malondialdehyde (MDA) levels were significantly reduced, indicating improved hepatic lipid metabolism and oxidative status. This was accompanied by a significant reduction in the expressions of sterol regulatory element binding protein-1 gene (Srebp-1), fatty acid synthase gene (Fasn), as well as fatty acid synthase (FASN), which are closely related to fatty acid synthesis in the liver. Overall, these findings suggest that curcumin supplementation at a dosage of 200 mg/kg could lead to significant improvements in egg quality and hepatic lipid metabolism.

A dataset of ant colonies' motion trajectories in indoor and outdoor scenes to study clustering behavior.

BACKGROUND: The motion and interaction of social insects (such as ants) have been studied by many researchers to understand clustering mechanisms. Most studies in the field of ant behavior have focused only on indoor environments (a laboratory setup), while outdoor environments (natural environments) are still underexplored. FINDINGS: In this article, we collect 10 videos of 3 species of ant colonies from different scenes, including 5 indoor and 5 outdoor scenes. We develop an image sequence marking software named VisualMarkData, which enables us to provide annotations of the ants in the videos. (i) It offers comprehensive annotations of states at the individual-target and colony-target levels. (ii) It provides a simple matrix format to represent multiple targets and multiple groups of annotations (along with their IDs and behavior labels). (iii) During the annotation process, we propose a simple and effective visualization that takes the annotation information of the previous frame as a reference, and then a user can simply click on the center point of each target to complete the annotation task. (iv) We develop a user-friendly window-based GUI to minimize labor and maximize annotation quality. In all 5,354 frames, the location information and the identification number of each ant are recorded for a total of 712 ants and 114,112 annotations. Moreover, we provide visual analysis tools to assess and validate the technical quality and reproducibility of our data. CONCLUSIONS: We provide a large-scale ant dataset with the accompanying annotation software. It is hoped that our work will contribute to a deeper exploration of the behavior of ant colonies.

Enhanced trace-amount terahertz vibrational absorption spectroscopy using surface spoof polarization in metasurface structures.

Terahertz (THz) absorption spectroscopy is a powerful tool for molecular label-free fingerprinting, but it faces a formidable hurdle in enhancing the broadband spectral signals in trace-amount analysis. In this paper, we propose a sensing method based on the geometry scanning of metal metasurfaces with spoof surface polarization sharp resonances by numerical simulation. This scheme shows a significant absorption enhancement factor of about 200 times in an ultra-wide terahertz band to enable the explicit identification of various analytes, such as a trace-amount thin lactose film samples. The proposed method provides a new, to the best of our knowledge, choice for the enhancement of wide terahertz absorption spectra, and paves the way for the detection of trace-amount chemical, organic, or biomedical materials in the terahertz regime.

PIEZO1 mediates a mechanothrombotic pathway in diabetes.

Thrombosis is the leading complication of common human disorders including diabetes, coronary heart disease, and infection and remains a global health burden. Current anticoagulant therapies that target the general clotting cascade are associated with unpredictable adverse bleeding effects, because understanding of hemostasis remains incomplete. Here, using perturbational screening of patient peripheral blood samples for latent phenotypes, we identified dysregulation of the major mechanosensory ion channel Piezo1 in multiple blood lineages in patients with type 2 diabetes mellitus (T2DM). Hyperglycemia activated PIEZO1 transcription in mature blood cells and selected high Piezo1­expressing hematopoietic stem cell clones. Elevated Piezo1 activity in platelets, red blood cells, and neutrophils in T2DM triggered discrete prothrombotic cellular responses. Inhibition of Piezo1 protected against thrombosis both in human blood and in zebrafish genetic models, particularly in hyperglycemia. Our findings identify a candidate target to precisely modulate mechanically induced thrombosis in T2DM and a potential screening method to predict patient-specific risk. Ongoing remodeling of cell lineages in hematopoiesis is an integral component of thrombotic risk in T2DM, and related mechanisms may have a broader role in chronic disease.

C3 Assignment: Camera Cubemap Color Assignment for Creative Interior Design.

Color design for 3D indoor scenes is a challenging problem due to many factors that need to be balanced. Although learning from images is a commonly adopted strategy, this strategy may be more suitable for natural scenes in which objects tend to have relatively fixed colors. For interior scenes consisting mostly of man-made objects, creative yet reasonable color assignments are expected. We propose C3 Assignment, a system providing diverse suggestions for interior color design while satisfying general global and local rules including color compatibility, color mood, contrast, and user preference. We extend these constraints from the image domain to [Formula: see text], and formulate 3D interior color design as an optimization problem. The design is accomplished in an omnidirectional manner to ensure a comfortable experience when the inhabitant observes the interior scene from possible positions and directions. We design a surrogate-assisted evolutionary algorithm to efficiently solve the highly nonlinear optimization problem for interactive applications, and investigate the system performance concerning problem complexity, solver convergence, and suggestion diversity. Preliminary user studies have been conducted to validate the rule extension from 2D to 3D and to verify system usability.

The secreted tyrosine kinase VLK is essential for normal platelet activation and thrombus formation.

Tyrosine phosphorylation of extracellular proteins is observed in cell cultures and in vivo, but little is known about the functional roles of tyrosine phosphorylation of extracellular proteins. Vertebrate lonesome kinase (VLK) is a broadly expressed secretory pathway tyrosine kinase present in platelet α-granules. It is released from platelets upon activation and phosphorylates substrates extracellularly. Its role in platelet function, however, has not been previously studied. In human platelets, we identified phosphorylated tyrosines mapped to luminal or extracellular domains of transmembrane and secreted proteins implicated in the regulation of platelet activation. To determine the role of VLK in extracellular tyrosine phosphorylation and platelet function, we generated mice with a megakaryocyte/platelet-specific deficiency of VLK. Platelets from these mice are normal in abundance and morphology but have significant changes in function both in vitro and in vivo. Resting and thrombin-stimulated VLK-deficient platelets exhibit a significant decrease in several tyrosine phosphobands. Results of functional testing of VLK-deficient platelets show decreased protease-activated receptor 4-mediated and collagen-mediated platelet aggregation but normal responses to adenosine 5'-diphosphate. Dense granule and α-granule release are reduced in these platelets. Furthermore, VLK-deficient platelets exhibit decreased protease-activated receptor 4-mediated Akt (S473) and Erk1/2 (T202/Y204) phosphorylation, indicating altered proximal signaling. In vivo, mice lacking VLK in megakaryocytes/platelets display strongly reduced platelet accumulation and fibrin formation after laser-induced injury of cremaster arterioles compared with control mice but with normal bleeding times. These studies show that the secretory pathway tyrosine kinase VLK is critical for stimulus-dependent platelet activation and thrombus formation, providing the first evidence that a secreted protein kinase is required for normal platelet function.