Compression drives diverse transcriptomic and phenotypic adaptations in melanoma.

Physical forces are prominent during tumor progression. However, it is still unclear how they impact and drive the diverse phenotypes found in cancer. Here, we apply an integrative approach to investigate the impact of compression on melanoma cells. We apply bioinformatics to screen for the most significant compression-induced transcriptomic changes and investigate phenotypic responses. We show that compression-induced transcriptomic changes are associated with both improvement and worsening of patient prognoses. Phenotypically, volumetric compression inhibits cell proliferation and cell migration. It also induces organelle stress and intracellular oxidative stress and increases pigmentation in malignant melanoma cells and normal human melanocytes. Finally, cells that have undergone compression become more resistant to cisplatin treatment. Our findings indicate that volumetric compression is a double-edged sword for melanoma progression and drives tumor evolution.

Device-independent quantum randomness-enhanced zero-knowledge proof.

Zero-knowledge proof (ZKP) is a fundamental cryptographic primitive that allows a prover to convince a verifier of the validity of a statement without leaking any further information. As an efficient variant of ZKP, noninteractive zero-knowledge proof (NIZKP) adopting the Fiat-Shamir heuristic is essential to a wide spectrum of applications, such as federated learning, blockchain, and social networks. However, the heuristic is typically built upon the random oracle model that makes ideal assumptions about hash functions, which does not hold in reality and thus undermines the security of the protocol. Here, we present a quantum solution to the problem. Instead of resorting to a random oracle model, we implement a quantum randomness service. This service generates random numbers certified by the loophole-free Bell test and delivers them with postquantum cryptography (PQC) authentication. By employing this service, we conceive and implement NIZKP of the three-coloring problem. By bridging together three prominent research themes, quantum nonlocality, PQC, and ZKP, we anticipate this work to inspire more innovative applications that combine quantum information science and the cryptography field.

Structural Heredity in Catalysis: CO2 Self-Selective CeO2 Nanocrystals for Efficient Photothermal CO2 Hydrogenation to Methane.

The chemical inertness of CO2 molecules makes their adsorption and activation on a catalyst surface one of the key challenges in recycling CO2 into chemical fuels. However, the traditional template synthesis and chemical modification strategies used to tackle this problem face severe structural collapse and modifier deactivation issues during the often-needed post-processing procedure. Herein, a CO2 self-selective hydrothermal growth strategy is proposed for the synthesis of CeO2 octahedral nanocrystals that participate in strong physicochemical interactions with CO2 molecules. The intense affinity for CO2 molecules persists during successive high-temperature treatments required for Ni deposition. This demonstrates the excellent structural heredity of the CO2 self-selective CeO2 nanocrystals, which leads to an outstanding photothermal CH4 productivity exceeding 9 mmol h-1 mcat -2 and an impressive selectivity of >99%. The excellent performance is correlated with the abundant oxygen vacancies and hydroxyl species on the CeO2 surface, which create many frustrated Lewis-pair active sites, and the strong interaction between Ni and CeO2 that promotes the dissociation of H2 molecules and the spillover of H atoms, thereby greatly benefitting the photothermal CO2 methanation reaction. This self-selective hydrothermal growth strategy represents a new pathway for the development of effective catalysts for targeted chemical reactions.

Biophysical informatics reveals distinctive phenotypic signatures and functional diversity of single-cell lineages.

MOTIVATION: In this work, we present an analytical method for quantifying both single-cell morphologies and cell network topologies of tumor cell populations and use it to predict 3D cell behavior. RESULTS: We utilized a supervised deep learning approach to perform instance segmentation on label-free live cell images across a wide range of cell densities. We measured cell shape properties and characterized network topologies for 136 single-cell clones derived from the YUMM1.7 and YUMMER1.7 mouse melanoma cell lines. Using an unsupervised clustering algorithm, we identified six distinct morphological subclasses. We further observed differences in tumor growth and invasion dynamics across subclasses in an in vitro 3D spheroid model. Compared to existing methods for quantifying 2D or 3D phenotype, our analytical method requires less time, needs no specialized equipment and is capable of much higher throughput, making it ideal for applications such as high-throughput drug screening and clinical diagnosis. AVAILABILITY AND IMPLEMENTATION: https://github.com/trevor-chan/Melanoma_NetworkMorphology. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Long noncoding RNA SNHG5 promotes podocyte injury via the microRNA-26a-5p/TRPC6 pathway in diabetic nephropathy.

Podocyte injury is a characteristic pathological hallmark of diabetic nephropathy (DN). However, the exact mechanism of podocyte injury in DN is incompletely understood. This study was conducted using db/db mice and immortalized mouse podocytes. High-throughput sequencing was used to identify the differentially expressed long noncoding RNAs in kidney of db/db mice. The lentiviral shRNA directed against long noncoding RNA small nucleolar RNA host gene 5 (SNHG5) or microRNA-26a-5p (miR-26a-5p) agomir was used to treat db/db mice to regulate the SNHG5/miR-26a-5p pathway. Here, we found that the expression of transient receptor potential canonical type 6 (TRPC6) was significantly increased in injured podocytes under the condition of DN, which was associated with markedly decreased miR-26a-5p. We determined that miR-26a-5p overexpression ameliorated podocyte injury in DN via binding to 3'-UTR of Trpc6, as evidenced by the markedly reduced activity of luciferase reporters by miR-26a-5p mimic. Then, the upregulated SNHG5 in podocytes and kidney in DN was identified, and it was proved to sponge to miR-26a-5p directly using luciferase activity, RNA immunoprecipitation, and RNA pull-down assay. Knockdown of SNHG5 attenuated podocyte injury in vitro, accompanied by an increased expression of miR-26a-5p and decreased expression of TRPC6, demonstrating that SNHG5 promoted podocyte injury by controlling the miR-26a-5p/TRPC6 pathway. Moreover, knockdown of SNHG5 protects against podocyte injury and progression of DN in vivo. In conclusion, SNHG5 promotes podocyte injury via the miR-26a-5p/TRPC6 pathway in DN. Our findings provide novel insights into the pathophysiology of podocyte injury and a potential new therapeutic strategy for DN.

Quantum Complementarity Approach to Device-Independent Security.

Complementarity is an essential feature of quantum mechanics. The preparation of an eigenstate of one observable implies complete randomness in its complementary observable. In quantum cryptography, complementarity allows us to formulate security analyses in terms of phase-error correction. However, the concept becomes much subtler in the device-independent regime that offers security without device characterization. Security proofs of device-independent quantum cryptography tasks are often complex and quite different from those of their more standard device-dependent cousins. The existing proofs pose huge challenges to experiments, among which large data-size requirement is a crux. Here, we show the complementarity security origin of the device-independent tasks. By linking complementarity with quantum nonlocality, we recast the device-independent scheme into a quantum error correction protocol. Going beyond the identical-and-independent-distribution case, we consider the most general attack. We generalize the sample entropy in classical Shannon theory for the finite-size analysis. Our method exhibits good finite-size performance and brings the device-independent scheme to a more practical regime. Applying it to the data in a recent ion-trap-based device-independent quantum key distribution experiment, one could reduce the requirement on data size to less than a third. Furthermore, the operational meaning of complementarity naturally extends device-independent scenarios to advantage key distillation, easing experiments by tolerating higher loss and lower transmittance.

Blocking FSH induces thermogenic adipose tissue and reduces body fat.

Menopause is associated with bone loss and enhanced visceral adiposity. A polyclonal antibody that targets the ß-subunit of the pituitary hormone follicle-stimulating hormone (Fsh) increases bone mass in mice. Here, we report that this antibody sharply reduces adipose tissue in wild-type mice, phenocopying genetic haploinsufficiency for the Fsh receptor gene Fshr. The antibody also causes profound beiging, increases cellular mitochondrial density, activates brown adipose tissue and enhances thermogenesis. These actions result from the specific binding of the antibody to the ß-subunit of Fsh to block its action. Our studies uncover opportunities for simultaneously treating obesity and osteoporosis.

Hippocampus- and thalamus-related fiber-specific white matter reductions in mild cognitive impairment.

Early diagnosis of mild cognitive impairment (MCI) fascinates screening high-risk Alzheimer's disease (AD). White matter is found to degenerate earlier than gray matter and functional connectivity during MCI. Although studies reveal white matter degenerates in the limbic system for MCI, how other white matter degenerates during MCI remains unclear. In our method, regions of interest with a high level of resting-state functional connectivity with hippocampus were selected as seeds to track fibers based on diffusion tensor imaging (DTI). In this way, hippocampus-temporal and thalamus-related fibers were selected, and each fiber's DTI parameters were extracted. Then, statistical analysis, machine learning classification, and Pearson's correlations with behavior scores were performed between MCI and normal control (NC) groups. Results show that: 1) the mean diffusivity of hippocampus-temporal and thalamus-related fibers are significantly higher in MCI and could be used to classify 2 groups effectively. 2) Compared with normal fibers, the degenerated fibers detected by the DTI indexes, especially for hippocampus-temporal fibers, have shown significantly higher correlations with cognitive scores. 3) Compared with the hippocampus-temporal fibers, thalamus-related fibers have shown significantly higher correlations with depression scores within MCI. Our results provide novel biomarkers for the early diagnoses of AD.

Brain-Computer Interfaces in Visualized Medicine.

The brain-computer interface (BCI), also known as a brain-machine interface (BMI), has attracted extensive attention in biomedical applications. More importantly, BCI technologies have substantially revolutionized early predictions, diagnostic techniques, and rehabilitation strategies addressing acute diseases because of BCI's innovations and clinical translations. Therefore, in this chapter, a comprehensive description of the basic concepts of BCI will be exhibited, and various visualization techniques employed in BCI's medical applications will be discussed.

Metformin-Loaded Chitosan Hydrogels Suppress Bladder Tumor Growth in an Orthotopic Mouse Model via Intravesical Administration.

Our previous study found that the intravesical perfusion of metformin has excellent inhibitory effects against bladder cancer (BC). However, this administration route allows the drug to be diluted and excreted in urine. Therefore, increasing the adhesion of metformin to the bladder mucosal layer may prolong the retention time and increase the pharmacological activity. It is well known that chitosan (Cs) has a strong adhesion to the bladder mucosal layer. Thus, this study established a novel formulation of metformin to enhance its antitumor activity by extending its retention time. In this research, we prepared Cs freeze-dried powder and investigated the effect of metformin-loaded chitosan hydrogels (MLCH) in vitro and in vivo. The results showed that MLCH had a strong inhibitory effect against proliferation and colony formation in vitro. The reduction in BC weight and the expression of tumor biomarkers in orthotopic mice showed the robust antitumor activity of MLCH via intravesical administration in vivo. The non-toxic profile of MLCH was observed as well, using histological examinations. Mechanistically, MLCH showed stronger functional activation of the AMPKα/mTOR signaling pathway compared with metformin alone. These findings aim to make this novel formulation an efficient candidate for managing BC via intravesical administration.

Mild hypothermia ameliorates hepatic ischemia reperfusion injury by inducing RBM3 expression.

Liver ischemia reperfusion injury (IRI) is a serious complication of certain liver surgeries, and it is difficult to prevent. As a potential drug-free treatment, mild hypothermia has been shown to promote positive outcomes in patients with IRI. However, the protective mechanism remains unclear. We established in vivo and in vitro models of hepatic ischemia reperfusion (IR) and mild hypothermia pretreatment. Hepatocytes were transfected with RNA-binding motif protein 3 (RBM3) overexpression plasmids, and IR was performed. Cell, culture medium, blood and tissue samples were collected to assess hepatic injury, oxidative stress, apoptosis and changes in RBM3 expression in the liver. Upregulation of RBM3 expression by mild hypothermia reduced the aminotransferase release, liver tissue injury and mitochondrial injury induced by liver IR. Hepatic IR-induced p38 and c-Jun N-terminal kinase (JNK) signaling pathway activation, oxidative stress injury and apoptosis could be greatly reversed by mild hypothermia. Overexpression of RBM3 mimicked the hepatoprotective effect of mild hypothermia. Mild hypothermia protects the liver from ischemia reperfusion-induced p38 and JNK signaling pathway activation, oxidative stress injury and apoptosis through the upregulation of RBM3 expression.

Biophysical Informatics Approach For Quantifying Phenotypic Heterogeneity In Cancer Cell Migration In Confined Microenvironments.

MOTIVATION: Cancer cell heterogeneity can manifest genetically and phenotypically. Bioinformatics methods have been used to analyze complex genomics and transcriptomics data, but have not been well-established for analyzing biophysical data of phenotypically heterogeneous tumor cells. Here, we take an informatics approach to analyze the biophysical data of MDA-MB-231 cells, a widely used breast cancer cell line, during their spontaneous migration through confined environments. Experimentally, we vary the constriction microchannel geometries (wide channel, short constriction, and long constriction) and apply drug treatments. We find that cells in the short constriction are similar in morphology to the cells in the wide channel. However, their fluorescence profiles are comparable to those in the long constriction. We demonstrate that the cell migratory phenotype is correlated more to mitochondria in a non-confined environment and more to actin in a confined environment. We demonstrate that the cells' migratory phenotypes are altered by ciliobrevin D, a dynein inhibitor, in both confined and non-confined environments. Overall, our approach elucidates phenotypic heterogeneity in cancer cells under confined microenvironments at single-cell resolution. RESULTS: Here, we apply a bioinformatics approach to a single cell invasion assay. We demonstrate that this method can determine distinctions in morphology, cytoskeletal activities, and mitochondrial activities under various geometric constraints and for cells of different speeds. Our approach can be readily adapted to various heterogeneity studies for different types of input biophysical data. In addition, this approach can be applied to studies related to biophysical changes due to differences in external stimuli, such as treatment effects on cellular and subcellular activities, at single-cell resolution. Finally, as similar bioinformatics methods have been widely applied in studies of genetic heterogeneity, biophysical information extracted using this approach can be analyzed together with the genetic data to relate genetic and phenotypic heterogeneity. AVAILABILITY: The data that support the findings of this study are available from the corresponding author upon reasonable request. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Experimental Refutation of Real-Valued Quantum Mechanics under Strict Locality Conditions.

Quantum mechanics is commonly formulated in a complex, rather than real, Hilbert space. However, whether quantum theory really needs the participation of complex numbers has been debated ever since its birth. Recently, a Bell-like test in an entanglement-swapping scenario has been proposed to distinguish standard quantum mechanics from its real-valued analog. Previous experiments have conceptually demonstrated, yet not satisfied, the central requirement of independent state preparation and measurements and leave several loopholes. Here, we implement such a Bell-like test with two separated independent sources delivering entangled photons to three separated parties under strict locality conditions that are enforced by spacelike separation of the relevant events, rapid random setting generation, and fast measurement. With the fair-sampling assumption and closed loopholes of independent source, locality, and measurement independence simultaneously, we violate the constraints of real-valued quantum mechanics by 5.30 standard deviations. Our results disprove the real-valued quantum theory to describe nature and ensure the indispensable role of complex numbers in quantum mechanics.

Erratum: PRMT4 promotes hepatocellular carcinoma progression by activating AKT/mTOR signaling and indicates poor prognosis: Erratum.

[This corrects the article DOI: 10.7150/ijms.62467.].

Paradoxically Sparse Chemosensory Tuning in Broadly Integrating External Granule Cells in the Mouse Accessory Olfactory Bulb.

The accessory olfactory bulb (AOB), the first neural circuit in the mouse accessory olfactory system, is critical for interpreting social chemosignals. Despite its importance, AOB information processing is poorly understood compared with the main olfactory bulb (MOB). Here, we sought to fill gaps in the understanding of AOB interneuron function. We used 2-photon GCaMP6f Ca2+ imaging in an ex vivo preparation to study chemosensory tuning in AOB external granule cells (EGCs), interneurons hypothesized to broadly inhibit activity in excitatory mitral cells (MCs). In ex vivo preparations from mice of both sexes, we measured MC and EGC tuning to natural chemosignal blends and monomolecular ligands, finding that EGC tuning was sparser, not broader, than upstream MCs. Simultaneous electrophysiological recording and Ca2+ imaging showed no differences in GCaMP6f-to-spiking relationships in these cell types during simulated sensory stimulation, suggesting that measured EGC sparseness was not due to cell type-dependent variability in GCaMP6f performance. Ex vivo patch-clamp recordings revealed that EGC subthreshold responsivity was far broader than indicated by GCaMP6f Ca2+ imaging, and that monomolecular ligands rarely elicited EGC spiking. These results indicate that EGCs are selectively engaged by chemosensory blends, suggesting different roles for EGCs than analogous interneurons in the MOB.SIGNIFICANCE STATEMENT The mouse accessory olfactory system (AOS) interprets social chemosignals, but we poorly understand AOS information processing. Here, we investigate the functional properties of external granule cells (EGCs), a major class of interneurons in the accessory olfactory bulb (AOB). We hypothesized that EGCs, which are densely innervated by excitatory mitral cells (MCs), would show broad chemosensory tuning, suggesting a role in divisive normalization. Using ex vivo GCaMP6f imaging, we found that EGCs were instead more sparsely tuned than MCs. This was not due to weaker GCaMP6f signaling in EGCs than in MCs. Instead, we found that many MC-activating chemosignals caused only subthreshold EGC responses. This indicates a different role for AOB EGCs compared with analogous cells in the main olfactory bulb.

Experimental Realization of Device-Independent Quantum Randomness Expansion.

Randomness expansion where one generates a longer sequence of random numbers from a short one is viable in quantum mechanics but not allowed classically. Device-independent quantum randomness expansion provides a randomness resource of the highest security level. Here, we report the first experimental realization of device-independent quantum randomness expansion secure against quantum side information established through quantum probability estimation. We generate 5.47×10^{8} quantum-proof random bits while consuming 4.39×10^{8} bits of entropy, expanding our store of randomness by 1.08×10^{8} bits at a latency of about 13.1 h, with a total soundness error 4.6×10^{-10}. Device-independent quantum randomness expansion not only enriches our understanding of randomness but also sets a solid base to bring quantum-certifiable random bits into realistic applications.

PRMT4 promotes hepatocellular carcinoma progression by activating AKT/mTOR signaling and indicates poor prognosis.

Background: Protein arginine methyltransferase 4 (PRMT4) has been reported to play a role in several common cancers; however, the function and mechanism of PRMT4 in hepatocellular carcinoma (HCC) are not fully understood. This study aimed to investigate the role and mechanism of PRMT4 in the progression of HCC. Methods: PRMT4 expression and clinicopathological characteristics were investigated using an HCC tissue microarray (TMA) consisting of 140 patient samples analyzed by immunohistochemistry. CCK-8, crystal violet and Transwell assays were used to determine cell proliferation, colony formation, migration, and invasion of HCC cell lines in which PRMT4 was overexpressed or downregulated. The underlying mechanism of PRMT4 function was explored by Western blot assays. Results: PRMT4 was highly expressed in HCC tumor tissues compared to adjacent nontumor tissues. PRMT4 expression was significantly associated with alpha-fetoprotein levels, tumor size, satellite nodules, and microvascular invasion. Patients with higher PRMT4 expression had a shorter survival time and higher recurrence rate. Functional studies demonstrated that PRMT4 overexpression promoted HCC cell proliferation, migration, and invasion in vitro, while knocking down PRMT4 inhibited these malignant behaviors. Additional results revealed that PRMT4 promoted the progression of HCC cells via activation of the AKT/mTOR signaling pathway. Furthermore, inhibition of the AKT/mTOR signaling by MK2206 or rapamycin significantly attenuated PRMT4-mediated malignant phenotypes. Conclusions: This study suggests that PRMT4 may promote the progression of HCC cells by activating the AKT/mTOR signaling pathway, which may be a valuable biomarker and potential target for HCC.

Measurement-Device-Independent Entanglement Witness of Tripartite Entangled States and Its Applications.

Entanglement witness is of great importance in characterizing quantum systems. The imperfections in conventional entanglement witness schemes could lead to the misidentification of a separated state as an entangled state. Measurement-device-independent entanglement witness (MDIEW) has been proposed and demonstrated to resolve the imperfect measurement devices. So far, however, the MDIEW has been restricted to a two-party qubit entangled state. Here, for the first time, we demonstrate MDIEW for multipartite entangled states. We experimentally detect the genuine entanglement and the entanglement structure of a tripartite entangled state based on an eight-photon interferometry. Furthermore, with the verified multipartite entangled state, we demonstrate quantum randomness generation and open-destination quantum key distribution in an measurement-device-independent manner. Our research presents an important step toward building a robust and secure quantum network.

Hypothermic oxygenated perfusion (HOPE) attenuates ischemia/reperfusion injury in the liver through inhibition of the TXNIP/NLRP3 inflammasome pathway in a rat model of donation after cardiac death.

Hypothermic oxygenated perfusion (HOPE) is a relatively new dynamic preservation procedure that has not been widely implemented in liver transplantation despite its advantages. Improved graft protection is one such advantage offered by HOPE and has been attributed to multiple mechanisms, one of which may be the modulation of the thioredoxin-interacting protein (TXNIP)/NOD-like receptor protein 3 (NLRP3) inflammasome pathway. The TXNIP/NLRP3 inflammasome pathway plays a critical role in sterile inflammation under oxidative stress as a result of ischemia/reperfusion injury (IRI). In the current study, we aimed to investigate the graft protection offered by HOPE and its impact on the TXNIP/NLRP3 inflammasome pathway. To simulate conditions of donation after cardiac death (DCD) liver transplantation, rat livers were exposed to 30 min of warm ischemia after cardiac arrest. Livers were then preserved under cold storage (CS) or with HOPE for 3 h. Livers were then subjected to 1 h of isolated reperfusion. Liver injuries were assessed on the isolated perfusion rat liver model system before and after reperfusion. Compared with the CS group, the HOPE group had a significant reduction in liver injury and improvement in liver function. Our findings also revealed that reperfusion injury induced liver damage and activated the TXNIP/NLRP3 inflammasome pathway in DCD rat livers. Pretreatment of DCD rat livers with HOPE inhibited the TXNIP/NLRP3 inflammasome pathway and attenuated liver IRI. Attenuation of oxidative stress as a result of HOPE led to the down-regulation of the TXNIP/NLRP3 inflammasome pathway and thus offered superior protection compared with the traditional CS method of organ preservation.-He, W., Ye, S., Zeng, C., Xue, S., Hu, X., Zhang, X., Gao, S., Xiong, Y., He, X., Vivalda, S., Li, L., Wang, Y., Ye, Q. Hypothermic oxygenated perfusion (HOPE) attenuates ischemia/reperfusion injury in the liver through inhibition of the TXNIP/NLRP3 inflammasome pathway in a rat model of donation after cardiac death.

Donor Treatment With a Hypoxia-Inducible Factor-1 Agonist Prevents Donation After Cardiac Death Liver Graft Injury in a Rat Isolated Perfusion Model.

The protective role of hypoxia-inducible factor-1 (HIF-1) against liver ischemia-reperfusion injury has been well proved. However its role in liver donation and preservation from donation after cardiac death (DCD) is still unknown. The objective of this study was to test the hypothesis that pharmaceutical stabilization of HIF-1 in DCD donors would result in a better graft liver condition. Male SD rats (6 animals per group) were randomly given the synthetic prolyl hydroxylase domain inhibitor FG-4592 (Selleck, 6 mg/kg of body weight) or its vehicle (dimethylsulfoxide). Six hours later, cardiac arrest was induced by bilateral pneumothorax. Rat livers were retrieved 30 min after cardiac arrest, and subsequently cold stored in University of Wisconsin solution for 24 h. They were reperfused for 60 min with Krebs-Henseleit bicarbonate buffer in an isolated perfused liver model, after which the perfusate and liver tissues were investigated. Pretreatment with FG-4592 in DCD donors significantly improved graft function with increased bile production and synthesis of adenosine triphosphate, decreased perfusate liver enzyme release, histology injury scores and oxidative stress-induced cell injury and apoptosis after reperfusion with the isolated perfused liver model. The beneficial effects of FG-4592 is attributed in part to the accumulation of HIF-1 and ultimately increased PDK1 production. Pretreatment with FG-4592 in DCD donors resulted in activation of the HIF-1 pathway and subsequently protected liver grafts from warm ischemia and cold-stored injury. These data suggest that the pharmacological HIF-1 induction may provide a clinically applicable therapeutic intervention to prevent injury to DCD allografts.