Analysis of 3D pathology samples using weakly supervised AI.

Human tissue, which is inherently three-dimensional (3D), is traditionally examined through standard-of-care histopathology as limited two-dimensional (2D) cross-sections that can insufficiently represent the tissue due to sampling bias. To holistically characterize histomorphology, 3D imaging modalities have been developed, but clinical translation is hampered by complex manual evaluation and lack of computational platforms to distill clinical insights from large, high-resolution datasets. We present TriPath, a deep-learning platform for processing tissue volumes and efficiently predicting clinical outcomes based on 3D morphological features. Recurrence risk-stratification models were trained on prostate cancer specimens imaged with open-top light-sheet microscopy or microcomputed tomography. By comprehensively capturing 3D morphologies, 3D volume-based prognostication achieves superior performance to traditional 2D slice-based approaches, including clinical/histopathological baselines from six certified genitourinary pathologists. Incorporating greater tissue volume improves prognostic performance and mitigates risk prediction variability from sampling bias, further emphasizing the value of capturing larger extents of heterogeneous morphology.

A Multimodal Generative AI Copilot for Human Pathology.

The field of computational pathology[1,2] has witnessed remarkable progress in the development of both task-specific predictive models and task-agnostic self-supervised vision encoders[3,4]. However, despite the explosive growth of generative artificial intelligence (AI), there has been limited study on building general purpose, multimodal AI assistants and copilots[5] tailored to pathology. Here we present PathChat, a vision-language generalist AI assistant for human pathology. We build PathChat by adapting a foundational vision encoder for pathology, combining it with a pretrained large language model and finetuning the whole system on over 456,000 diverse visual language instructions consisting of 999,202 question-answer turns. We compare PathChat against several multimodal vision language AI assistants and GPT4V, which powers the commercially available multimodal general purpose AI assistant ChatGPT-4[7]. PathChat achieved state-of-the-art performance on multiple-choice diagnostic questions from cases of diverse tissue origins and disease models. Furthermore, using open-ended questions and human expert evaluation, we found that overall PathChat produced more accurate and pathologist-preferable responses to diverse queries related to pathology. As an interactive and general vision-language AI Copilot that can flexibly handle both visual and natural language inputs, PathChat can potentially find impactful applications in pathology education, research, and human-in-the-loop clinical decision making.

Integration analysis of transcriptome and proteome profiles brings new insights of somatic embryogenesis of two eucalyptus species.

BACKGROUND: Somatic embryogenesis (SE) is recognized as a promising technology for plant vegetative propagation. Although previous studies have identified some key regulators involved in the SE process in plant, our knowledge about the molecular changes in the SE process and key regulators associated with high embryogenic potential is still poor, especially in the important fiber and energy source tree - eucalyptus. RESULTS: In this study, we analyzed the transcriptome and proteome profiles of E. camaldulensis (with high embryogenic potential) and E. grandis x urophylla (with low embryogenic potential) in SE process: callus induction and development. A total of 12,121 differentially expressed genes (DEGs) and 3,922 differentially expressed proteins (DEPs) were identified in the SE of the two eucalyptus species. Integration analysis identified 1,353 (131 to 546) DEGs/DEPs shared by the two eucalyptus species in the SE process, including 142, 13 and 186 DEGs/DEPs commonly upregulated in the callus induction, maturation and development, respectively. Further, we found that the trihelix transcription factor ASR3 isoform X2 was commonly upregulated in the callus induction of the two eucalyptus species. The SOX30 and WRKY40 TFs were specifically upregulated in the callus induction of E. camaldulensis. Three TFs (bHLH62, bHLH35 isoform X2, RAP2-1) were specifically downregulated in the callus induction of E. grandis x urophylla. WGCNA identified 125 and 26 genes/proteins with high correlation (Pearson correlation > 0.8 or < -0.8) with ASR3 TF in the SE of E. camaldulensis and E. grandis x urophylla, respectively. The potential target gene expression patterns of ASR3 TF were then validated using qRT-PCR in the material. CONCLUSIONS: This is the first time to integrate multiple omics technologies to study the SE of eucalyptus. The findings will enhance our understanding of molecular regulation mechanisms of SE in eucalyptus. The output will also benefit the eucalyptus breeding program.

Diverse mode operation fiber laser mode-locked by nonlinear multimode interference.

We present an all-fiber passively mode-locked (ML) laser with a nonlinear multimode interference (NLMI)-based saturable absorber (SA) capable of generating five pulse modes. The SA consists of two centrally aligned graded index multimode fiber (GIMF) with different diameters (105-50 µm) and features a widely adjustable transmission with saturable/reverse-saturable absorption. Based on this, dissipative soliton (DS), Q-switched rectangular pulse (QRP), dissipative soliton resonance (DSR), noise-like pulse (NLP) and bright-dark pulse pairs (BDP) are observed at three dispersions without additional filter. The DS has a pulse energy, bandwidth and duration of up to 1.15 nJ, 17.98 nm and ∼2.78 ps. The achievable pulse duration and energy of DSR and NLP are 5.21, 48.06 ns and 4.53, 5.12 nJ, respectively. Furthermore, it is demonstrated that the BDP is superimposed by a chair-case pulse (CP) and a rectangular pulse (RP) belonging to orthogonal polarization states. The versatility, flexibility, simplicity and energy scalability of the large-core hybrid GIMF-SA, make it interesting and highly attractive in ultrafast photonics.

Programming cell-surface signaling by phase-separation-controlled compartmentalization.

The landscape of cell-surface signaling is formidably complex. Robust tools capable of manipulating the spatiotemporal distribution of cell-surface proteins (CSPs) for dissecting signaling are in high demand. Some CSPs are regulated via multivalency-driven liquid-liquid phase separation (LLPS). Employing the robustness and versatility of LLPS, we decided to engineer LLPS-based tools for precisely manipulating CSPs. We generated membrane-tethering LLPS systems by fusing multivalent modular phase-separation scaffold pairs with CSP binders. Phase separation of the scaffold pairs, concomitant compartmentalization of CSPs on membranes, and cluster-dependent signaling outputs of CSPs require membrane recruitment of one or both scaffolds. We also engineered orthogonal phase-separation systems to segregate CSPs into mutually exclusive compartments. The engineered phase-separation systems can robustly cluster individual CSPs, co-cluster two or more CSPs, or segregate different CSPs into distinct compartments on cell surfaces. These tools will enable the dissection of complicated cell-signaling landscapes with high precision.

Development and validation of a lung metastases-predicting nomogram for intermediate- to high-risk differentiated thyroid carcinoma patients.

Aim: This research aimed to construct a clinical model for forecasting the likelihood of lung metastases in differentiated thyroid carcinoma (DTC) with intermediate- to high-risk. Methods: In this study, 375 DTC patients at intermediate to high risk were included. They were randomly divided into a training set (70%) and a validation set (30%). A nomogram was created using the training group and then validated in the validation set using calibration, decision curve analysis (DCA) and receiver operating characteristic (ROC) curve. Results: The calibration curves demonstrated excellent consistency between the predicted and the actual probability. ROC analysis showed that the area under the curve in the training cohort was 0.865 and 0.845 in the validation cohort. Also, the DCA curve indicated that this nomogram had good clinical utility. Conclusion: A user-friendly nomogram was constructed to predict the lung metastases probability with a high net benefit.

[Box: see text].

Genetic variants in m5C modification genes are associated with survival of patients with HBV-related hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors with a high mortality rate. The 5-methylcytosine (m5C), a type of RNA modification, plays crucial regulatory roles in HCC carcinogenesis, metastasis, and prognosis. However, a few studies have investigated the effect of genetic variants in m5C modification genes on survival of patients with hepatitis B virus (HBV)-related HCC. In the present study, we evaluated associations between 144 SNPs in 15 m5C modification genes and overall survival (OS) in 866 patients with the HBV-related HCC. Expression quantitative trait loci (eQTL) analysis and differential expression analysis were conducted to investigate biological mechanisms. As a result, we identified that two SNPs (NSUN7 rs2437325 A > G and TRDMT1 rs34434809 G > C) were significantly associated with HBV-related HCC OS with adjusted allelic hazards ratios of 1.25 (95% confidence interval = 1.05-1.48 and P = 0.011) and 1.19 (1.02-1.38 and P = 0.027), respectively, with a trend of combined risk genotypes (Ptrend < 0.001). Moreover, the results of eQTL analyses showed that both NSUN7 rs2437325 G and TRDMT1 rs34434809 C alleles were associated with a reduced mRNA expression level in 208 normal liver tissues (P = 0.007 and P < 0.001, respectively). Taken together, genetic variants in the m5C modification genes may be potential prognostic biomarkers of HBV-related HCC after hepatectomy, likely through mediating the mRNA expression of corresponding genes.

Reconfiguration of DNA nanostructures induced by enzymatic ligation treatment.

Enzymatic ligation is a popular method in DNA nanotechnology for structural enforcement. When employed as stability switch for chosen components, ligation can be applied to induce DNA nanostructure reconfiguration. In this study, we investigate the reinforcement effect of ligation on addressable DNA nanostructures assembled entirely from short synthetic strands as the basis of structural reconfiguration. A careful calibration of ligation efficiency is performed on structures with programmable nicks. Systematic investigation using comparative agarose gel electrophoresis enables quantitative assessment of enhanced survivability with ligation treatment on a number of unique structures. The solid ligation performance sets up the foundation for the ligation-based structural reconfiguration. With the capability of switching base pairing status between permanent and transient (ON and OFF) by a simple round of enzymatic treatment, ligation induced reconfiguration can be engineered for DNA nanostructures accordingly.

DIA-Based Proteomic Analysis Reveals MYOZ2 as a Key Protein Affecting Muscle Growth and Development in Hybrid Sheep.

Hybridization of livestock can be used to improve varieties, and different hybrid combinations produce unique breeding effects. In this study, male Southdown and Suffolk sheep were selected to hybridize with female Hu sheep to explore the effects of male parentage on muscle growth and the development of offspring. Using data-independent acquisition technology, we identified 119, 187, and 26 differentially abundant proteins (DAPs) between Hu × Hu (HH) versus Southdown × Hu (NH), HH versus Suffolk × Hu (SH), and NH versus SH crosses. Two DAPs, MYOZ2 and MYOM3, were common to the three hybrid groups and were mainly enriched in muscle growth and development-related pathways. At the myoblast proliferation stage, MYOZ2 expression decreased cell viability and inhibited proliferation. At the myoblast differentiation stage, MYOZ2 expression promoted myoblast fusion and enhanced the level of cell fusion. These findings provide new insights into the key proteins and metabolic pathways involved in the effect of male parentage on muscle growth and the development of hybrid offspring in sheep.

U-Shaped Association between Serum Chloride Levels and In-Hospital Mortality in Patients with Congestive Heart Failure in Intensive Care Units.

Serum chloride level has clinical significance in the prognosis of heart failure. Little is known regarding the association between serum chloride levels and in-hospital mortality in patients with heart failure.This retrospective study used clinical data obtained from the Medical Information Mart for Intensive Care Database. The study cohort comprised patients who were categorized on the basis of their serum chloride levels, and the primary endpoint was in-hospital mortality. To assess the impact of serum chloride levels at the time of intensive care unit admission on in-hospital mortality, we used various statistical approaches, including multivariable logistic regression models, a generalized additive model, and a two-piecewise linear regression model. In addition, subgroup analysis was conducted to examine the robustness of the main findings.This study comprised 15,983 participants. When compared with the reference group (Q5), the groups with the highest (Q7) and lowest (Q1) blood chloride levels exhibited increased in-hospital mortality, with fully adjusted odds ratios (ORs) of 1.36 [95% confidence interval (CI): 1.08-1.71] and 1.25 (95% CI: 1-1.56), respectively. A U-shaped relationship was observed between blood chloride levels and in-hospital mortality, with the lowest risk observed at a threshold of 105.017 mmol/L. The effect sizes and corresponding CIs below and above the threshold were 0.969 (95% CI: 0.957-0.982) and 1.039 (95% CI: 1.002-1.076), respectively. Stratified analyses demonstrated the robustness of this correlation.The relationship between serum chloride levels and in-hospital mortality in patients with heart failure was U-shaped, with an inflection point of 105.017 mmol/L.

Dilute RuCo Alloy Synergizing Single Ru and Co Atoms as Efficient and CO-Resistant Anode Catalyst for Anion Exchange Membrane Fuel Cells.

Ruthenium (Ru) is considered a promising candidate catalyst for alkaline hydroxide oxidation reaction (HOR) due to its hydrogen binding energy (HBE) like that of platinum (Pt) and its much higher oxygenophilicity than that of Pt. However, Ru still suffers from insufficient intrinsic activity and CO resistance, which hinders its widespread use in anion exchange membrane fuel cells (AEMFCs). Here, we report a hybrid catalyst (RuCo)NC+SAs/N-CNT consisting of dilute RuCo alloy nanoparticles and atomically single Ru and Co atoms on N-doped carbon nanotubes The catalyst exhibits a state-of-the-art activity with a high mass activity of 7.35 A mgRu -1. More importantly, when (RuCo)NC+SAs/N-CNT is used as an anode catalyst for AEMFCs, its peak power density reaches 1.98 W cm-2, which is one of the best AEMFCs properties of noble metal-based catalysts at present. Moreover, (RuCo)NC+SAs/N-CNT has superior long-time stability and CO resistance. The experimental and density functional theory (DFT) results demonstrate that the dilute alloying and monodecentralization of the exotic element Co greatly modulates the electronic structure of the host element Ru, thus optimizing the adsorption of H and OH and promoting the oxidation of CO on the catalyst surface, and then stimulates alkaline HOR activity and CO tolerance of the catalyst.

Identification of WUSCHEL-related homeobox gene and truncated small peptides in transformation efficiency improvement in Eucalyptus.

BACKGROUND: The WUSCHEL-related Homeobox (WOX) genes, which encode plant-specific homeobox (HB) transcription factors, play crucial roles in regulating plant growth and development. However, the functions of WOX genes are little known in Eucalyptus, one of the fastest-growing tree resources with considerable widespread cultivation worldwide. RESULTS: A total of nine WOX genes named EgWOX1-EgWOX9 were retrieved and designated from Eucalyptus grandis. From the three divided clades marked as Modern/WUS, Intermediate and Ancient, the largest group Modern/WUS (6 EgWOXs) contains a specific domain with 8 amino acids: TLQLFPLR. The collinearity, cis-regulatory elements, protein-protein interaction network and gene expression analysis reveal that the WUS proteins in E. grandis involve in regulating meristems development and regeneration. Furthermore, by externally adding of truncated peptides isolated from WUS specific domain, the transformation efficiency in E. urophylla × E. grandis DH32-29 was significant enhanced. The transcriptomics data further reveals that the use of small peptides activates metabolism pathways such as starch and sucrose metabolism, phenylpropanoid biosynthesis and flavonoid biosynthesis. CONCLUSIONS: Peptides isolated from WUS protein can be utilized to enhance the transformation efficiency in Eucalyptus, thereby contributing to the high-efficiency breeding of Eucalyptus.

Identification and functional characterization of two trans-isopentenyl diphosphate synthases and one squalene synthase involved in triterpenoid biosynthesis in Platycodon grandiflorus.

MAIN CONCLUSION: Two trans-isopentenyl diphosphate synthase and one squalene synthase genes were identified and proved to be involved in the triterpenoid biosynthesis in Platycodon grandiflorus. Platycodon grandiflorus is a commonly used traditional Chinese medicine. The main bioactive compounds of P. grandiflorus are triterpenoid saponins. The biosynthetic pathway of triterpenoid saponins in P. grandiflorus has been preliminarily explored. However, limited functional information on related genes has been reported. A total of three trans-isopentenyl diphosphate synthases (trans-IDSs) genes (PgFPPS, PgGGPPS1 and PgGGPPS2) and one squalene synthase (SQS) gene (PgSQS) in P. grandiflorus were screened and identified from transcriptome dataset. Subcellular localization of the proteins was defined based on the analysis of GFP-tagged. The activity of genes was verified in Escherichia coli, demonstrating that recombinant PgFPPS catalysed the production of farnesyl diphosphate. PgGGPPS1 produced geranylgeranyl diphosphate, whereas PgGGPPS2 did not exhibit catalytic activity. By structural identification of encoding genes, a transmembrane region was found at the C-terminus of the PgSQS gene, which produced an insoluble protein when expressed in E. coli but showed no apparent effect on the enzyme function. Furthermore, some triterpenoid saponin synthesis-related genes were discovered by combining the component content and the gene expression assays at the five growth stages of P. grandiflorus seedlings. The accumulation of active components in P. grandiflorus was closely associated with the expression level of genes related to the synthesis pathway.

Continuous chromatin state feature annotation of the human epigenome.

MOTIVATION: Segmentation and genome annotation (SAGA) algorithms are widely used to understand genome activity and gene regulation. These methods take as input a set of sequencing-based assays of epigenomic activity, such as ChIP-seq measurements of histone modification and transcription factor binding. They output an annotation of the genome that assigns a chromatin state label to each genomic position. Existing SAGA methods have several limitations caused by the discrete annotation framework: such annotations cannot easily represent varying strengths of genomic elements, and they cannot easily represent combinatorial elements that simultaneously exhibit multiple types of activity. To remedy these limitations, we propose an annotation strategy that instead outputs a vector of chromatin state features at each position rather than a single discrete label. Continuous modeling is common in other fields, such as in topic modeling of text documents. We propose a method, epigenome-ssm-nonneg, that uses a non-negative state space model to efficiently annotate the genome with chromatin state features. We also propose several measures of the quality of a chromatin state feature annotation and we compare the performance of several alternative methods according to these quality measures. RESULTS: We show that chromatin state features from epigenome-ssm-nonneg are more useful for several downstream applications than both continuous and discrete alternatives, including their ability to identify expressed genes and enhancers. Therefore, we expect that these continuous chromatin state features will be valuable reference annotations to be used in visualization and downstream analysis. AVAILABILITY AND IMPLEMENTATION: Source code for epigenome-ssm is available at https://github.com/habibdanesh/epigenome-ssm and Zenodo (DOI: 10.5281/zenodo.6507585). SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Wavelength selection of dual-mechanism LiDAR with reflection and fluorescence spectra for plant detection.

With the continuous expansion and refinement in plant detection range, reflection, and fluorescence spectra present great research potentials and commercial values. Referring technical advantages with hyperspectral and fluorescence lidar for monitoring plants, the synchronous observation with reflection and fluorescence signals achieved by one lidar system has attracted wide attention. This paper plans to design and construct a dual-mechanism lidar system that can obtain spatial information, reflection, and fluorescence signals simultaneously. How to select the optimal detected bands to the dual-mechanism lidar system for monitoring plants is an essential step. Therefore, this paper proposes a two-step wavelength selection method to determine the optimal bands combination by considering the spectral characteristic of reflection and fluorescence signals themselves, and the hardware performance of lidar units comprehensively. The optimal bands combination of 4 reflection bands of 481 nm, 541 nm, 711.5 nm, 775.5 nm, and 2 fluorescence bands of 686.5 nm, 737 nm was determined. Besides, compared with the original reflection or fluorescence bands, the overall accuracy and average accuracy of the optimal band combination were respectively improved by 2.51%, 15.45%, and 7.8%, 29.06%. The study demonstrated the reliability and availability of the two-step wavelength selection method, and can provide references for dual-mechanism lidar system construction.

Single-Crystalline Li2Sn(IO3)6 Microwires: Combining Optical-Waveguiding and Frequency-Doubling Functions.

High-quality single-crystalline Li2Sn(IO3)6 microwires (MWs) have been successfully prepared by using a facile hydrothermal method. The as-synthesized Li2Sn(IO3)6 MWs exhibit regular hexagonal prism morphology, excellent surface smoothness, and remarkable diameter uniformity. The optical propagation loss has been determined to be as low as 0.026 dB µm-1 at 785 nm wavelength, implying the low-loss optical waveguiding capability of the Li2Sn(IO3)6 MWs. The effective frequency-doubling conversions of the fundamental frequency light source in the wavelength range from 916 to 1560 nm have been observed, and the second-harmonic generation (SHG) conversion efficiency has been measured to be 2.1% with a 1560 nm fundamental pump source (pulse duration of 10 ns, and average power of 9.06 nW) transmitted through a 1.32-µm-diameter and 300-µm-length Li2Sn(IO3)6 MW. These intriguing optical waveguiding and strong SHG conversion capabilities of the Li2Sn(IO3)6 MWs suggest its potential applications for photonic devices in micrometer scale.

Microvesicles-hydrogel breaks the cycle of cellular senescence by improving mitochondrial function to treat osteoarthritis.

BACKGROUND: Osteoarthritis (OA) is an age-related disease characterised by the accumulation of senescent chondrocytes, which drives its pathogenesis and progression. Senescent cells exhibit distinct features, including mitochondrial dysfunction and the excessive accumulation and release of reactive oxygen species (ROS), which are highly correlated and lead to a vicious cycle of increasing senescent cells. Stem cell therapy has proven effective in addressing cellular senescence, however, it still has issues such as immune rejection and ethical concerns. Microvesicles (MVs) constitute the primary mechanism through which stem cell therapy exerts its effects, offering a cell-free approach that circumvents these risks and has excellent anti-ageing potential. Nonetheless, MVs have a short in vivo half-life, and their secretion composition varies considerably under diverse conditions. This study aims to address these issues by constructing a ROS-responsive hydrogel loaded with pre-stimulant MVs. Through responding to ROS levels this hydrogel intelligently releases MVs, and enhancing mitochondrial function in chondrocytes to improving cellular senescence. RESULT: We employed Interferon-gamma (IFN-γ) as a stem cell-specific stimulus to generate IFN-γ-microvesicles (iMVs) with enhanced anti-ageing effects. Simultaneously, we developed a ROS-responsive carrier utilising 3-aminophenylboronic acid (APBA)-modified silk fibroin (SF) and polyvinyl alcohol (PVA). This carrier served to protect MVs, prolong longevity, and facilitate intelligent release. In vitro experiments demonstrated that the Hydrogel@iMVs effectively mitigated cell senescence, improved mitochondrial function, and enhanced cellular antioxidant capacity. In vivo experiments further substantiated the anti-ageing capabilities of the Hydrogel@iMVs. CONCLUSION: The effect of MVs can be significantly enhanced by appropriate pre-stimulation and constructing a suitable carrier. Therefore, we have developed a ROS-responsive hydrogel containing IFN-γ pre-stimulated iMVs to target the characteristics of ageing chondrocytes in OA for therapeutic purposes. Overall, this novel approach effectively improving mitochondrial dysfunction by regulating the balance between mitochondrial fission and fusion, and the accumulation of reactive oxygen species was reduced, finally, alleviates cellular senescence, offering a promising therapeutic strategy for OA.

Molecular Mechanism of m6A Methylation Modification Genes METTL3 and FTO in Regulating Heat Stress in Sheep.

Heat stress is an important environmental factor affecting livestock production worldwide. Primary hepatocytes and preadipocytes derived from Hu sheep were used to establish a heat stress model. Quantitative reverse transcriptase-PCR (qRT-PCR) analysis showed that heat induction significantly increased the expression levels of heat stress protein (HSP) genes and the N6-methyladenosine (m6A) methylation modification genes: methyltransferase-like protein 3 (METTL3), methyltransferase-like protein 14 (METTL14), and fat mass and obesity associated protein (FTO). Heat stress simultaneously promoted cell apoptosis. Transcriptome sequencing identified 3980 upregulated genes and 2420 downregulated genes related to heat stress. A pathway enrichment analysis of these genes revealed significant enrichment in fatty acid biosynthesis, degradation, and the PI3K-Akt and peroxisome proliferator-activated receptor (PPAR) signaling pathways. Overexpression of METTL3 in primary hepatocytes led to significant downregulation of HSP60, HSP70, and HSP110, and significantly increased mRNA m6A methylation; FTO interference generated the opposite results. Primary adipocytes showed similar results. Transcriptome analysis of cells under METTL3 (or FTO) inference and overexpression revealed differentially expressed genes enriched in the mitogen-activated protein kinase (MAPK) signaling pathways, as well as the PI3K-Akt and Ras signaling pathways. We speculate that METTL3 may increase the level of m6A methylation to inhibit fat deposition and/or inhibit the expression of HSP genes to enhance the body's resistance to heat stress, while the FTO gene generated the opposite molecular mechanism. This study provides a scientific basis and theoretical support for sheep feeding and management practices during heat stress.

The Role of MMP-9 and MMP-9 Inhibition in Different Types of Thyroid Carcinoma.

Matrix metalloproteinase-9 (MMP-9), one of the most investigated and studied biomarkers of the MMPs family, is a zinc-dependent proteolytic metalloenzyme whose primary function is degrading the extracellular matrix (ECM). It has been proved that MMP-9 expression elevates in multiple pathological conditions, including thyroid carcinoma. MMP-9 has a detectable higher level in malignant or metastatic thyroid tumor tissues than in normal or benign tissues and acts as an additional marker to distinguish different tumor stages because of its close correlations with clinical features, such as lymph node metastasis, TNM stage, tumor size and so on. Natural and non-natural MMP-9 inhibitors suppress its expression, block the progression of diseases, and play a role in therapy consequently. MMP-9 inhibitory molecules also assist in treating thyroid tumors by suppressing the proliferation, invasion, migration, metastasis, viability, adhesion, motility, epithelial-mesenchymal transition (EMT), and other risk factors of different thyroid cancer cells. In a word, discovering and designing MMP-9 inhibitors provide great therapeutic effects and promising clinical values in various types of thyroid carcinoma.

Quantum information in holographic duality.

We give a pedagogical review of how concepts from quantum information theory build up the gravitational side of the anti-de Sitter/conformal field theory correspondence. The review is self-contained in that it only presupposes knowledge of quantum mechanics and general relativity; other tools-including holographic duality itself-are introduced in the text. We have aimed to give researchers interested in entering this field a working knowledge sufficient for initiating original projects. The review begins with the laws of black hole thermodynamics, which form the basis of this subject, then introduces the Ryu-Takayanagi proposal, the Jafferis-Lewkowycz-Maldacena-Suh (JLMS) relation, and subregion duality. We discuss tensor networks as a visualization tool and analyze various network architectures in detail. Next, several modern concepts and techniques are discussed: Rényi entropies and the replica trick, differential entropy and kinematic space, modular Berry phases, modular minimal entropy, entanglement wedge cross-sections, bit threads, and others. We discuss the extent to which bulk geometries are fixed by boundary entanglement entropies, and analyze the relations such as the monogamy of mutual information, which boundary entanglement entropies must obey if a state has a semiclassical bulk dual. We close with a discussion of black holes, including holographic complexity, firewalls and the black hole information paradox, islands, and replica wormholes.