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The Qinghai–Tibet Plateau (QTP) is a unique ecological area that has faced issues like diminishing ecosystem stability and increasing pressures on resources and the environment. These issues have arisen as a result of the combined impact of global warming and human activities in recent times. The study of the growth and distribution patterns of schizothoracinae fishes can support guiding policy decisions about the conservation of aquatic species and ecological habitats in the QTP. The investigation on fish resources was carried out in the QTP section of the Nujiang River during the spring and autumn seasons of 2017, 2018, and 2019. A total of seven sampling sites were established based on variations in elevation. According to length–weight relationship (LWR) analysis, Schizothorax nukiangensis mainly displayed a negative allometric growth while Ptychobarbus kaznakovi and Schizopygopsis thermalis mainly showed near isometric growth or positive allometric growth in the QTP section of the Nujiang River. Due to temperature and food abundance, the three schizothoracinae fishes showed better growth performance in autumn than spring. Spatial heterogeneity exhibited a greater influence on the LWR of S. nukiangensis and P. kaznakovi than seasonal variation. In contrast, seasonal variation on S. thermalis showed greater influence than spatial heterogeneity. According to the linear mixed effect model (LMM), both spatial factors and seasons had influence on fish growth in the QTP. Schizothorax nukiangensis was identified as the predominant species from CWL to BS, spanning an altitude range of 1800 to 2700 m. Ptychobarbus kaznakovi was identified as the main species at LL, BB, and BR, occupying an altitude range of 2700 to 3800 m. Schizopygopsis thermalis is primarily distributed at altitudes beyond 4000 m and along the tributary river Yuqu. Principal coordinates analysis (PCOA) and nonmetric multidimensional scaling (NMDS) divided schizothoracinae fish populations into three clusters by spatial differences. Redundancy analysis (RDA) and Monte Carlo Permutation analysis revealed that habitat elevation and water temperature had a significant impact on schizothoracinae fish distribution. This article enhances our understanding of the distribution and environmental adaptation of indigenous fish in the Qinghai–Tibet Plateau.

Objectives: This study aimed to explore the relationship between red blood cell distribution width (RDW) and all-cause mortality in critically ill patients undergoing intra-aortic balloon pumping (IABP) in the intensive care unit (ICU). Methods: This study retrospectively analyzed data from the Medical Information Mart for Intensive Care IV (MIMIC-IV) database. The primary endpoint was the 30-day mortality rate, while the secondary endpoint was the in-hospital mortality rate. Restricted cubic splines were used to assess the dose–response relationship. The receiver operating characteristic (ROC) curve and Kaplan-Meier curve analysis were carried out to evaluate the predictive performance of RDW. Moreover, multiple logistic regression analyses and subgroup analyses were conducted to investigate the relationship between RDW and 30-day mortality. Finally, propensity score matching (PSM) was performed to adjust for the imbalance of covariates. Results: In total, 732 patients were finally identified from the MIMIC-IV database in this study. The RDW of patients in the non-survivor group was significantly higher compared with those in the survivor group (P

Photothermal techniques are infrared remote sensing techniques that have been used for biomedical applications, as well as industrial non-destructive testing (NDT). Machine learning is a branch of artificial intelligence, which includes a set of algorithms for learning from past data and analyzing new data, without being explicitly programmed to do so. In this paper, we first review the latest development of machine learning and its applications in photothermal techniques. Next, we present our latest work on machine learning for data analysis in opto-thermal transient emission radiometry (OTTER), which is a type of photothermal technique that has been extensively used in skin hydration, skin hydration depth profiles, skin pigments, as well as topically applied substances and skin penetration measurements. We have investigated different algorithms, such as random forest regression, gradient boosting regression, support vector machine (SVM) regression, and partial least squares regression, as well as deep learning neural network regression. We first introduce the theoretical background, then illustrate its applications with experimental results.

Abstract Lip‐reading is a process of interpreting speech by visually analysing lip movements. Recent research in this area has shifted from simple word recognition to lip‐reading sentences in the wild. This paper attempts to use phonemes as a classification schema for lip‐reading sentences to explore an alternative schema and to enhance system performance. Different classification schemas have been investigated, including character‐based and visemes‐based schemas. The visual front‐end model of the system consists of a Spatial‐Temporal (3D) convolution followed by a 2D ResNet. Transformers utilise multi‐headed attention for phoneme recognition models. For the language model, a Recurrent Neural Network is used. The performance of the proposed system has been testified with the BBC Lip Reading Sentences 2 (LRS2) benchmark dataset. Compared with the state‐of‐the‐art approaches in lip‐reading sentences, the proposed system has demonstrated an improved performance by a 10% lower word error rate on average under varying illumination ratios.

Lunar in-situ resource utilization (ISRU) has been put on the agenda by many countries. Due to the special material nature and low gravity environment, the lunar regolith demonstrates significantly different behavior from terrestrial geomaterials. However, the systematic understanding of its geotechnical behavior is now seriously restricted by the scarcity of lunar regolith and the difficulty in simulating lunar gravity. A new lunar regolith simulant, termed as China University of Mining and Technology Number One (CUMT-1), has been developed to recover properties of the lunar regolith and simulate the lunar gravity by adopting the recently advanced geotechnical magnetic-similitude-gravity model testing (GMMT) method. The CUMT-1 simulant was prepared by reproducing the in-situ formation and fragmentation of the lunar matrix, which plays a key role in the irregular particle morphology. The mineralogical compositions, particle morphology and gradation, specific gravity, bulk density, void ratio, shear strength, and compressibility were determined. After quantifying the magnetization and magnetic-similitude-gravity characteristics, an application of the cone penetration resistance under low gravity was further given. The obtained results are compared to the values known for lunar regolith samples and other simulants, which demonstrates promising characteristics for use in geotechnical engineering-based and scientific-based applications, especially considering the influence of lunar gravity.

Autophagy and endoplasmic reticulum stress (ER stress) are important in numerous pathological processes in traumatic brain injury (TBI). Growing evidence has indicated that pyroptosis-associated inflammasome is involved in the pathogenesis of TBI. Platelet derived growth factor (PDGF) has been reported to be as a potential therapeutic drug for neurological diseases. However, the roles of PDGF, autophagy and ER stress in pyroptosis have not been elucidated in the TBI. This study investigated the roles of ER stress and autophagy after TBI at different time points. We found that the ER stress and autophagy after TBI were inhibited, and the expressions of pyroptosis-related proteins induced by TBI, including NLRP3, Pro-Caspase1, Caspase1, GSDMD, GSDMD P30, and IL-18, were decreased upon PDGF treatment. Moreover, the rapamycin (RAPA, an autophagy activator) and tunicamycin (TM, an ER stress activator) eliminated the PDGF effect on the pyroptosis after TBI. Interestingly, the sodium 4-phenylbutyrate (4-PBA, an ER stress inhibitor) suppressed autophagy but 3-methyladenine (3-MA, an autophagy inhibitor) not for ER stress. The results revealed that PDGF improved the functional recovery after TBI, and the effects were markedly reversed by TM and RAPA. Taken together, this study provides a new insight that PDGF is a potential therapeutic strategy for enhancing the recovery of TBI.

A multi-mesh trammel net has been developed and used for sampling freshwater fishes. However, little is known about the catch efficiency of the net. This research investigated the catch efficiency of a multi-mesh trammel net (nominal mesh size; 10.0, 30.0, 50.0, and 70.0 mm) for fish sampling in the Yangtze River of China. Catch composition and factors affecting catch per unit effort based on fish number (CPUEN), weight (CPUEW), and species number (CPUES) were analyzed. The results showed that the net was capable of capturing a wide range of fish sizes (total length, 5.5 to 121.0 cm) and species (n = 50). Increasing soak time from 9.4 to 24.0 h resulted in a decrease in CPUEN and CPUEW while a longer soak time increased CPUES. CPUEN, CPUEW, and CPUES varied significantly with fishing locations. The net provides a potential complement to the current fish sampling techniques used in freshwater ecosystems (e.g., large rivers, lakes, and reservoirs). The findings of this research help to improve our understanding of the catch efficiency of the multi-mesh trammel net and provides insight into better designs for gears and methods for sampling diverse fish sizes and species.

Tris (1,3-dichloro-2-propyl) phosphate (TDCIPP), widely applied as flame retardant into a variety of products, can be physically leached out to the aquatic environment. Measurable values of TDCIPP have been found in the environment and within biota. Many toxicological assessments have shown that TDCIPP could cause developmental toxicity and oxidative stress in fish. In this study, we focused on the effects of TDCIPP on the growth and oxidative stress of an important commercial fish species in China, silver carp (Hypophthalmichthys molitrix). Fish larvae was exposed to environmentally relevant concentrations (0.05, 0.5, 5 and 50 μg/L) of TDCIPP for 7, 14 and 28 days. Simultaneously, the transcription levels of genes associated with the growth hormone/insulin-like growth factor (GH/IGF) axis and the antioxidative enzymes were examined. The body length and body mass of silver carp larvae decreased significantly only under exposure to 5 and 50 μg/L of TDCIPP at 14 days compared with the control group, while differences on those paraments were observed at 0.05, 0.5, 5 and 50 μg/L when larvae were exposed for 28 days. The observation evidenced the time- and dose- dependent growth inhibitions caused by TDCIPP on silver carp larvae. Exposure to TDCIPP also decreased the contents of GH and IGF1 in fish attended by significant down-regulation of gh and igf1. Moreover, TDCIPP up-regulated the expression of cat, sod1 and gstt followed by an increase of the activities of catalase (CAT) and superoxide dismutase (SOD) and the levels of malondialdehyde (MDA) and glutathione (GSH), but the activities of glutathione peroxidase (GPX) were decreased. These results suggested that growth inhibition and oxidative stress co-occurred in silver carp larvae after exposure to environmentally relevant concentrations of TDCIPP accompanied by the abnormal expression of genes which associated with the GH/IGF axis and antioxidative enzymes.

N-isopropyl-N-phenyl-1,4-phenylenediamine (IPPD) is used as a ubiquitous antioxidant worldwide, it is an additive in tire rubber easily discharged into the surrounding environment. At present, there is no study concerning the subacute toxicity of IPPD on fish. We used zebrafish embryos (2 h post-fertilization) exposed to IPPD for 5 days at concentrations of 0, 0.0012, 0.0120 and 0.1200 mg/L to investigate its toxic effects of embryonic development, disruption of growth hormone/insulin-like growth factor (GH/IGF) and hypothalamic-pituitary-thyroid (HPT) axis. The results showed that IPPD exposure decreased hatchability, weakened movement ability, reduced body length, and caused multiple types of deformities in zebrafish embryos. The expression of genes involved to GH/IGF and HPT axis were altered after exposure to IPPD in zebrafish larvae. Meanwhile, exposure to IPPD significantly decreased thyroxine (T4) and 3,5,3′-triiodothyronine (T3) contents in larvae, which indicated that HPT axis was in a disturbed state. Moreover, treatment of IPPD decreased the enzymatic activities of superoxide dismutase (SOD) and catalase (CAT) as well as levels of glutathione (GSH). While the contents of malondialdehyde (MDA) were elevated after exposure to IPPD. The present study thus demonstrated that IPPD induced oxidative stress, caused developmental toxicity and disrupted the GH/IGF and HPT axis of zebrafish, which could be responsible for developmental impairment and growth inhibition.

Dam construction on the upper Yangtze River has dramatically altered riverine ecosystems and caused habitat fragmentation of fishes, which might influence the genetic structure of fish populations. In this study, we examined the possible genetic effects of dam construction on Chinese lizard gudgeon (Saurogobio dabryi) populations in the upper Yangtze River, China. Seven populations were sampled, and genetic structure was analyzed using single nucleotide polymorphism (SNP) markers through the specific locus amplified fragment sequencing (SLAF-seq) method. The numbers of SNPs were lower in the upstream populations than in the downstream populations. Genetic similarity was increased from downstream to upstream. The upstream populations of S. dabryi might be more vulnerable to genetic drift than those downstream. Structure analysis indicated three distinct genetic groups of S. dabryi in the upper Yangtze River, among which the genetic differentiation values (Fst) were at a high level. The genetic differentiation of S. dabryi exhibited a close correlation with spatial distance. We did not detect a significant correlation between isolation time and genetic differentiation, suggesting that impacts of dams on the genetic structure of S. dabryi can be relatively minimal on a short time scale. The results quantify the genetic diversity and population structure patterns of S. dabryi after habitat fragmentation caused by dams, which will provide a reference for resource protection and management of this species in the upper Yangtze River.

Mercury (Hg) is a global environmental contaminant, and excessive mercury levels in water can adversely affect the growth of fish. Silver carp (Hypophthalmichthys molitrix) is one of the important freshwater aquaculture fish in China, and its natural resources have been critically declining. However, the effects of Hg2+ exposure on the growth hormone/insulin-like growth factor (GH/IGF) axis and its toxic mechanism are still unclear. In this study, we systematically evaluated the bioaccumulation, histomorphology, antioxidant status, hormone levels, and GH/IGF axis toxicity of juvenile silver carp after exposure to environmental-related concentrations of Hg2+ (0, 0.05, 0.5, 5, and 50 µg/L) for 28 days. Results showed that the Hg2+ bioaccumulation in the liver increased with a rise in Hg2+ concentration and time of exposure. The body length (BL), body weight (BW), weight growth rate (WGR) and specific growth rate (SGR) all decreased after Hg2+ exposure. The serum levels of growth hormones (GH and IGF) and thyroid hormones (T3 and T4) were significantly decreased, and the expressions of GH/IGF axis-related genes were significantly downregulated after 7, 14, and 28 days of Hg2+ exposure. Correlations between the growth parameters and growth hormones or expression of genes in GH/IGF axis further suggested that environmentally relevant concentrations of Hg2+ could have adverse effects on growth. In addition, with increasing Hg2+ exposure, superoxide activities of dismutase (SOD), catalase (CAT), and glutathione S-transferase (GST)and levels of reduced glutathione (GSH) and malondialdehyde (MDA) were significantly increased, whereas the activity of glutathione peroxidase (GPx) significantly decreased and oxidative stress-related gene significantly changed. Liver lesions were mainly characterized by inflammatory cell infiltration, hepatocyte necrosis and fat vacuolation after exposure to Hg2+. Taken together, the results indicate that Hg2+ exposure leads to growth inhibition and oxidative stress in juvenile silver.

N-(1,3-dimethylbutyl)-N′-phenyl-p-phenylenediamine (6PPD) is used as a ubiquitous rubber antioxidant worldwide and has been shown to be potentially toxic to aquatic organisms. In this study, zebrafish embryos were exposed to 6PPD for five days starting at two hours post-fertilization at concentrations of 0, 0.0022, 0.022, and 0.22 mg/L to investigate its effects on embryonic development, the growth hormone/insulin-like growth factor (GH/IGF) axis, and the hypothalamic-pituitary-thyroid (HPT) axis. The results showed that the 96 h LC50 of 6PPD was 2.2 mg/L. 6PPD exposure decreased hatchability, lowered autonomous movement, reduced body length in zebrafish embryos and caused deformities. The hormones levels and the expression of genes related to GH/IGF and HPT axis were altered after exposure to 6PPD in zebrafish larvae. These results indicated that the GH/IGF and HPT axis was disturbed. Moreover, treatment of 6PPD produced oxidative stress in zebrafish embryos. Overall, the present study thus demonstrated that exposure to 0.22 mg/L 6PPD caused developmental toxicity and disrupted the GH/IGF and HPT axis of zebrafish, which could be responsible for developmental impairment and growth inhibition.

Non-indigenous fish invasions have posed a serious threat to global fish diversity and aquatic ecosystem security. Studying the invasion sources, pathways, and genetic mechanisms by means of population genetics is helpful in the management and control of non-indigenous fishes. In this study, we used mitochondrial Cyt b gene, D-Loop region and microsatellite markers to analyze the genetic diversity and population structure of 12 Coilia brachygnathus populations from the native and invaded regions of the Yangtze River Basin in order to explore the invasion sources, pathways, and genetic mechanisms of C. brachygnathus in the Three Gorges Reservoir. The results showed that the main invasion sources of C. brachygnathus in the Three Gorges Reservoir were the Poyanghu Lake, Dongtinghu Lake, Changhu Lake, and other populations in the middle reaches of the Yangtze River. The invasion pathway may have involved moving upstream through the operation of ship locks. The genetic diversity of C. brachygnathus in the invasive populations was significantly smaller than in the native populations, indicating a founder effect. The low genetic diversity did not affect the successful invasion, confirming that genetic diversity and successful invasion do not always have a simple causal relationship. These results can provide basic data for the prevention and control of C. brachygnathus in the Three Gorges Reservoir and study case for understanding the mechanism of invasion genetics.

Promoting blood–spinal cord barrier (BSCB) repair at the early stage plays a crucial role in treatment of spinal cord injury (SCI). Excessive activation of autophagy can prevent recovery of BSCB after SCI. Basic fibroblast growth factor (bFGF) has been shown to promote BSCB repair and locomotor function recovery in SCI. However, the therapeutic effect of bFGF via direct administration on SCI is limited because of its rapid degradation and dilution at injury site. Based on these considerations, controlled release of bFGF in the lesion area is becoming an attractive strategy for SCI repair. At present, we have designed a sustained-release system of bFGF (called ALG-bFGF) using sodium alginate hydrogel, which is able to load large amounts of bFGF and suitable for in situ administration of bFGF in vivo. Here, traumatic SCI mice models and oxygen glucose deprivation (OGD)–stimulated human brain microvascular endothelial cells were performed to explore the effects and the underlying mechanisms of ALG-bFGF in promoting SCI repair. After a single in situ injection of ALG-bFGF hydrogel into the injured spinal cord, sustained release of bFGF from ALG hydrogel distinctly prevented BSCB destruction and improved motor functional recovery in mice after SCI, which showed better therapeutic effect than those in mice treated with bFGF solution or ALG. Evidences have demonstrated that autophagy is involved in maintaining BSCB integrity and functional restoration in animals after SCI. In this study, SCI/OGD exposure–induced significant upregulations of autophagy activation-related proteins (Beclin1, ATG5, LC3II/I) were distinctly decreased by ALG-bFGF hydrogel near the baseline and not less than it both in vivo and in vitro, and this inhibitory effect contributed to prevent BSCB destruction. Finally, PI3K inhibitor LY294002 and KLF4 inhibitor NSC-664704 were applied to further explore the underlying mechanism by which ALG-bFGF attenuated autophagy activation to alleviate BSCB destruction after SCI. The results further indicated that ALG-bFGF hydrogel maintaining BSCB integrity by inhibiting autophagy activation was regulated by PI3K/Akt/FOXO1/KLF4 pathway. In summary, our current study revealed a novel mechanism by which ALG-bFGF hydrogel improves BSCB and motor function recovery after SCI, providing an effective therapeutic strategy for SCI repair.

Gravity is the primary load source in geotechnical engineering, and its effect becomes extremely important in these cases such as lunar research station construction and in situ resource utilization. However, at the current stage, the study on the effect of gravity-induced stress gradients on the behavior of geomaterials is seriously lacking. In this work, the size-dependent behaviour of representative volume element (RVE) of granular matter under the gravity-induced stress gradient is studied. A homogenization theory is proposed firstly, which homogenizes the granular matter into stress gradient continuum through RVE. Then, numerical triaxial loading for RVEs with various heights and particle sizes is carried out under 0∼10 g gravity. The results show that the size effect and its origination appear to have no obvious influence on isotropic compression. However, the macroscopic shear strength, elastic modulus, and volumetric deformation all show size effect dependence, and the gravity-induced stress gradient leads to significant differences between different originations of size effect. The valence, orientation, and elongation degree of microscopic void cells are further analyzed, which suggests that applying of stress gradient results in the evolution of void cells demonstrates a dependence on both the size effect and its origination. The results indicate that the gravity-induced stress gradient and corresponding size effect should be paid sufficient attention to granular mechanics of terrestrial and off-earth engineering.

The aim of this study is to develop new analysis techniques for skin capacitive image stitching and occlusion measurements. Through image stitching, small skin capacitive images can be stitched into large skin capacitive images and, therefore, provide more skin image information. Through occlusion, e.g., keeping the measurement device on skin for a period of time, the skin health status can be studied through time-dependent response curves. Results show that time-dependent skin capacitive imaging curves can tell us the information about transdermal water loss (TEWL) as well as skin surface profiles. By using the structural similarity index measure (SSIM), the TEWL map can be constructed, which shows the water loss map on the skin surface. We first present the theoretical background and then the experimental results.

Lead (Pb) widely exists in the water environment and has severe toxic effects on aquatic organisms. The yellow catfish (Pelteobagrus fulvidraco) is one of the most important commercial species in China, and moreover, its natural populations are declining with the degradation of environmental water quality. However, little is known about the toxic effects of Pb on its immune organs. This study was performed to determine waterborne Pb exposure on bioaccumulation, histomorphology, antioxidant status, apoptotic and immune response in the head kidney and spleen of yellow catfish. Experimental fish were randomly allocated into twelve tanks (3 tanks per group), and the Pb concentrations of the four groups were 0, 5, 50, and 500 μg/L, respectively. The results reflected that the Pb bioaccumulation of the head kidney and spleen increased with increasing Pb exposure dose and time. Severe histological alterations in the head kidney and spleen were observed at concentration 500 ug/L. With increasing Pb exposure concentrations, the plasma activity of superoxide dismutase (SOD) and catalase (CAT) significantly increased after exposure 7 days and 14 days, and the levels significantly decreased after exposure 28 days. The change trend of glutathione (GSH) levels was opposite to that of SOD and CAT at corresponding exposure time. The plasma malondialdehyde (MDA) levels together with the activities of plasma alkaline phosphatase (AKP) and acid phosphatase (ACP) increased significantly with the increasing Pb concentrations. In contrast, the levels of lysozyme (LYZ), complement 3 (C3) and immunoglobulin M (IgM) decreased significantly with increasing Pb concentrations. Moreover, Pb exposure induced transcriptional upregulation of heat shock protein 70 (hsp70), metallothionein (mt), sod, cat, interleukin-10 (il-10), transforming growth factor-β (tgf-β), and tumor necrosis factor-α (tnf-α), bcl-2-associated X protein (bax), and cysteinyl aspartate specific proteinase -9 (caspase-9), genes in the head kidney and spleen tissues, while downregulating the levels of the lyz, c3, igm and B-cell lymphoma-2 (bcl-2) genes. Our data provide evidence that Pb impaired immune function and tissue integrity in yellow catfish through oxidative stress, inflammatory and apoptosis, and the results can serve as reference data to better protect water environments from Pb eco-toxicants.

Stratum corneum (SC) is the outermost skin layer. SC hydration is important for its cosmetic properties and barrier function. SC trans-epidermal water loss (TEWL) measurements and skin water content measurements are two key indexes used for SC characterisation. The instrument stability and accuracy are vitally important when measuring small changes. In this paper, we present our latest study on the effect of sun tan lotion on skin by using skin TEWL and skin water content measurements. We developed techniques to improve the measurement stability and to visualise small changes, as well as developed machine learning algorithms for processing the skin capacitive images. The overall results show that TEWL and skin water content measurements are capable of measuring the subtle changes of skin conditions due to the application of sun tan lotions. The results show that the TEWL values decreased after the sun tan lotion application. The sun tan lotion with SPF 20 had the lowest decrease, whilst the sun tan lotion with SPF 50+ had the highest decrease. The results also show that the skin water content increased after the sun tan lotion application, with SPF 20 having the highest increase, whilst SPF 50+ had the lowest increase.

Abstract Hepatocellular carcinoma (HCC) still presents poor prognosis with low overall survival rates and limited therapeutic options available. Recently, attention has been drawn to peptidomic analysis, an emerging field of proteomics for the exploration of new potential peptide drugs for the treatment of various diseases. However, research on the potential function of HCC peptides is lacking. Here, we analyzed the peptide spectrum in HCC tissues using peptidomic techniques and explored the potentially beneficial peptides involved in HCC. Changes in peptide profiles in HCC were examined using liquid chromatography-mass spectrometry (LC–MS/MS). Analyze the physicochemical properties and function of differently expressed peptides using bioinformatics. The effect of candidate functional peptides on HCC cell growth and migration was evaluated using the CCK-8, colony formation, and transwell assays. Transcriptome sequencing analysis and western blot were employed to delve into the mode of action of potential peptide on HCC. Peptidomic analysis of HCC tissue yielded a total of 8683 peptides, of which 452 exhibited up-regulation and 362 showed down-regulation. The peptides that were differentially expressed, according to bioinformatic analysis, were closely linked to carbon metabolism and the mitochondrial inner membrane. The peptide functional validation identified a novel peptide, PDLC (peptide derived from liver cancer), which was found to dramatically boost HCC cell proliferation through the Ras/Raf/MEK/ERK signaling cascade. Our research defined the peptide’s properties and pattern of expression in HCC and identified a novel peptide, PDLC, with a function in encouraging HCC progression, offering an entirely new potential therapeutic target the disease.