Black Phosphorus Flake-Enabled Wireless Neuromodulation for Epilepsy Treatment.

Epilepsy is a prevalent and severe neurological disorder and generally requires prolonged electrode implantation and tether brain stimulation in refractory cases. However, implants may cause potential chronic immune inflammation and permanent tissue damage due to material property mismatches with soft brain tissue. Here, we demonstrated a nanomaterial-enabled near-infrared (NIR) neuromodulation approach to provide nongenetic and nonimplantable therapeutic benefits in epilepsy mouse models. Our study showed that crystal-exfoliated photothermal black phosphorus (BP) flakes could enhance neural activity by altering the membrane capacitive currents in hippocampus neurons through NIR photothermal neuromodulation. Optical stimulation facilitated by BP flakes in hippocampal slices evoked action potentials with a high spatiotemporal resolution. Furthermore, BP flake-enabled NIR neuromodulation of hippocampus neural circuits can suppress epileptic signals in epilepsy model mice with minimal invasiveness and high biocompatibility. Consequently, nanomaterial-enabled NIR neuromodulation may open up opportunities for nonimplantable optical therapy of epilepsy in nontransgenic organisms.

IndGOterm: a qualitative method for the identification of individually dysregulated GO terms in cancer.

Individual pathway analysis can dissect heterogeneities among different cancer patients and provide efficient guidelines for individualized therapy. However, the existence of the batch effect brings extensive limitations for the application of many individual methods for pathway analysis. Previously, researchers proposed that methods based on within-sample relative expression ordering (REO) of the genes are notably insensitive to 'batch effects'. In this article, we focus on the Gene Ontology (GO) database and propose an individual qualitative GO term analysis method (IndGOterm) based on the REO of genes. Compared with some current widely used single-sample enrichment analysis methods, such as ssGSEA and GSVA, IndGOterm has a predominance of ignoring the batch effects caused by diverse technologies. Through the survival and drug responses analysis, we found IndGOterm could capture more terms connected to cancer than other single-sample enrichment analysis methods. Furthermore, through the application of IndGOterm, we found some terms that present different dysregulation models that manifest heterogenetic in homologous patients. Collectively, these results attested that IndGOterm could capture useful information from patients and be a useful tool to reveal the intrinsic characteristic of cancer. An open-source R statistical analysis package 'IndGOterm' is available at https://github.com/robert19960424/IndGOterm.

Nitrogen Removal Performance and Microbial Community Structure of IMTA Ponds (Apostistius japonicus-Penaeus japonicus-Ulva).

Denitrification and anaerobic ammonium oxidation (anammox) are key processes for nitrogen removal in aquaculture, reducing the accumulated nitrogen nutrients to nitrogen gas or nitrous oxide gas. Complete removal of nitrogen from aquaculture systems is an important measure to solve environmental pollution. In order to evaluate the nitrogen removal potential of marine aquaculture ponds, this study investigated the denitrification and anammox rates, the flux of nitrous oxide (N2O) at the water-air interface, the sediment microbial community structure, and the gene expression associated with the nitrogen removal process in integrated multi-trophic aquaculture (IMTA) ponds (Apostistius japonicus-Penaeus japonicus-Ulva) with different culture periods. The results showed that the denitrification and anammox rates in sediments increased with the increase of cultivation periods and depth, and there was no significant difference in nitrous oxide gas flux at the water-air interface between different cultivation periods (p > 0.05). At the genus and phylum levels, the abundance of microorganisms related to nitrogen removal reactions in sediments changed significantly with the increase of cultivation period and depth, and was most significantly affected by the concentration of particulate organic nitrogen (PON) in sediments. The expression of denitrification gene (narG, nirS, nosZ) in surface sediments was significantly higher than that in deep sediments (p < 0.05), and was negatively correlated with denitrification rate. All samples had a certain anammox capacity, but no known anammox bacteria were found in the microbial diversity detection, and the expression of gene (hzsB) related to the anammox process was extremely low, which may indicate the existence of an unknown anammox bacterium. The data of this study showed that the IMTA culture pond had a certain potential for nitrogen removal, and whether it could make a contribution to reducing the pollution of culture wastewater still needed additional practice and evaluation, and also provided a theoretical basis for the nitrogen removal research of coastal mariculture ponds.

Profile of the gut microbiota of Pacific white shrimp under industrial indoor farming system.

The gut microbial communities interact with the host immunity and physiological functions. In this study, we investigated the bacterial composition in Litopenaeus vannamei shrimp's gut and rearing water under different host (developmental stage: juvenile and adult; health status: healthy and diseased) and environmental factors (temperature 25 °C and 28 °C; and light intensity: low and high). The PCoA analysis showed that all water samples were clustered together in a quarter, whereas the gut samples spread among three quarters. In terms of functional bacteria, gut samples of adult shrimp, healthy adult shrimp, adult shrimp raised at 28 °C, and juvenile shrimp under high light intensity exhibited a higher abundance of Vibrionaceae compared to each other opposite group. Gut samples of juvenile shrimp, infected adult shrimp, juvenile shrimp with low light intensity, and adult shrimp with a water temperature of 25 °C showed a higher abundance of Pseudoaltromonadaceae bacteria compared to each other opposite group. Gut samples of juvenile shrimp, healthy adult shrimp, adult shrimp raised at a water temperature of 28 °C, and juvenile shrimp with high light intensity showed the higher abundance of Firmicutes/Bacteroidota ratio compared to each other opposite group. Our results showed that L. vannamei juveniles are more sensitive to bacterial infections; besides, water temperature of 28 °C and high light intensity groups were both important conditions improving the shrimp gut bacterial composition under industrial indoor farming systems. KEY POINTS: • Bacteria diversity was higher among shrimp intestinal microbiota compared to the rearing water. • Shrimp juveniles are more sensitive to bacterial infection compared to adults. • Water temperature of 28 °C and high light intensity are recommended conditions for white shrimp aquaculture.

The effect of air exposure and re-water on gill microstructure and molecular regulation of Pacific white shrimp Penaeus vannamei.

The Penaeus vannamei is an important shrimp species with enormous commercial and ecological values. In production process, the air exposure resistance is vital for live transportation without water. We tested the air exposure resistant ability of P. vannamei, and carried out gill histological observation and gene expression analysis. The physiology and molecular response to the air exposure stress of P. vannamei was revealed. We found that body weight could affect the air exposure tolerance. Air exposure caused epithelial cell of gill filament shrinking and tissue fluid exudation within half of hour, and triggered oxidative stress response. After retrieved to water, epithelial cell shrinking and tissue fluid exudation recovered gradually, but oxidative and antioxidant response is still going on. Organisms reduced oxidative stress by regulating levels of antioxidants and antioxidant enzymes that remove reactive oxygen species (ROS) and RNA and DNA processing to repair tissue damage, and expression of apoptosis associated-genes altered. Furthermore, the survive shrimps could live steadily more than 5 days, and their gill filament recovered to normal state, proving that the damage of air exposure is reversible. These findings could be considered in the waterless live transportation of P. vannamei.

Characteristics of Household Transmission of COVID-19.

BACKGROUND: Since December 2019, SARS-CoV-2 has extended to most parts of China with >80 000 cases and to at least 100 countries with >60 000 international cases as of 15 March 2020. Here we used a household cohort study to determine the features of household transmission of COVID-19. METHODS: A total of 105 index patients and 392 household contacts were enrolled. Both index patients and household members were tested by SARS-CoV-2 RT-PCR. Information on all recruited individuals was extracted from medical records and confirmed or supplemented by telephone interviews. The baseline characteristics of index cases and contact patients were described. Secondary attack rates of SARS-CoV-2 to contact members were computed and the risk factors for transmission within the household were estimated. RESULTS: Secondary transmission of SARS-CoV-2 developed in 64 of 392 household contacts (16.3%). The secondary attack rate to children was 4% compared with 17.1% for adults. The secondary attack rate to the contacts within the households with index patients quarantined by themselves since onset of symptoms was 0% compared with 16.9% for contacts without quarantined index patients. The secondary attack rate to contacts who were spouses of index cases was 27.8% compared with 17.3% for other adult members in the households. CONCLUSIONS: The secondary attack rate of SARS-CoV-2 in household is 16.3%. Age of household contacts and spousal relationship to the index case are risk factors for transmission of SARS-CoV-2 within a household. Quarantine of index patients at home since onset of symptoms is useful to prevent the transmission of SARS-Co-2 within a household.

Optimization of cell lines as tumour models by integrating multi-omics data.

Cell lines are widely used as in vitro models of tumorigenesis. However, an increasing number of researchers have found that cell lines differ from their sourced tumour samples after long-term cell culture. The application of unsuitable cell lines in experiments will affect the experimental accuracy and the treatment of patients. Therefore, it is imperative to identify optimal cell lines for each cancer type. Here, we review the methods used to evaluate cell lines since 2005. Furthermore, gene expression, copy number and mutation profiles from The Cancer Genome Atlas and the Cancer Cell Line Encyclopedia are used to calculate similarity between tumours and cell lines. Then, the ideal cell lines to use for experiments for eight types of cancers are found by combining the results with Gene Ontology functional similarity. After verification, the optimal cell lines have the same genomic characteristics as their homologous tumour samples. The contaminated cell lines identified in previous research are also determined to be unsuitable in vitro cancer models here. Moreover, our study suggests that some of the commonly used cell lines are not suitable cancer models. In summary, we provide a reference for ideal cell lines to use in in vitro experiments and contribute to improving the accuracy of future cancer research. Furthermore, this research provides a foundation for identifying more effective treatment strategies.

Effects of water recirculation rate on the microbial community and water quality in relation to the growth and survival of white shrimp (Litopenaeus vannamei).

BACKGROUND: Microbial community and its management are crucial to the stabilization of culture environment for recirculating aquaculture system (RAS). Although several studies have been carried out for the microbial community of RAS, few studies were on the RAS for shrimp. Water recirculation ratio is an important factor for the microbial community and the management of RAS. Therefore, low (LC), medium (MC) and high (HC) recirculation ratio systems were set to explore the microbial community constitution of RAS for Litopenaeus vannamei and study the effect of water recirculation rate on it. RESULTS: The bacterial community of bioreactor was mainly dominated by Proteobacteria (41.6-70.7%), followed with Planctomycetes (12.5-31.0%), Bacteroidetes (10.5-26.0%), Actinobacteria (1.1-4.8%) and Verrucomicrobia (1.4-6.8%) phylum. The most dominant family of bioreactor was Rhodobacteraceae or Planctomycetaceae. The bacterial community of culture water was simpler than bioreactor and dominated by Proteobacteria (61.8-96.4%). The dominant bacterial groups of bioreactor and culture water are also different among the three water recirculation rates, and the proportions of dominant groups showed a trend with the variety of water recirculation rate. Water quality indexes including ammonia and nitrite decreased with the increasing of water recirculation rate. According to the growth performance of L. vannamei, shrimp had better performance of growth rate and final weight in MC and HC, however, shrimp had higher survival and yield in LC. Shrimp survival and yield had an inverse correlation with water recirculation rate. CONCLUSIONS: The results demonstrate the microbial community of RAS for shrimp, highlight the importance of further studies on the function of bacterial taxa, and promote the understanding of the effects of water recirculation rate on the microbiota. The findings suggest that water recirculation rate has important impacts on the microbial community, water quality and shrimp growth. Increasing the water recirculation rate could improve the water quality and promote the growth of shrimp. However, the survival rate and yield of L. vannamei are higher under low water recirculation rate. Recirculation rate is an effective method to manage RAS, and its impact on RAS needs further study, especially in the application of low level of water recirculation.

Pharmacokinetic profiles of florfenicol in spotted halibut, Verasper variegatus, at two water temperatures.

The pharmacokinetic profiles of florfenicol in the spotted halibut (Verasper variegatus) were investigated at 15 and 20°C water temperatures, respectively. Florfenicol content in plasma samples was analyzed using an HPLC method. Drug concentration versus time data were best fitted to a three-compartment model after a single intravenous administration (15 mg/kg BW), and fitted to a two-compartment model after an oral administration (30 mg/kg BW) at 15 and 20°C. The florfenicol concentration in the blood increased slowly during the 12 hr following an oral administration at 15°C, with a peak concentration (Cmax ) of 9.1 mg/L, and then declined gradually. The half-lives of absorption, distribution, and elimination phase were 2.18, 5.66 and 14.25 hr, respectively. The bioavailability (F) was calculated to be 24.14%. After an oral administration at 20°C, shorter half-lives of absorption (1.33 hr), distribution (2.51 hr) and elimination (9.71 hr), a higher Cmax (12.2 mg/L), and a similar F (23.98%) were found. Based on the pharmacokinetics and pharmacodynamics, an oral dose of 30 mg/kg BW was suggested to be efficacious for bacterial disease control in spotted halibut farming.

Individualized predictive signatures for 5-fluorouracil-based chemotherapy in right- and left-sided colon cancer.

5-Fluorouracil (5-FU)-based adjuvant chemotherapy (ACT) is widely used for the treatment of colon cancer. Colon cancers with different primary tumor locations are clinically and molecularly distinct, implied through their response to 5-FU-based ACT. In this work, using 69 and 133 samples of patients with stage II-III right-sided and left-sided colon cancer (RCC and LCC) treated with post-surgery 5-FU-based ACT, we preselected gene pairs whose relative expression orderings were significantly correlated with the disease-free survival of patients by univariate Cox proportional hazards model. Then, from the identified prognostic-related gene pairs, a forward-stepwise selection algorithm was formulated to search for an optimal subset of gene pairs that resulted in the highest concordance index, referred to as the gene pair signature (GPS). We identified prognostic signatures, 3-GPS and 5-GPS, for predicting response to 5-FU-based ACT of patients with RCC and LCC, respectively, which were validated in independent datasets of GSE14333 and GSE72970. With the aid of the signatures, the transcriptional and genomic characteristics between the predicted responders and non-responders were explored. Notably, both in RCC and LCC, the predicted responders to 5-FU-based ACT were characterized by hypermutation, whereas the predicted non-responders were characterized by frequent copy number alternations. Finally, in comparison with the established relative expression ordering-based signature, which was developed without considering the differences between RCC and LCC, the newly proposed signatures had a better predictive performance. In conclusion, 3-GPS or 5-GPS can robustly predict response to 5-FU-based ACT for patients with RCC or LCC, respectively, in an individual level.

Differential expression analysis at the individual level reveals a lncRNA prognostic signature for lung adenocarcinoma.

BACKGROUND: Deregulations of long non-coding RNAs (lncRNAs) have been implicated in cancer initiation and progression. Current methods can only capture differential expression of lncRNAs at the population level and ignore the heterogeneous expression of lncRNAs in individual patients. METHODS: We propose a method (LncRIndiv) to identify differentially expressed (DE) lncRNAs in individual cancer patients by exploiting the disrupted ordering of expression levels of lncRNAs in each disease sample in comparison with stable normal ordering. LncRIndiv was applied to lncRNA expression profiles of lung adenocarcinoma (LUAD). Based on the expression profile of LUAD individual-level DE lncRNAs, we used a forward selection procedure to identify prognostic signature for stage I-II LUAD patients without adjuvant therapy. RESULTS: In both simulated data and real pair-wise cancer and normal sample data, LncRIndiv method showed good performance. Based on the individual-level DE lncRNAs, we developed a robust prognostic signature consisting of two lncRNA (C1orf132 and TMPO-AS1) for stage I-II LUAD patients without adjuvant therapy (P = 3.06 × 10-6, log-rank test), which was confirmed in two independent datasets of GSE50081 (P = 1.82 × 10-2, log-rank test) and GSE31210 (P = 7.43 × 10-4, log-rank test) after adjusting other clinical factors such as smoking status and stages. Pathway analysis showed that TMPO-AS1 and C1orf132 could affect the prognosis of LUAD patients through regulating cell cycle and cell adhesion. CONCLUSIONS: LncRIndiv can successfully detect DE lncRNAs in individuals and be applied to identify prognostic signature for LUAD patients.

HIF-1 α had pivotal effects on downregulation of miR-210 decreasing viability and inducing apoptosis in hypoxic chondrocytes.

Hypoxia-inducible factor 1-alpha (HIF-1 α ) and some microRNA (miRNAs) play pivotal roles in response to hypoxia-related physiologic and pathophysiologic responses. Up to date, the regulatory mechanisms of these molecules were largely unknown in chondrocytes. In this study, to study the mechanisms of degradation and homeostasis of chondrocytes, the effects of miRNAs and HIF-1 α on chondrocytes in physiologic environment were investigated. We found that the overexpression of miR-210 and HIF-1 α was present on hypoxia in C28/I2 human chondrocytes significantly by qRT-PCR and western plot. Further study displayed that miR-210 played positive role as a promoter in regulation and its regulated molecules (bcl-xl and PHD-2) in C28/I2 cells on hypoxia by silenced miR-210, silenced HIF-1 α , and adding miR-210. Moreover, downregulated miR-210 could significantly repress the viability and increase the apoptosis in C28/I2 cells on hypoxia, compared to those on normoxia. Furthermore, miR-210 could not modulate viability and apoptosis in C28/I2 cells with the HIF-1 α knockdown on hypoxia and normoxia. Taken together, this study demonstrated that the MiR-210 was involved in an HIF-1 α -dependent way in C28/I2 human chondrocytes for the first time. It also suggested that miR-210 downregulation decreased viability and induced apoptosis in hypoxic chondrocytes depending on HIF-1 α .

Blocked autophagy by miR-101 enhances osteosarcoma cell chemosensitivity in vitro.

The adjuvant chemotherapy, such as cisplatin, doxorubicin, and methotrexate has significantly improved survival of osteosarcoma patients. However, the chemoresistance which arose with the chemotherapy blocks achieving favorable outcomes for some patients and finally led to relapse or metastatic disease. Studies have shown paradoxical functions of autophagy in tumor development, which has been demonstrated by microRNAs. In the present study, we determined the involvement of autophagy during the chemotherapy of osteosarcoma cell line, U-2 OS, and further determined the regulation of miR-101 on the autophagy in the U-2 OS cells. Results demonstrated that doxorubicin treatment of U-2 OS cells induced significantly high level of autophagy-characteristic acidic vesicular organelles (AVOs), and induced significant autophagy related protein expression in U-2 OS cells. While the miR-101 could significantly reduce the doxorubicin-induced AVOs and block the autophagy related protein expression in U-2 OS cells. Moreover, the autophagy blockage by miR-101 sensitized the U-2 OS cells to doxorubicin treatment. In summary, miR-101 blocks autophagy during the chemotherapy in osteosarcoma cells and enhances chemosensitivity in vitro.

Pharmacokinetics of sulfamonomethoxine in tongue sole (Cynoglossus semilaevis) after intravenous and oral administration.

The pharmacokinetic profiles of sulfamonomethoxine (SMM) were investigated in flatfish tongue soles in the present study. After a single injection of SMM (40 mg/kg BW) to caudal vein of tongue sole at 20 °C, plasma drug concentration versus time data were best fitted to a three-compartment model, characterized with 0.2, 5.7, and 80.4 h for the half-life (t 1/2) of fast distribution, slow distribution, and elimination, respectively. The apparent volume of distribution was 0.1 L/kg, and the body clearance was 0.03 L/h/kg. After oral administration of SMM (200 mg/kg BW) to tongue soles at 20 °C, plasma drug concentrations were best fitted to a two-compartment model, of which the mean half-life of absorption (t 1/2ka) and elimination (t 1/2ß ) were 1.7 and 95.7 h, respectively. The maximal absorption concentration (C max) was estimated as 58 mg/L at 2.5 h, and the mean systemic bioavailability (F) was 39.5 % in tongue soles after oral administration.

Nongenetic Precise Neuromodulation and Spatiotemporal Neuroprotection for Epilepsy Therapy via Rationally Designed Multifunctional Nanotransducer.

The precise modulation of electrical activity in specific neuronal populations is paramount for rectifying abnormal neurological functions and is a critical element in the therapeutic arsenal for neurological disorders. However, achieving a balance between minimal invasiveness and robust neuroprotection poses a considerable challenge. Herein, we present a nanoneuromodulation strategy integrating neuroprotective features to effectively address epilepsy with minimal invasiveness and enable wireless functionality. Strategically engineered nanotransducer, adorned with platinum (Pt) decoration with titanium disulfide (TiS2) (TiS2/Pt), enables precise modulation of neuronal electrical activity in vitro and in vivo, ensuring exceptional temporal fidelity under millisecond-precision near-infrared (NIR) light pulses irradiation. Concurrently, TiS2/Pt showcase a pronounced enhancement in enzyme-mimicking activity, offering a robust defense against oxidative neurological injury in vitro. Nanotransducer-enabled wireless neuromodulation with biocatalytic neuroprotective capacity is highly effective in alleviating epileptic high-frequency neural activity and diminishing oxidative stress levels, thereby restoring redox equilibrium. This integrated therapeutic approach reduces the severity of epilepsy, demonstrating minimal invasiveness and obviating the requirements for genetic manipulation and optical fiber implantation, while providing an alternative avenue for neurological disorder treatment.

Automated and ultrasensitive point-of-care glycoprotein detection using boronate-affinity enhanced organic electrochemical transistor patch.

Quantifying trace glycoproteins in biofluids requires ultrasensitive components, but feedback is not available in the current portable platforms of point-of-care (POC) diagnosis technologies. A compact and ultrasensitive bioelectrochemical patch was based on boronate-affinity amplified organic electrochemical transistors (BAAOECTs) for POC use was developed to overcome this dilemma. Benefit from the cascading signal enhancement deriving from boronate-affinity targeting multiple regions of glycoprotein and OECTs' inherent signal amplification capability, the BAAOECTs achieved a detection limit of 300 aM within 25 min, displaying about 3 orders of magnitude improvement in sensitivity compared with the commercial electrochemical luminescence (ECL) kit. By using a microfluidic chip, a microcontroller module, and a wireless sensing system, the testing workflows of the above patch was automated, allowing for running the sample-to-answer pipeline even in a resource-limited environment. The reliability of such portable biosensing platform is well recognized in clinical diagnostic applications of heart failure. Overall, the remarkable enhanced sensitivity and automated workflow of BAAOECTs biosensing platform provide a prospective and generalized design policy for expanding the POC diagnosis capabilities of glycoproteins.

Injectable Mesh-Like Conductive Hydrogel Patch for Elimination of Atrial Fibrillation.

Irregular electrical impulses in atrium are the leading cause of atrial fibrillation (AF), resulting in fatal arrhythmia and sudden cardiac death. Traditional medication and physical therapies are widely used, but generally suffer problems in serious physical damage and high surgical risks. Flexible and soft implants have great potential to be a novel approach for heart diseases therapy. A conductive hydrogel-based mesh cardiac patch is developed for application in AF elimination. The designed mesh patch with rhombic-shaped structure exhibits excellent flexibility, surface conformability, and deformation compliance, making it fit well with heart surface and accommodate to the deformation during heart beating. Moreover, the mechanical elastic and shape-memory properties of the mesh patch enable a minimally invasive injection of the patch into living animals. The mesh patch is implanted on the atrium surface for one month, indicating good biocompatibility and stability. Furthermore, the conductive patch can effectively eliminate AF owing to the conductivity and high charge storage capability (CSC) of the hydrogel. The proposed scheme of cardiac bioelectric signal modulation using conductive hydrogel brings new possibility for the treatment of arrhythmia diseases.

Robust, stretchable bioelectronic interfaces for cardiac pacing enabled by interfacial transfer of laser-induced graphene via water-response, nonswellable PVA gels.

Implantable cardiac pacemakers are crucial therapeutic tools for managing various cardiac conditions. For effective pacing, electrodes should exhibit flexibility, deformability, biocompatibility, and high conductivity/capacitance. Laser-induced graphene (LIG) shows promise due to its exceptional electrical and electrochemical properties. However, the fragility of LIG and the non-stretchability of polyimide substrates pose challenges when interfacing with the beating heart. Here, we present a simple method for fabricating robust, flexible, and stretchable bioelectronic interfaces by transferring LIG via water-responsive, nonswellable polyvinyl alcohol (PVA) gels. PVA solution penetrates the porous structure of LIG and solidifies into PVA xerogel as the solvent evaporates. The robust PVA xerogel enables the smooth transfer of LIG and prevents stretching of the LIG network during this process, which helps maintain its conductivity. When hydrated, the xerogel becomes a stable, nonswellable hydrogel. This gives the LIG-PVA hydrogel (LIG-PVA-H) composites with excellent conductivity (119.7 ± 4.3Ω sq-1), high stretchability (up to 420%), reliability (cyclic stretch under 15% strain, with ∼ 1-time resistance increase), and good stability in phosphate buffered saline. The LIG-PVA-H composites were used as biointerfaces for electrocardiogram signal recording and electrical pacing on rat hearts ex vivo and in vivo, using commercial setups and a custom-built implantable wireless device. This work expands the application of LIG in bioelectronic interfaces and facilitates the development of electrotherapy for cardiac diseases.

Molecular cloning and expression analysis of cytochrome P450 3A gene in the turbot Scophthalmus maximus.

In this study, the cytochrome P450 3A (CYP3A) gene was cloned from the turbot Scophthalmus maximus for the first time using reverse transcription-polymerase chain reaction (RT-PCR) and rapid amplification of cDNA ends approaches. The amino acid sequences were analyzed with corresponding software programs. The cDNA of CYP3A was 1,969 bp in length, which contained a 5'-untranslated region (UTR) of 34 bp, a 3'-UTR of 404 bp and an open reading frame of 1,530 bp encoding a predicted protein of 509 amino acids (GenBank accession No. JN216889). The deduced protein had a molecular weight of 58.09 kDa and an isoelectric point of 5.75. Amino acid sequence alignment indicated that turbot CYP3A shared 60-67% homology with other fish species. It consists of a signal peptide, six conservative substrate recognition sites (SRS 1-6) and the conserved heme-binding motif FXXGXXXCXG in all CYP3As. Quantitative real-time RT-PCR analysis indicated that turbot CYP3A mRNA was widely expressed in liver, kidney, gill, muscle, stomach, intestine, gallbladder and spleen, with the highest level in liver and the lowest in muscle. After oral administration of sulfamethazine, CYP3A expression in all experimental groups enhanced compared with control, and the expression varied with administration time. It suggested that CYP3A expression could be induced by sulfamethazine. Our findings provided molecular characterization and expression profile of turbot CYP3A, and revealed the important role that turbot CYP3A played in drug metabolisms.

Identifying individualized prognostic signature and unraveling the molecular mechanism of recurrence in early-onset colorectal cancer.

BACKGROUND: The incidence and mortality of early-onset colorectal cancer (EOCRC; < 50 years old) is increasing worldwide, with a high recurrence rate. The inherent heterogeneity of EOCRC makes its treatment challenging. Hence, to further understand the biology and reveal the molecular mechanisms of EOCRC, a recurrence risk signature is needed to guide clinical management. METHODS: Based on the relative expression orderings (REOs) of genes in each sample, a prognostic signature was developed and validated utilizing multiple independent datasets. The underlying molecular mechanisms between distinct prognostic groups were explored via integrative analysis of multi-omics data. RESULTS: The prognostic signature consisting of 6 gene pairs (6-GPS) could predict the recurrence risk for EOCRC at the individual level. High-risk EOCRC classified by 6-GPS showed a poor prognosis but a good response to adjuvant chemotherapy. Moreover, high-risk EOCRC was characterized by epithelial-mesenchymal transition (EMT) and enriched angiogenesis, and had higher mutation burden, immune cell infiltration, and PD-1/PD-L1 expression. Furthermore, we identified four genes associated with relapse-free survival in EOCRC, including SERPINE1, PECAM1, CDH1, and ANXA1. They were consistently differentially expressed at the transcriptome and proteome levels between high-risk and low-risk EOCRCs. They were also involved in regulating cancer progression and immune microenvironment in EOCRC. Notably, the expression of SERPINE1 and ANXA1 positively correlated with M2-like macrophage infiltration. CONCLUSION: Our results indicate that 6-GPS can robustly predict the recurrence risk of EOCRC, and that SERPINE1, PECAM1, CDH1, and ANXA1 may serve as potential therapeutic targets. This study provides valuable information for the precision treatment of EOCRC.