Identifying secretory proteins from blood, saliva or other body fluids has become an effective method of diagnosing diseases. Existing secretory protein prediction methods are mainly based on conventional machine learning algorithms and are highly dependent on the feature set from the protein. In this article, we propose a deep learning model based on the capsule network and transformer architecture, SecProCT, to predict secretory proteins using only amino acid sequences. The proposed model was validated using cross-validation and achieved 0.921 and 0.892 accuracy for predicting blood-secretory proteins and saliva-secretory proteins, respectively. Meanwhile, the proposed model was validated on an independent test set and achieved 0.917 and 0.905 accuracy for predicting blood-secretory proteins and saliva-secretory proteins, respectively, which are better than conventional machine learning methods and other deep learning methods for biological sequence analysis. The main contributions of this article are as follows: (1) a deep learning model based on a capsule network and transformer architecture is proposed for predicting secretory proteins. The results of this model are better than the those of existing conventional machine learning methods and deep learning methods for biological sequence analysis; (2) only amino acid sequences are used in the proposed model, which overcomes the high dependence of existing methods on the annotated protein features; (3) the proposed model can accurately predict most experimentally verified secretory proteins and cancer protein biomarkers in blood and saliva.

The nocebo effect, such as nausea and vomiting, is one of the major reasons patients discontinue therapy. The underlying mechanisms remain unknown due to a lack of reliable experimental models. The goal of this study was to develop a new animal model of nocebo-related nausea by combining observational learning and Pavlovian conditioning paradigms.

Moderate traumatic brain injury (TBI) in children often happen when there's a sudden blow to the frontal bone, end with long unconscious which can last for hours and progressive cognitive deficits. However, with regard to the influences of moderate TBI during children adulthood, injury-induced alterations of locomotive ability, long-term memory performance, and hippocampal electrophysiological firing changes have not yet been fully identified. In this study, lateral fluid percussion (LFP) method was used to fabricate moderate TBI in motor and somatosensory cortex of the 6-weeks-old mice. The motor function, learning and memory function, extracellular CA1 neural spikes were assessed during acute and subacute phase. Moreover, histopathology was performed on day post injury (DPI) 16 to evaluate the effect of TBI on tissue and cell morphological changes in cortical and hippocampal CA1 subregions. After moderate LFP injury, the 6-weeks-old mice showed severe motor deficits at the early stage in acute phase but gradually recovered later during adulthood. At the time points in acute and subacute phase after TBI, novel object recognition (NOR) ability and spatial memory functions were consistently impaired in TBI mice; hippocampal firing frequency and burst probability were hampered. Analysis of the altered burst firing shows a clear hippocampal theta rhythm drop. These electrophysiological impacts were associated with substantially lowered NOR preference as compared to the sham group during adulthood. These results suggest that moderate TBI introduced at motorsenory cortex in 6-weeks-old mice causes obvious motor and cognitive deficits during their adulthood. While the locomotive ability progressively recovers, the cognitive deficits persisted while the mice mature as adult mice. The cognitive deficits may be attributed to the general suppressing of whole neural network, which could be labeled by marked reduction of excitability in hippocampal CA1 subregion.

Vitamin A is a fat-soluble micronutrient that is essential for human health. In this study, the daily vitamin A intake of Chinese residents was evaluated by investigating the vitamin A content of various foods. The results show that the dietary intake of vitamin A in common foods was 460.56 ugRAE/day, which is significantly lower than the recommended dietary reference intake of vitamin A (800 ugRAE/day for adult men and 700 ugRAE/day for adult women). Vegetables contributed the most to daily vitamin A dietary intake, accounting for 54.94% of vitamin A intake (253.03 ugRAE/day), followed by eggs, milk, aquatic products, meat, fruit, legumes, coarse cereals, and potatoes. Therefore, an increase in the vitamin A content of vegetables and the fortification of vegetable oils with vitamin A are effective ways to increase vitamin A intake to meet the recommended dietary guidelines in China. The assessment results support the design of fortified foods.

Oncogenic microRNAs are essential components in regulating the gene expression of cancer cells. Especially miR21, which is a major player involved of tumor initiation, progression, invasion and metastasis in several cancers. The delivery of anti-miR21 sequences has significant potential for cancer treatment. Nevertheless, since anti-miR21 sequences are extremely unstable and they need to obtain certain concentration to function, it is intensely difficult to build an effective delivery system for them. The purpose of this work is to construct a self-assembled glutathione (GSH)-responsive system with tumor accumulation capacity for effective anti-miR21 delivery and cancer therapy. A novel drug delivery nanosphere carrying millions of anti-miR21 sequences was developed through the rolling circle transcription (RCT) method. GSH-responsive cationic polymer polyethyleneimine (pOEI) was synthesized to protect the nanosphere from degradation by Dicer or other RNase in normal cells and optimize the pompon-like nanoparticle to suitable size. Dehydroascorbic acid (DHA), a targeting molecule, which is a substrate of glucose transporter 1 (GLUT 1) and highly expressed on malignant tumor cells, was connected to pOEI through PEG, and then the polymer was used for contracting a RNA nanospheres into nanopompons. The anti-miR21 nanopompons showed its potential for effective cancer therapy.

This work aimed to investigate the effect of fucoidan (FPS) on urate transporters induced by uric acid (UA). The results showed that UA stimulated the expression of glucose transporter 9 (GLUT9) and urate transporter 1 (URAT1) in HK-2 cells, and FPS could reverse the effect. Moreover, UA could activate NF-κB, JNK and PI3K/Akt pathways, but both pathway inhibitors and FPS inhibited the UA-induced activation of these three pathways. These data suggested that FPS effectively inhibited the expression induction of reabsorption transporters URAT1 and GLUT9 by UA, through repressing the activation of NF-κB, JNK and PI3K/Akt signal pathways in HK-2 cells. The in vitro research findings support the in vivo results that FPS reduces serum uric acid content in hyperuricemia mice and rats through inhibiting the expression of URAT1 and GLUT9 in renal tubular epithelial cells. This study provides a theoretical basis for the application of FPS in the treatment of hyperuricemia.

Heat stress is an important issue in dairy cattle feeding management affecting summer health and economic efficiency. This experiment combined 16S rDNA sequencing(3,864,982 tags, 30 sequencing data), metagenomic sequencing(1,269,441,128 reads, 18 sequencing data), metabolomics analysis(72 sequencing data) and blood index analysis. Ten cows in each animal type (growing heifers, heifers, and lactating cows) were selected for sample collection in April and August. Here, we characterized both the changes in metabolites, rumen microbial communities and their functional potential and the effects of heat stress on serum biochemical, immune, oxidative stress, and hormonal indices derived from rumen fluid and serum samples from cows during different growth stages and in different climates. The generated data expand the resources for the rumen microbiome related to heat stress and age and provide useful datasets for research on developing therapeutic strategies to achieve high summer milk production in cows. These datasets will help researchers study the effects of heat stress on the physiological metabolism of Holstein cows and the time-dependent changes associated with growth stages.

Physical exercise effectively alleviates chronic pain associated with complex regional pain syndrome type-I. However, the mechanism of exercise-induced analgesia has not been clarified. Recent studies have shown that the specialized pro-resolving lipid mediator resolvin E1 promotes relief of pathologic pain by binding to chemerin receptor 23 in the nervous system. However, whether the resolvin E1-chemerin receptor 23 axis is involved in exercise-induced analgesia in complex regional pain syndrome type-I has not been demonstrated. In the present study, a mouse model of chronic post-ischemia pain was established to mimic complex regional pain syndrome type-I and subjected to an intervention involving swimming at different intensities. Chronic pain was reduced only in mice that engaged in high-intensity swimming. The resolvin E1-chemerin receptor 23 axis was clearly downregulated in the spinal cord of mice with chronic pain, while high-intensity swimming restored expression of resolvin E1 and chemerin receptor 23. Finally, shRNA-mediated silencing of chemerin receptor 23 in the spinal cord reversed the analgesic effect of high-intensity swimming exercise on chronic post-ischemic pain and the anti-inflammatory polarization of microglia in the dorsal horn of the spinal cord. These findings suggest that high-intensity swimming can decrease chronic pain via the endogenous resolvin E1-chemerin receptor 23 axis in the spinal cord.

Diseases of the cardiac system caused by silicon dioxide exposure have captured wide public attention. Upon entering the blood circulation, ultrafine particles have the potential to influence cardiomyocytes, leading to myocardial ischemia or even cardiac failure, and the molecular mechanisms remain to be completely elucidated. In this study, the toxicity of ultrafine particles on cardiomyocytes from rats exposed to silica nanoparticles was observed. Rats were randomly divided into a normal saline control group and three exposure groups (2, 5 and 10 mg/kg·body weight) that were intratracheally treated with 60‑nm silica nanoparticles. Alterations in body weight, routine blood factors and myocardial enzymes, histopathological and microstructural alterations, apoptosis and the expression of apoptosis‑associated proteins were assessed at the end of the exposure period. The silicon levels in the heart and serum, and myocardial enzymes in exposed rats were significantly increased in a dose‑dependent manner. In addition, exposure to the silica nanoparticles caused notable histological and ultrastructural alterations in the hearts of these animals. Furthermore, a significant apoptotic effect was observed in the exposure groups. The present data suggest that silica nanoparticles may enter the circulatory system through the lungs, and are distributed to the heart causing cardiovascular injury. Silica nanoparticle‑induced apoptosis via the mitochondrial pathway may serve an important role in observed cardiac damage.

To date, there is no effective therapy for pathological cardiac hypertrophy, which can ultimately lead to heart failure. Bellidifolin (BEL) is an active xanthone component of Gentianella acuta (G. acuta) with a protective function for the heart. However, the role and mechanism of BEL action in cardiac hypertrophy remain unknown. In this study, the mouse model of cardiac hypertrophy was established by isoprenaline (ISO) induction with or without BEL treatment. The results showed that BEL alleviated cardiac dysfunction and pathological changes induced by ISO in the mice. The expression of cardiac hypertrophy marker genes, including ANP, BNP, and β-MHC, were inhibited by BEL both in mice and in H9C2 cells. Furthermore, BEL repressed the epigenetic regulator bromodomain-containing protein 4 (BRD4) to reduce the ISO-induced acetylation of H3K122 and phosphorylation of RNA Pol II. The Nox4/ROS/ADAM17 signalling pathway was also inhibited by BEL in a BRD4 dependent manner. Thus, BEL alleviated cardiac hypertrophy and cardiac dysfunction via the BRD4/Nox4/ROS axes during ISO-induced cardiac hypertrophy. These findings clarify the function and molecular mechanism of BEL action in the therapeutic intervention of cardiac hypertrophy.

Rab22a-NeoF fusion protein has recently been reported as a promising target for osteosarcoma lung metastasis. However, how this fusion protein is regulated in cells remains unknown. Here, using multiple screenings, it is reported that Rab22a-NeoF1 fusion protein is degraded by an E3 ligase STUB1 via the autophagy receptor NDP52-mediated lysosome pathway, which is facilitated by PINK1 kinase. Mechanistically, STUB1 catalyzes the K63-linked ubiquitin chains on lysine112 of Rab22a-NeoF1, which is responsible for the binding of Rab22a-NeoF1 to NDP52, resulting in lysosomal degradation of Rab22a-NeoF1. PINK1 is able to phosphorylate Rab22a-NeoF1 at serine120, which promotes ubiquitination and degradation of Rab22a-NeoF1. Consistently, by upregulating PINK1, Sorafenib and Regorafenib can inhibit osteosarcoma lung metastasis induced by Rab22a-NeoF1. These findings reveal that the lysosomal degradation of Rab22a-NeoF1 fusion protein is targetable for osteosarcoma lung metastasis, proposing that Sorafenib and Regorafenib may benefit cancer patients who are positive for the RAB22A-NeoF1 fusion gene.

Parkinson's disease (PD) is a common neurodegenerative disease with aggregation of α-synuclein (α-syn) in substantia nigra (SN). The association between the α-syn and ferroptosis in PD remains unclear. GSE49036 was obtained from the Gene Expression Omnibus (GEO) database and intersected with ferroptosis genes. Bioinformatics analysis was used to identify the potential differentially expressed genes (DEGs) included the development of Gene set enrichment analysis (GSEA), Kyoto Encyclopedia of Genes and Genomes (KEGG) and protein-protein interaction (PPI) network. We screened 8 key genes were modulated and crosslinked by 238 miRNAs. Additionally, 5 hub genes were predicted and 38 lncRNAs targeting 3 key miRNAs were revealed. Finally, 3 hub genes (PIK3CA, BRD4, ATM) and the key lncRNA (NEAT1) were verified in neurotoxic PD models. The in vitro experiments showed that PIK3CA and ATM were significantly upregulated or the BRD4 was downregulated in the rotenone treatment and they could be rescued by the specific ferroptosis inhibitor, liproxstatin-1. The expression of the key lncRNA NEAT1 were consistent with the hub genes in same models. This study identified the proposed NEAT1-PIK3CA/ATM ceRNA network may be a specific biomarker in α-syn driving ferroptosis as well as to predict clinical outcomes and therapeutic targets in PD patients.

Rotenone has recently been widely used to establish Parkinson's disease (PD) models to replicate the features of PD. However, the mechanisms involved in rotenone neurotoxicity have not been elucidated. The aim of the present study was to identify the neurotoxicity of rotenone through intraperitoneal injection in mice and to investigate the global changes of phosphorylation proteomic profiles in rotenone-injured SH-SY5Y cells through a label-free proteomic analysis using a PTMScan with LC-MS/MS. ICR (Institute of Cancer Research) mice were intraperitoneally injected with different dosages of rotenone (1 mg/kg/d or 3 mg/kg/d) daily for 21 consecutive days. Rotenone caused a dose-dependent decrease in locomotor activities and a decrease in the number of Nissl-positive and tyrosine hydroxylase (TH)-immunoreactive neurons in the substantia nigra pars compacta (SNpc). Here, 194 phosphopeptides on 174 proteins were detected in SH-SY5Y cells, and 37 phosphosites on 33 proteins displayed statistically significant changes in expression after rotenone injury. The downregulation of phosphorylated Akt and mTOR was further confirmed by western blot analysis. A specific Akt activator, SC79, could protect cell viability and induce autophagy in rotenone-injured SH-SY5Y cells. This study indicates the involvement of the Akt/mTOR (mammalian target of rapamycin) signaling pathway in rotenone-injured SH-SY5Y cells and provides molecular information for the neurotoxicity of rotenone.

Traumatic brain injury (TBI) is a major risk factor to develop epilepsy and cognitive impairments. Neuropeptide oxytocin has been previously evidenced to produce antiepileptic effects. However, the involvement of central oxytocin in TBI-induced epileptic status and cognitive dysfunctions is not fully elucidated. In this study, we aim to investigate the role of oxytocin on a TBI model followed by seizure induction to clarify whether the epilepsy and cognitive deficits could be mitigated by oxytocin. TBI was established by weight drop and epileptic behaviors were induced by pentylenetetrazole (PTZ) injection in mice. Moreover, oxytocin was microinjected into the medial prefrontal cortex (mPFC) to observe the effects on the epilepsy and cognition. The blood-brain barrier (BBB) function and the neuroinflammation were measured by Evans Blue staining and enzyme-linked immunosorbent assays, respectively. Mice exposed to TBI demonstrate increased vulnerability to PTZ-mediated seizures and cognitive disturbances with a decrease in peripheral and brain oxytocin levels. Additionally, TBI reduces oxytocin, disrupts the BBB permeability and triggers neuroinflammation in mPFC in PTZ-treated mice. Intra-mPFC oxytocin simultaneously mitigates epilepsy and cognitive impairments. Finally, oxytocin restores BBB integrity and reduces mPFC inflammation in PTZ-treated TBI mice. These findings showed that intra-mPFC oxytocin suppressed the seizure vulnerability and cognitive deficits in TBI mice. The normalization of BBB integrity and inhibition of neuroinflammation may be involved in the antiepileptic and cognition-improved effects of oxytocin, suggesting that targeting inflammatory procedure in mPFC may decrease the risk to develop epilepsy and cognitive impairments in individuals previously experienced TBI.

Flight loss in birds is as characteristic of the class Aves as flight itself. Although morphological and physiological differences are recognized in flight-degenerate bird species, their contributions to recurrent flight degeneration events across modern birds and underlying genetic mechanisms remain unclear. Here, in an analysis of 295 million nucleotides from 48 bird genomes, we identify two convergent sites causing amino acid changes in ATGLSer321Gly and ACOT7Ala197Val in flight-degenerate birds, which to our knowledge have not previously been implicated in loss of flight. Functional assays suggest that Ser321Gly reduces lipid hydrolytic ability of ATGL, and Ala197Val enhances acyl-CoA hydrolytic activity of ACOT7. Modeling simulations suggest a switch of main energy sources from lipids to carbohydrates in flight-degenerate birds. Our results thus suggest that physiological convergence plays an important role in flight degeneration, and anatomical convergence often invoked may not.

Ischemia-reperfusion injury (IRI) of the liver is a primary cause of post-liver-surgery complications and ischemic preconditioning (IPC) has been verified to protect against ischemia-reperfusion injury. TIM-4 activation plays an important role in macrophage mediated hepatic IRI. This study aimed to determine whether IPC protects against hepatic IRI through inhibiting TIM-4 activation. In this study, a model of warm liver ischemia (90 min) and reperfusion for 6 h was used. Mice were subjected to ischemia-reperfusion injury with or without ischemic preconditioning and TIM4 blocking antibody. Western blot was determined to detect the expression of TIM4 protein and mitochondrial apoptosis-related protein expression. Liver function was evaluated using the level of alanine transaminase (ALT) and aspartate transaminase (AST), cell apoptosis and pathological examination. We found that compared with the control group, ischemic preconditioning reduced IRI by decreasing hepatocyte apoptosis, ALT, AST, CD68 and CD3 positive cells, tissue myeloperoxidase activity(MPO), and downregulating TIM-4 expression. TIM4 blocking could reduce CD68 and CD3 positive cells in liver. Furthermore, activated monocytes transfusion significantly abolished the protect effect of IPC with increased hepatocyte apoptosis, ALT, AST, CD68 and CD3 positive cells while TIM-4 knockdown monocytes lost this effect. These results suggested that IPC protects against hepatic IRI by downregulating TIM-4 and indicated TIM-4 would be a novel therapeutic target to minimize IRI.

High-dose glucocorticoid (GC) therapy always causes osteoporosis partly by inducing osteoblast apoptosis. However, the underlying mechanisms of GC-induced apoptosis remain elusive. Haem oxygenase-1 (HO-1) is a cytoprotective protein that rescues cells from H2O2 or high glucose-induced apoptosis. In bone metabolism, HO-1 also participates in osteoclast and osteoblast differentiation.

MYCN amplification is an independent poor prognostic factor in patients with high-risk neuroblastoma (NB). Further exploring the molecular regulatory mechanisms in MYCN-amplified NB will help to develop novel therapy targets. In this study, methylenetetrahydrofolate dehydrogenase 1 (MTHFD1) was identified as the differentially expressed gene (DEG) highly expressed in MYCN-amplified NB, and it showed a positive correlation with MYCN and was associated with a poor prognosis of NB patients. Knockdown of MTHFD1 inhibited proliferation and migration, and induced apoptosis of NB cells in vitro. Mouse model experiments validated the tumorigenic effect of MTHFD1 in NB in vivo. In terms of the mechanism, ChIP-qPCR and dual-luciferase reporter assays demonstrated that MTHFD1 was directly activated by MYCN at the transcriptional level. As an important enzyme in the folic acid metabolism pathway, MTHFD1 maintained the NADPH redox homeostasis in MYCN-amplified NB. Knockdown of MTHFD1 reduced cellular NADPH/NADP+ and GSH/GSSG ratios, increased cellular reactive oxygen species (ROS) and triggered the apoptosis of NB cells. Moreover, genetic knockdown of MTHFD1 or application of the anti-folic acid metabolism drug methotrexate (MTX) potentiated the anti-tumor effect of JQ1 both in vitro and in vivo. Taken together, MTHFD1 as an oncogene is a potential therapeutic target for MYCN-amplified NB. The combination of MTX with JQ1 is of important clinical translational significance for the treatment of patients with MYCN-amplified NB.

Porcine epidemic diarrhea virus (PEDV) causes severe morbidity and mortality among newborn piglets. It significantly threatens the porcine industry in China and around the globe. To accelerate the developmental pace of drugs or vaccines against PEDV, a deeper understanding of the interaction between viral proteins and host factors is crucial. The RNA-binding protein, polypyrimidine tract-binding protein 1 (PTBP1), is crucial for controlling RNA metabolism and biological processes. The present work focused on exploring the effect of PTBP1 on PEDV replication. PTBP1 was upregulated during PEDV infection. The PEDV nucleocapsid (N) protein was degraded through the autophagic and proteasomal degradation pathways. Moreover, PTBP1 recruits MARCH8 (an E3 ubiquitin ligase) and NDP52 (a cargo receptor) for N protein catalysis and degradation through selective autophagy. Furthermore, PTBP1 induces the host innate antiviral response via upregulating the expression of MyD88, which then regulates TNF receptor-associated factor 3/ TNF receptor-associated factor 6 expression and induces the phosphorylation of TBK1 and IFN regulatory factor 3. These processes activate the type Ⅰ IFN signaling pathway to antagonize PEDV replication. Collectively, this work illustrates a new mechanism related to PTBP1-induced viral restriction, where PTBP1 degrades the viral N protein and induces type Ⅰ IFN production to suppress PEDV replication.

Ganoderma lucidum spores (GLS) exhibit disease prevention properties, but no study has been carried out on the anti-diabetic cardiomyopathy property of GLS. The aim of this study was to evaluate the hyperglycemia-mediated cardiomyopathy protection and mechanisms of GLS in streptozotocin (STZ)induced diabetic rats.