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Long noncoding RNAs (lncRNAs) are noncoding RNAs with length greater than 200 nt. The biological roles and mechanisms mediated by lncRNAs have been extensively investigated. Hypoxia is a proven microenvironmental factor that promotes solid tumor metastasis. Epithelial-mesenchymal transition (EMT) is one of the major mechanisms induced by hypoxia to contribute to metastasis. Many lncRNAs have been shown to be induced by hypoxia and their roles have been delineated. In this review, we focus on the hypoxia-inducible lncRNAs that interact with protein/protein complex and chromatin/epigenetic factors, and the mechanisms that contribute to metastasis. The role of a recently discovered lncRNA RP11-390F4.3 in hypoxia-induced EMT is discussed. Whole genome approaches to delineating the association between lncRNAs and histone modifications are discussed. Other topics related to hypoxia-induced tumor progression but require further investigation are also mentioned. The clinical significance and treatment strategy targeted against lncRNAs are discussed. The review aims to identify suitable lncRNA targets that may provide feasible therapeutic venues for hypoxia-involved cancers.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a global crisis, urgently necessitating the development of safe, efficacious, convenient-to-store, and low-cost vaccine options. A major challenge is that the receptor-binding domain (RBD)-only vaccine fails to trigger long-lasting protective immunity if used alone for vaccination. To enhance antigen processing and cross-presentation in draining lymph nodes (DLNs), we developed an interferon (IFN)-armed RBD dimerized by an immunoglobulin fragment (I-R-F). I-R-F efficiently directs immunity against RBD to DLNs. A low dose of I-R-F induces not only high titers of long-lasting neutralizing antibodies (NAbs) but also more comprehensive T cell responses than RBD. Notably, I-R-F provides comprehensive protection in the form of a one-dose vaccine without an adjuvant. Our study shows that the pan-epitope modified human I-R-F (I-P-R-F) vaccine provides rapid and complete protection throughout the upper and lower respiratory tracts against a high-dose SARS-CoV-2 challenge in rhesus macaques. Based on these promising results, we have initiated a randomized, placebo-controlled, phase I/II trial of the human I-P-R-F vaccine (V-01) in 180 healthy adults, and the vaccine appears safe and elicits strong antiviral immune responses. Due to its potency and safety, this engineered vaccine may become a next-generation vaccine candidate in the global effort to overcome COVID-19.

Most studies focus on the first and second signals of T cell activation. However, the roles of cytokines in immunotherapy are not fully understood, and cytokines have not been widely used in patient care. Clinical application of cytokines is limited due to their short half-life in vivo, severe toxicity at therapeutic doses, and overall lack of efficacy. Several modifications have been engineered to extend their half-life and increase tumor targeting, including polyethylene glycol conjugation, fusion to tumor-targeting antibodies, and alteration of cytokine/cell receptor-binding affinity. These modifications demonstrate an improvement in either increased antitumor efficacy or reduced toxicity. However, these cytokine engineering strategies may still be improved further, as each strategy poses advantages and disadvantages in the delicate balance of targeting tumor cells, tumor-infiltrating lymphocytes, and peripheral immune cells. This review focuses on selected cytokines, including interferon-α, interleukin (IL)-2, IL-15, IL-21, and IL-12, in both preclinical studies and clinical applications. We review next-generation designs of these cytokines that improve half-life, tumor targeting, and antitumor efficacy. We also present our perspectives on the development of new strategies to potentiate cytokine-based immunotherapy.

Human retina development involves multiple well-studied signaling pathways that promote the genesis of a wide arrange of different cell types in a complex architectural structure. Human embryonic stem cells (hESCs)-derived retinal organoids could recapitulate the human retinal development. We performed single-cell RNA-seq of retinal organoids from 5 time points (D36, D66, D96, D126, D186) and identified 9 distinct populations of cells. In addition, we analyzed the molecular characteristics of each main population and followed them from genesis to maturity by pseudotime analysis and characterized the cell-cell interactions between different cell types. Interestingly, we identified insulin receptor (INSR) as a specifically expressed receptor involved in the genesis of photoreceptors, and pleiothropin (PTN)-protein tyrosine phosphatase receptor type Z1 (PTPRZ1) as a mediator of a previously unknown interaction between Muller and retinal progenitor cells. Taken together, these findings provide a rich transcriptome-based lineage map for studying human retinal development and modeling developmental disorders in retinal organoids.

A case of abducens nerve palsy was introduced in this paper. A female patient, 37 years old, she complained double vision for 4 days. Acupuncture was applied and no other treatment was cooperated. Main acupoints included Jīngming (睛明BL1), Chengqi (承泣ST1), Tongzĭliao (瞳子髎GB1), Shuĭgōu (水沟GV26), belly side of lateral rectus muscle and Fēngchi (风池GB20). After consecutive treatment for 10 days, the orientation of the right eye was corrected and the patient narrated that double vision disappeared, the symptoms such as dizziness, distending pain of the eyeball disappeared. This therapy provided a new thought and approach to the treatment of abducens nerve palsy.

Objectives: Comparative analysis of laboratory data in moderate-to-severe COVID-19 patients presenting with or without ground-glass opacities (GGOs). Methods: This retrospective study examined 61 patients with moderate-to-severe COVID-19, as defined by the report of the WHO-China Joint Mission on COVID-19. All patients were admitted to the Department of Infectious Diseases, Wuhan Union Hospital from Dec 28, 2019 to Feb 22, 2020 and classified into a GGO group or a non-GGO group based on CT results. The clinical characteristics and laboratory data of the two groups were compared. Data were analyzed using univariate and multivariate analysis, and using receiver operating characteristic (ROC) analysis. Results: Forty-five patients were in the GGO group (73.8%, 21 females, 24 males, mean age 54.8±17.8 years) and 16 were in the non-GGO group (26.2%, 11 females, 5 males, mean age 53±14.9 years). The levels of IL-2, IL-4, and IFN-γ were greater in the GGO group (all P

Plant exosome-like nanovesicles, being innately replete with bioactive lipids, proteins, RNA, and other pharmacologically active molecules, offer unique morphological and compositional characteristics as natural nanocarriers. Furthermore, their compelling physicochemical traits underpin their modulative role in physiological processes, all of which have fostered the concept that these nanovesicles may be highly proficient in the development of next-generation biotherapeutic and drug delivery nanoplatforms to meet the ever-stringent demands of current clinical challenges. This review systemically deals with various facets of plant exosome-like nanovesicles ranging from their origin and isolation to identification of morphological composition, biological functions, and cargo-loading mechanisms. Efforts are made to encompass their biotherapeutic roles by elucidating their immunological modulating, anti-tumor, regenerative, and anti-inflammatory roles. We also shed light on re-engineering these nanovesicles into robust, innocuous, and non-immunogenic nanovectors for drug delivery through multiple stringent biological hindrances to various targeted organs such as intestine and brain. Finally, recent advances centered around plant exosome-like nanovesicles along with new insights into transdermal, transmembrane and targeting mechanisms of these vesicles are also elucidated. We expect that the continuing development of plant exosome-like nanovesicle-based therapeutic and delivery nanoplatforms will promote their clinical applications.

A Gram-staining-negative bacterium, strain HHU 13199T, was isolated from a marine sediment sample collected from South China Sea (119°19.896’E, 19°41.569’N) at a depth of 2918 m. The 16S rRNA gene sequence analysis indicated that strain HHU 13199T represents a member of the genus Salinimonas with the highest sequence similarity (99.8%) to the type strain S. iocasae KX18D6T. However, the average nucleotide identity values and digital DNA–DNA hybridization between strain HHU 13199T and closely related members of the genus Salinimonas were all below the cut-off level (95–96 % and 70%, respectively) for species delineation. This strain grew with sea salt of 0.5–18% (w/v) (optimum, 2–5%), but no growth observed when using NaCl instead. The major fatty acids are C16:0, summed feature 3 (C16:1ω7c and/or C16:1ω6c), and summed feature 8 (C18:1ω7c and/or C18:1ω6c). The predominant isoprenoid quinone is ubiquinone-8. The polar lipids mainly consist of phosphatidylethanolamine, and phosphatidylglycerol. Genomic characterization revealed that strain HHU 13199T harbors a distinct type I-F CRISPR-Cas system and plenty of genes associated with heavy metal resistance, including a transposon (Tn6333) conferring mercury resistance. In addition, a phylogenetic tree based on the bac120 core genes suggested that the genus Salinimonas should be a subclade within Alteromonas. On the basis of the phenotypic, phylogenetic and chemotaxonomic characterizations, strain HHU 13199T represents a novel species of the genus Salinimonas, for which the name Salinimonas profundi sp. nov. is proposed. The type strain is HHU 13199T (= KCTC 72837T = MCCC 1K04127T).

Background Pleomorphic adenoma (PA) is the most common benign tumor that occurs in the salivary glands; however, tracheobronchial PA is rarely observed. To the best of our knowledge, fewer than 50 cases have been reported in the literature. We report a 49-year-old woman who had been treated for asthma for 2 years before being diagnosed with PA of the trachea. Case summary A 49-year-old woman was referred to our hospital due to dyspnea upon exertion and chronic cough with wheezing for 2 years. Laboratory tests showed an elevated white blood cell count, absolute neutrophil count, and percentage of neutrophils. A chest computerized tomography scan showed a well-defined, soft-tissue density lesion measuring 2.4 cm × 2.1 cm in the lower trachea. Flexible bronchoscopy revealed that nearly 90% of the tracheal lumen was obstructed. The histopathological and immunohistochemistry features suggested PA of the trachea. Furthermore, we review the characteristics of 29 patients with tracheobronchial PA over the last 30 years. Conclusion Tracheobronchial PA occurs without gender predominance, mostly in the lower or upper trachea, and has a low recurrence rate. The median age at diagnosis is 48 years. The most common symptoms are cough, stridor, dyspnea, and wheezing.

Phenylalanine ammonia lyase (PAL) is the first committed step in the formation of phenylpropanoids, and catalyses the deamination of L-phenylalanine (L-Phe) to yield cinnamic acid. While PALs are common in plants, PAL genes involved in alkaloid biosynthesis in Cephalotaxus hainanensis have never been described. To obtain better knowledge of PAL genes and their number and function involved in Cephalotaxus alkaloid biosynthesis four PAL genes were screened and cloned. In vitro enzymatic analysis showed that all four PAL recombinant proteins could convert L-Phe to product trans-cinnamic acid, and showed strict substrate specificity. Moreover, the expression profiles of four ChPALs were analysed using qRT-PCR, which showed that they had higher transcript levels in roots and stems, and that different ChPALs displayed different response sensitivities and change patterns in response to stimuli. Several metabolic compounds were measured in stimulated leaves using UPLC-MS, and indicating the concentration of Cephalotaxus alkaloids and cinnamic acid in leaves subjected to different conditions. These concentrations increased significantly after treatment with 100 mM NaCl, 100 mM mannitol, 100 μM SA and 10 μM ABA. The expression levels of four PAL genes showed indications of upregulation after treatment. These results supply an important foundation for further research on candidate genes involved in the biosynthesis of Cephalotaxus alkaloids.

The long history of cultivation and breeding has left a variety of footprints in the genomes of Asian cultivated rice (Oryza sativa L.). In this study, we focus on two types of genomic footprints, introgression and differentiation, in a population of more than 1200 Chinese rice accessions. We found that a Xian/indica and a temperate Geng/japonica accession respectively contained an average of 19.3-Mb and 6.8-Mb alien introgressed chromosomal segments, of which many contained functional sequence variants, quantitative trait loci, or genes controlling flowering, grain, and resistance traits. Notably, we found most introgressions, including the known heterotic loci Hd3a and TAC1, were distributed differentially between the female and male parents of three-line indica hybrid rice, indicating their potential contribution to heterosis. We also found many differentiated regions between subgroups within a subpopulation contained agronomically important loci, such as DTH7, Hd1 for heading date, and qCT7 for cold tolerance, providing new candidates for studying local adaptation or heterosis. Tracing these footprints allows us to better understand the genetic exchange or differentiation underlying agronomic traits in modern Chinese rice cultivars. These findings also provide potential targets for rice genetic research and breeding.

Immune checkpoint blockade therapies have shown clinical promise in a variety of cancers, but how tumor-infiltrating T cells are activated remains unclear. In this study, we explore the functions of PD-L1 on dendritic cells (DCs), which highly express PD-L1. We observe that PD-L1 on DC plays a critical role in limiting T cell responses. Type 1 conventional DCs are essential for PD-L1 blockade and they upregulate PD-L1 upon antigen uptake. Upregulation of PD-L1 on DC is mediated by type II interferon. While DCs are the major antigen presenting cells for cross-presenting tumor antigens to T cells, subsequent PD-L1 upregulation protects them from killing by cytotoxic T lymphocytes, yet dampens the antitumor responses. Blocking PD-L1 in established tumors promotes re-activation of tumor-infiltrating T cells for tumor control. Our study identifies a critical and dynamic role of PD-L1 on DC, which needs to be harnessed for better invigoration of antitumor immune responses., The role of PD-L1 expression on tumor-infiltrating immune cells in promoting tumor immune escape is not fully understood. Here, the authors show that PD-L1 expression by dendritic cells plays a crucial role in hindering anti-tumor T cell responses and is essential for the therapeutic efficacy of PD-L1 blockade.

We retrospectively evaluated the echocardiographic data of ambrisentan-treated patients with pulmonary arterial hypertension (PAH) (NCT01808313).Change from baseline in right ventricle (RV) systolic function, right heart structure, and pulmonary artery systolic pressure (PASP) prognosis to Weeks 12 and 24 was evaluated by echocardiography.In the overall population, the mean tissue Doppler-derived tricuspid lateral annular systolic velocity (S') increased by 0.6 cm/s at both Weeks 12 (p 0.001) and 24 (p = 0.004) and tricuspid annular plane systolic excursion increased by 0.13 cm at Week 12 and 0.15 cm at Week 24 (both p 0.001). A marked decrease in transverse and longitudinal RV and RA diameter at Weeks 12 and 24 was observed. A significant decrease in diastolic eccentricity index at both Weeks 12 (-0.1; p = 0.02) and 24 (-0.1; p = 0.001). The decrease in PASP from baseline was significant at both Weeks 12 (-9.5 mmHg; p0.001) and 24 (-7.6 mmHg; p0.001), while a decrease in the estimated right atrium pressure was found to be significant at Week 24 (-0.8mmHg; p = 0.01).Significant improvements in a number of RV echocardiographic parameters were observed at Weeks 12 and 24 after ambrisentan treatment in patients with PAH.

The purpose of this work was to use near-infrared reflectance spectroscopy (NIRS) to investigate the spectral characteristics and frontal lobe activation in patients with obsessive-compulsive disorder (OCD) during a verbal fluency task. Thirty-seven patients with OCD, who met the diagnostic criteria of International Classification of Diseases 10 (ICD-10), were recruited. The total score of the Symptom Checklist (SCL-90, grade 1-5) was ≥160 points. The total score of the Yale-Brown Obsessive Compulsive Scale was ≥7 points. The changes in frontal lobe blood flow were measured by NIRS when completing a verbal fluency task. Then, the differences between obsessive-compulsive thoughts and obsessive-compulsive behaviors in OCD, and the concentration variation of oxygenate hemoglobin (Oxy-Hb) and deoxygenate hemoglobin (Deoxy-Hb) were investigated. The difference was significant (P

The application of resting state functional MRI (RS-fMRI) in Parkinson’s disease (PD) was widely performed using standard statistical tests, however, the machine learning (ML) approach has not yet been investigated in PD using RS-fMRI. In current study, we utilized the mean regional amplitude values as the features in patients with PD (n = 72) and in healthy controls (HC, n = 89). The t-test and linear support vector machine were employed to select the features and make prediction, respectively. Three frequency bins (Slow-5: 0.0107–0.0286 Hz; Slow-4: 0.0286–0.0821 Hz; conventional: 0.01–0.08 Hz) were analyzed. Our results showed that the Slow-4 may provide important information than Slow-5 in PD, and it had almost identical classification performance compared with the Combined (Slow-5 and Slow-4) and conventional frequency bands. Similar with previous neuroimaging studies in PD, the discriminative regions were mainly included the disrupted motor system, aberrant visual cortex, dysfunction of paralimbic/limbic and basal ganglia networks. The lateral parietal lobe, such as right inferior parietal lobe (IPL) and supramarginal gyrus (SMG), was detected as the discriminative features exclusively in Slow-4. Our findings, at the first time, indicated that the ML approach is a promising choice for detecting abnormal regions in PD, and a multi-frequency scheme would provide us more specific information.

Acute intermittent porphyria (AIP) is a rare inherited disorder, which is caused by the partial deficiency of hydroxymethylbilane synthase (HMBS), an enzyme of the heme biosynthetic pathway. Abdominal pain, neuropsychiatric disturbance and neuropathy are the typical manifestations of the disease. Complications such as posterior reversible encephalopathy syndrome (PRES), a rare type of brain lesion present on MRI, are also observed in patients with AIP. The present study reports on the case of a 36‑year‑old Chinese female patient with AIP and PRES. Genomic DNA were obtained from peripheral blood leukocytes and genomic regions of the HMBS gene were amplified as 2 fragments, which together contained all the exons and flanking intronic regions. Sanger sequencing of the amplified DNA fragments from the patient and the patient's family revealed a novel frameshift deletion (c.405‑406delAA) in exon 8 of the HMBS gene. This mutation leads to a subsequent truncated protein (p.Glu135AspfsX74). The recombinant mutant protein had 62% activity relative to the wild‑type protein but similar thermostability. It was confirmed that this novel mutation was the cause of AIP. Accumulation of D‑aminolevulinic acid (ALA) due to HMBS dysfunction is a potential mechanism of PRES. The manifestation of PRES may be associated with ALA‑induced cytotoxicity and the destruction of the blood‑brain barrier. In summary, in the present study, a novel pathogenic HMBS mutation was identified, expanding on the molecular heterogeneity of AIP.

Photoreceptors are critical components of the retina and play a role in the first step of the conversion of light to electrical signals. The differentiation and degeneration of photoreceptors are regulated by specific genes and proteins. With the development of epigenetic approaches, scientists have discovered that histone modifications, such as acetylation, methylation, ubiquitylation, and phosphorylation, may modulate the processes of photoreceptor differentiation and degeneration. Histone acetylation is regulated by two opposing classes of enzymes, namely, histone acetyltransferases (HATs) and histone deacetylases (HDACs), which add and remove acetyl groups to and from target histones, respectively, causing changes in transcriptional activity. Herein, we review the effects of HATs and HDACs on the differentiation and degeneration of photoreceptors and discuss the underlying mechanisms of these effects.

Transdermal drug delivery is favored in clinical therapy because of its ability to overcome the shortcomings of the first pass elimination of the liver caused by traditional oral administration and the irreversibility of the injection. However, skin stratum corneum (SC) forms a big barrier that precludes most of the biomacromolecules. Herein, we propose the engineering of transformed Escherichia coli (E. coli) derived outer membrane vesicles, detoxified by lysozymes (named TEVs) as the carrier for transdermal drug delivery. TEVs were derived from transgenic E. coli and then modified by an integrin alpha(v)beta(3) (αvβ3) targeting peptide and co-loaded with indocyanine green (ICG) (P-TEVs-G). TEVs were shown to have excellence in penetrating through intact SC without any additional enhancement, followed by targeting of melanoma cells. TEVs are promising nanoplatforms for transdermal and tumor targeting drug delivery with high efficacy and biosafety, possessing great potential in the treatment of superficial tumors.

Amyloid-β (Aβ) plaque deposits in the brain are considered to be one of the main pathological markers of Alzheimer's disease (AD). The sequential proteolytic cleavage of amyloid precursor protein (APP) by the aspartyl proteases β-site APP-cleaving enzyme 1 (BACE1) and γ-secretase produces Aβ. Therefore, BACE1 inhibition is a very attractive target for the treatment of AD. Our previous work identified a DNA aptamer named A1 that can bind to BACE1 with high affinity and specificity and exhibits a distinct inhibitory effect on BACE1 activity in an AD cell model. The purpose of this research was to test the effect of aptamer A1 in Tg6799 mice. Four-month-old Tg6799 mice were randomly divided into two groups and treated with aptamer A1 and ineffective aptamer A1scr, respectively, by intracerebroventricular injection. Subsequent behavioral experiments showed that treatment with the aptamer A1 improved the cognitive abilities of the AD mice. Western blot indicated that BACE1 and soluble amyloid precursor protein β (sAPPβ) expression significantly decreased in the A1-treated mice. Moreover, aptamer A1 reduced the content of Aβ42 and the number and density of senile plaques in AD mice. Therefore, our results indicate that aptamer A1 is a novel specific and potent BACE1 inhibitor and is a promising potential target for the treatment of AD.

Supplemental Digital Content is available in the text, Background: Post-operative pain is unpleasant for patients and may worsen surgical recovery. Peri-operative multimodal analgesia has been used for many years; however, its efficacy still needs improvement. In the present study, a thorough peri-operative pain counseling and stratified management program based on risk assessment was implemented, with the goal of improving post-operative analgesia and patient satisfaction. Methods: This prospective, controlled, pilot study included 361 patients who underwent elective surgery. Of these 361 patients, 187 received peri-operative pain risk assessment and stratified analgesia and counseling (stratified analgesia group), while 174 received conventional multimodal analgesia (conventional group). The two groups were compared regarding the post-operative pain intensity, rescue analgesia administration, post-operative quality of recovery as assessed via the quality of recovery 40 questionnaire, total dosage of peri-operative opioids, analgesic satisfaction, and analgesic costs. Results: Compared with the conventional group, the stratified analgesia group reported decreased pain intensity during motion at 24 h post-operatively and required lower dosages of rescue analgesia (P = 0.03). The total quality of recovery 40 questionnaire score and the scores for physical wellbeing and pain were significantly better in the stratified analgesia group than the conventional group (P = 0.04); the stratified analgesia group also reported better scores for analgesic satisfaction (P = 0.03) and received lower dosages of opioids (P = 0.03). Analgesic costs were lower in the stratified analgesia group than the conventional group; the cost-effective ratio was 109 in the conventional group and 62 in the stratified analgesia group. Conclusions: The analgesic efficacy was improved by the implementation of stratified analgesia based on surgical pain risk assessment and counseling. This stratified analgesia protocol increased the patients’ analgesic satisfaction and improved the quality of recovery without increasing healthcare costs. The present findings may help improve the efficacy of peri-operative multimodal analgesia in clinical practice. Clinical Trial Registry: NCT02728973; https://clinicaltrials.gov/ct2/show/NCT02728973?term=NCT02728973&draw=2&rank=1.

—Isodon hsiwenii, a new species from Yunnan in Southwest China, is here described and illustrated. In order to clarify the phylogenetic placement of the new species within Isodon, Bayesian and maximum likelihood analyses based on two nuclear ribosomal DNA regions and four plastid DNA regions for 71 Asian Isodon species were conducted. The results indicate that I. hsiwenii is a member of the largest and poorly resolved Clade III, as sister species of I. hirtellus. Isodon hsiwenii can be distinguished from I. hirtellus by various morphological differences.

Histamine H1 receptor (H1R) and histamine H4 receptor (H4R) are essential in allergic inflammation. The roles of H4R have been characterized in T cell subsets, whereas the functional properties of H4R in monocytes remain unclear. In the current study, the responses of H4R in peripheral monocytes from patients with allergic rhinitis (AR) were investigated. The results confirmed that H4R has the functional effects of mediating cytokine production (i.e., down-regulating IFN-γ and up-regulating IL-6) in cells from a monocyte cell line following challenge with histamine. We demonstrated that when monocytes from AR patients were stimulated with allergen extracts of house dust mite (HDM), IFN-γ secretion was dependent on H4R activity, but IL-6 secretion was based on H1R activity. Furthermore, a combination of H1R and H4R antagonists was more effective at blocking the inflammatory response in monocytes than treatment with either type of antagonist alone.

Periplaneta americana L. is a Traditional Chinese Medicine that has been used in clinic treatment of various diseases for a long history. However, the therapeutic potential and the underlying mechanism of Periplaneta americana L. in the skin wound therapy was not investigated comprehensively yet. This study aims to investigate the influence of the crude ethanol extract of PAL in the different wound stages including: (1) the migration and chemotaxis to skin cells in the first stage; (2) proliferation and cells cycle of skin cells in the second stage; (3) remodeling effect and secretion of growth factors, collagens in the third stage; (4) as well as the influence in the blood vessels regeneration in the late stage. The crude ethanol extract of PAL was shown to (1) promote the keratinocytes proliferation and regulate the cells cycle of fibroblasts significantly; (2) stimulate the migration of keratinocytes and fibroblasts obviously; (3) enhance the EGF and VEGF secretion both in vitro & in vivo; (4) accelerate the wound healing, collagen synthesis and angiogenesis. The crude ethanol extract of KFX was shown a promising therapeutic agent for the wound therapy with great efficacy to accelerate the wound healing with improved quality.

Modulation of the embryonic stem cell state is beneficial for elucidating the innate mechanisms of development and regenerative medicine. Ion flux plays important roles in modulating the transition between stemness and differentiation in mouse embryonic stem cells (mESCs). Optogenetics is a novel tool for manipulating ion flux. To investigate the impact of optical stimulation on embryonic stem cells, optogenetically engineered V6.5 mESCs were used to measure the depolarization mediated by ChR2 on the proliferation, self-renewal, and differentiation of mESCs. Blue light stimulation significantly inhibited ChR2-GFP-V6.5 ESC proliferation and disrupted the cell cycle progression, reducing the proportion of cells in the S phase. Interestingly, optical stimulation could inhibit ChR2-GFP-V6.5 ESC self-renewal and trigger differentiation by activating the extracellular regulated protein kinase (ERK) signaling pathway. Our data suggest that membrane potential changes play pivotal roles in regulating the proliferation, self-renewal and initiation of differentiation of mESCs.

Background Memantine, a low- to moderate-affinity uncompetitive N-methyl-D-aspartate receptor antagonist, has been shown to improve cognitive functions in animal models of Alzheimer’s disease (AD). Here we treated APP/PS1 AD mice with a therapeutic dose of memantine (20 mg/kg/day) and examined its underlying mechanisms in ameliorating cognitive defects. Methods Using behavioral, electrophysiological, optogenetic and morphology approaches to explore how memantine delay the pathogenesis of AD. Results Memantine significantly improved the acquisition in Morris water maze (MWM) in APP/PS1 mice without affecting the speed of swimming. Furthermore, memantine enhanced EC to CA1 synaptic neurotransmission and promoted dendritic spine regeneration of EC neurons that projected to CA1. Conclusions Our study reveals the underlying mechanism of memantine in the treatment of AD mice.

Background: Conventional prognostic models do not fully reflect the severity of hepatitis B virus (HBV)-related acute-on-chronic liver failure (ACLF). This study aimed to establish an effective and convenient nomogram for patients with HBV-related ACLF.Methods: A nomogram was developed based on a retrospective cohort of 1,353 patients treated at the Third Affiliated Hospital of Sun Yat-sen University from January 2010 to June 2016. The predictive accuracy and discriminatory ability of the nomogram were determined by a concordance index (C-index) and calibration curve, and were compared with current scoring systems. The results were validated using an independent retrospective cohort of 669 patients consecutively treated at the same institution from July 2016 to March 2018. This study is registered at ClinicalTrials.gov (NCT03992898).Results: Multivariable analysis of the derivation cohort found that independent predictors of 90-day survival were age, white blood cell (WBC) count, hemoglobin (Hb), aspartate aminotransferase (AST), total bilirubin (TBil), international normalized ratio, serum creatinine (Cr), alpha fetoprotein (AFP), serum sodium (Na), hepatic encephalopathy (HE), pre-existing chronic liver disease(PreLD), and HBV DNA load. All factors were included in the nomogram. The nomogram calibration curve for the probability of 90-day survival indicated that nomogram-based predictions were in good agreement with actual observations. The C-index of the nomogram was 0.790, which was statistically significantly greater than those for the current scoring systems in the derivation cohort (P < 0.001). The results were confirmed in the validation cohort.Conclusions: The proposed nomogram is more accurate in predicting the 90-day survival of patients with HBV-related ACLF than current commonly used methods.

The inflammasome promotes inflammation-associated diseases, including cancer, and contributes to the radiation-induced tissue damage. However, the role of inflammasome in radiation-induced antitumor effects is unclear. We observed that tumors transplanted in Casp1-/- mice were resistant to radiation treatment compared with tumors in wild-type (WT) mice. To map out which molecule in the inflammasome pathway contributed to this resistant, we investigated the antitumor effect of radiation in several inflammasome-deficient mice. Tumors grown in either Aim2-/- or Nlrp3-/- mice remained sensitive to radiation, like WT mice, whereas Aim2-/-Nlrp3-/- mice showed radioresistance. Mechanistically, extracellular vesicles (EVs) and EV-free supernatant derived from irradiated tumors activated both Aim2 and Nlrp3 inflammasomes in macrophages, leading to the production of interleukin-1β (IL-1β). IL-1β treatment helped overcome the radioresistance of tumors growing in Casp1-/- and Aim2-/-Nlrp3-/- mice. IL-1 signaling in dendritic cells (DCs) promoted radiation-induced antitumor immunity by enhancing the cross-priming activity of DCs. Overall, we demonstrated that radiation-induced activation of the AIM2 and NLRP3 inflammasomes coordinate to induce some of the antitumor effects of radiation by triggering IL-1 signaling in DCs, leading to their activation and cross-priming.

Background: To explore the association of DNA methylation and gene expression in the pathology of obesity.Methods: (1) Genomic DNA methylation and mRNA expression profile of visceral adipose tissue (VAT) were performed in a comprehensive database of gene expression in obese and normal subjects. (2) Functional enrichment analysis and construction of differential methylation gene regulatory networks were performed. (3) Validation of the two different methylation sites and corresponding gene expression was done in a separate microarray dataset. (4) Correlation analysis was performed on DNA methylation and mRNA expression data.Results: A total of 77 differentially expressed mRNAs matched with differentially methylated genes. Analysis revealed two different methylation sites corresponding to two unique genes—s100a8-cg09174555 and s100a9-cg03165378. Through the verification test of two interesting different expression positions [differentially methylated positions (DMPs)] and their corresponding gene expression, we found that methylation in these genes was negatively correlated to gene expression in the obesity group. Higher S100A8 and S100A9 expressions in obese subjects were validated in a separate microarray dataset.Conclusion: This study confirmed the relationship between DNA methylation and gene expression and emphasized the important role of S100A8 and S100A9 in the pathogenesis of obesity.

Carmine radish is famous for containing a natural red pigment (red radish pigment). However, the expression of anthocyanin biosynthesis-related genes during the dynamic development stages of the fleshy roots in carmine radish has not been fully investigated. Here, based on HPLC quantification of anthocyanin levels from our previous study, young fleshy roots of the carmine radish “Hongxin 1” obtained at the dynamic development stages of fleshy roots (seedling stage (SS), initial expansion (IE), full expansion (FE), bolting stage (BS), initial flowering stage (IFS), full bloom stage (FBS) and podding stage (PS)) were used for RNA-Seq. Approximately 126 comodulated DEGs related to anthocyanin biosynthesis (common DEGs in the dynamic growth stages of fleshy roots in carmine radish) were identified, from which most DEGs appeared to be likely to participate in anthocyanin biosynthesis, including two transcription factors, RsMYB and RsRZFP. In addition, some related proteins, e.g., RsCHS, RsDFR, RsANS, RsF′3H, RsF3GGT1, Rs3AT1, RsGSTF12, RsUFGT78D2 and RsUDGT-75C1, were found as candidate contributors to the regulatory mechanism of anthocyanin synthesis in the fleshy roots of carmine radish. In addition, 11 putative DEGs related to anthocyanin synthesis were evaluated by qRT-PCR via the (2-ΔΔCT) method; the Pearson correlation analysis indicated excellent concordance between the RNA-Seq and qRT-PCR results. Furthermore, GO enrichment analysis showed that “anthocyanin-containing compound biosynthetic process” and “anthocyanin-containing compound metabolic process” were commonly overrepresented in the dynamic growth stages of fleshy roots after the initial expansion stage. Moreover, five significantly enriched pathways were identified among the DEGs in the dynamic growth stages of fleshy roots in carmine radish, namely, flavonoid biosynthesis, flavone and flavonol biosynthesis, diterpenoid biosynthesis, anthocyanin biosynthesis, and benzoxazinoid biosynthesis. In conclusion, these results will expand our understanding of the complex molecular mechanisms of anthocyanin biosynthesis in the fleshy roots of carmine radish and the putative candidate genes involved in this process.

Double-stranded RNA (dsRNA) is a virus-encoded signature capable of triggering intracellular Rig-like receptors (RLR) to activate antiviral signaling, but whether intercellular dsRNA structural reshaping mediated by the N6-methyladenosine (m6A) modification modulates this process remains largely unknown. Here, we show that, in response to infection by the RNA virus Vesicular Stomatitis Virus (VSV), the m6A methyltransferase METTL3 translocates into the cytoplasm to increase m6A modification on virus-derived transcripts and decrease viral dsRNA formation, thereby reducing virus-sensing efficacy by RLRs such as RIG-I and MDA5 and dampening antiviral immune signaling. Meanwhile, the genetic ablation of METTL3 in monocyte or hepatocyte causes enhanced type I IFN expression and accelerates VSV clearance. Our findings thus implicate METTL3-mediated m6A RNA modification on viral RNAs as a negative regulator for innate sensing pathways of dsRNA, and also hint METTL3 as a potential therapeutic target for the modulation of anti-viral immunity., N6-methyladenosine (m6A) RNA modification regulates RNA metabolism, and has been implicated in immune regulation. Here, the authors show that the m6A methyltransferase, METTL3, translocates into the cytoplasm to increase viral RNA m6A modification, decreases viral ds RNA content, and thereby dampens the RIG/MDA5-induced anti-viral immunity.

Laplacea alpestris is a member of the genus Laplacea, which distributes in Central and South America. Genetic information of L. alpestris would provide guidance for the phylogenetic position of this species. Here, we reported and characterized its complete chloroplast (cp) genome using Illumina pair-end sequencing data. The total chloroplast genome size of this species was 157,211 bp, including inverted repeats (IRs) of 26,103 bp, separated by a large single copy (LSC) and a small single copy (SSC) of 86,749 and 18,256 bp, respectively. A total of 132 genes, including 37 tRNA, 8 rRNA, and 87 protein-coding genes were identified. Phylogenetic analysis showed that L. alpestris formed a monophyletic clade with Laplacea fruticosa, and then grouped with Apterosperma oblata. The systematic position of Southeast Asian Laplacea species needs further studies.

While IL-2 can potently activate both NK and T cells, its short in vivo half-life, severe toxicity, and propensity to amplify Treg cells are major barriers that prevent IL-2 from being widely used for cancer therapy. In this study, we construct a recombinant IL-2 immunocytokine comprising a tumor-targeting antibody (Ab) and a super mutant IL-2 (sumIL-2) with decreased CD25 binding and increased CD122 binding. The Ab-sumIL2 significantly enhances antitumor activity through tumor targeting and specific binding to cytotoxic T lymphocytes (CTLs). We also observe that pre-existing CTLs within the tumor are sufficient and essential for sumIL-2 therapy. This next-generation IL-2 can also overcome targeted therapy-associated resistance. In addition, preoperative sumIL-2 treatment extends survival much longer than standard adjuvant therapy. Finally, Ab-sumIL2 overcomes resistance to immune checkpoint blockade through concurrent immunotherapies. Therefore, this next-generation IL-2 reduces toxicity while increasing TILs that potentiate combined cancer therapies., Interleukin-2 (IL-2) based cancer therapy is limited by severe toxicity and strong Treg amplification at the therapeutic dosage. Here, the authors develop a recombinant IL-2 immunocytokine which is comprised of a tumor-targeting antibody fused to a super mutant IL-2 and show in mouse models that this next-generation IL2 has reduced toxicity and enhanced antitumor activity.

Pseudoalteromonas is widely distributed in the marine environments and the biofilms formed by Pseudoalteromonas promote settlement of many species of invertebrates. Here, we show the complete genome of Pseudoalteromonas atlantica ECSMB14104, which was isolated from biofilms formed in the East China Sea and exhibited inducing activity on the Mytilus coruscus settlement. Complete genome of this strain containsa total of 3325 genes and the GC content of 41.02%. This genomic information is contributed to molecular mechanism of P. atlantica ECSMB14104 regulating mussel settlement.

The (pro)renin receptor [(P)RR] binds to prorenin to activate the renin-angiotensin system and is essential for the development of many different organ systems. Whether the (P)RR also plays a role in lung development is unknown. Immunostaining was used to determine the spatial-temporal distribution of (P)RR in the embryonic, postnatal, and adult lungs. We created a lung-specific (P)RR knockout mouse [ Foxd1cre/+ -(P)RRflox/flox] and assessed changes in lung morphology, cell proliferation, and apoptosis using immunohistochemistry and TUNEL staining. (P)RR function was confirmed by using siRNA to knock down (P)RR in human bronchial epithelial cells (HBECs) and then using the CCK-8 assay and flow cytometry to assess cell proliferation and apoptosis. Gene expression changes after knockdown were assessed by RT-PCR and Western blotting. (P)RR is expressed in the club cells of the bronchial epithelium, and expression increases throughout development. Lung-specific (P)RR knockout disrupted branching morphogenesis, leading to lung hypoplasia and neonatal mortality. These defects were associated with increased apoptosis and decreased proliferation of the pulmonary epithelial and mesenchymal cells and may be mediated by downregulation of Wnt11, β-catenin, and Axin2. (P)RR regulates lung development through canonical Wnt/β-catenin signaling and may present a new target for strategies to treat lung hypoplasia.

Pacific white shrimp is the major farmed shrimp species in the world. It is known to be very sensitive to the environmental and management changes such as intensification, which is one of the primary necessities to increase shrimp production, but represents a stressful condition, and needs to be managed properly to diminish its negative effects in aquaculture. In this study, juvenile Pacific white shrimp were fed diets supplementing with equal quantities of Astragalus membranaceus, Codonopsis pilosula and Glycyrrhiza uralensis extracts in different concentrations (0, 1.0, 2.0 and 3.0 g/kg) for 8 weeks. We subsequently estimated the effects of supplemented diets on growth performance, haematological parameters, and histological changes of hepatopancreas. Results revealed that the supplemented mixture had no benefits on growth and survival rate, but had favourable effects on haemocyte count, number of granulocytes, and hemocyanin concentration in the haemolymph (p > 0.05). We observed that R cells and B cells were increased in hepatopancreatic tubules of shrimps fed on supplemented diets. Besides, a diet containing 2.0 g/kg of extract mixture maintained the decreased levels of alanine aminotransferase (p 0.05). Among the used concentrations, 2.0 g/kg seemed to be the most suitable concentration.

Purpose: Neoadjuvant chemoradiotherapy (neoCRT) is a standard treatment for locally advanced rectal cancer (LARC); however, resistance to chemoradiotherapy is one of the main obstacles to improving treatment outcomes. The goal of this study was to identify factors involved in the radioresistance of colorectal cancer and to clarify the underlying mechanisms. Experimental Design: A genome-wide RNAi screen was used to search for candidate radioresistance genes. After RFC4 knockdown or overexpression, colorectal cancer cells exposed to X-rays both in vitro and in a mouse model were assayed for DNA damage, cytotoxicity, and apoptosis. Moreover, the regulatory effects and mechanisms of RFC4 in DNA repair were investigated in vitro. Finally, the relationships between RFC4 expression and clinical parameters and outcomes were investigated in 145 patients with LARC receiving neoCRT. Results: RFC4, NCAPH, SYNE3, LDLRAD2, NHP2, and FICD were identified as potential candidate radioresistance genes. RFC4 protected colorectal cancer cells from X-ray–induced DNA damage and apoptosis in vitro and in vivo. Mechanistically, RFC4 promoted nonhomologous end joining (NHEJ)-mediated DNA repair by interacting with Ku70/Ku80 but did not affect homologous recombination–mediated repair. Higher RFC4 expression in cancer tissue was associated with weaker tumor regression and poorer prognosis in patients with LARC treated with neoCRT, which likely resulted from the effect of RFC4 on radioresistance, not chemoresistance. Conclusions: RFC4 was identified as a radioresistance factor that promotes NHEJ-mediated DNA repair in colorectal cancer cells. In addition, the expression level of RFC4 predicted radiotherapy responsiveness and the outcome of neoadjuvant radiotherapy in patients with LARC.

The purpose of this research was to estimate the effects of different meditation exercises on the improvement of sleep disorders in older people using pairwise and network meta-analyses. Qigong, Yoga, and Tai Chi could help older people improve their sleep disorders. Meditation exercises may have a role in the management of insomnia in older people. Chronic sleep loss or sleep disorders is a public health problem affecting older people and cause many health problems. We aim to estimate the effects of different meditation exercises on relieving and improvement of sleep disorders in older people using the pairwise and network meta-analyses. Randomized controlled trials, which were published in English and reported on meditation exercises for sleep disorders in the older people, were retrieved from PubMed and EMBASE up to May 2018. Publication bias of the included studies were assessed by the Cochrane Collaboration recommendations. Network meta-analysis was performed by ADDIS, and all test models used random-effects model. Pooled effect sizes were presented with weighted mean differences (WMDs) and 95% confidence interval (CI). A total of ten studies were included in our research. Pairwise comparisons indicated that Qigong could significantly improve the quality of sleep in older people with sleep disorders compared with Activities (WMD = − 4.28, 95% CI − 5.75 to − 2.81). In addition, there were significant differences in Education vs. Usual care (WMD = 2.60, 95% CI 1.03–4.17) and Tai Chi vs. Activities (WMD = − 1.05, 95% CI − 1.73 to − 0.38). With great consistence and convergence, network meta-analysis showed that there was a significant difference in Qigong vs. Activities (WMD = − 4.23, 95% CI − 8.31 to − 0.21). Moreover, Qigong showed a best outcome in relieving sleep disorders, followed by Yoga. Qigong, Yoga, and Tai Chi improved sleep disorders in the older people, and Qigong intervention had the best effect followed by Yoga. A long-term clinical verification should be needed in the future.

Objectives: Patients with early-stage distal rectal cancer, if treated with radical surgery, usually suffer a poor quality of life. Definitive radiotherapy or chemoradiotherapy may be another treatment option for them. The aim of this study was to evaluate the role of definitive external beam radiotherapy or chemoradiotherapy in treating distal rectal cancer with stage cT1-2N0. Methods: We performed a retrospective study of 231 distal rectal cancer patients who were staged as cT1-2N0 from March 2002 to March 2015. All patients were treated by definitive radiotherapy or chemoradiotherapy. Overall survival (OS), progression-free survival (PFS), and short-term efficacy were analyzed. Multivariate analysis was performed to explore clinical factors significantly associated with PFS, local recurrence-free survival (LRFS), and distant metastasis-free survival (DMFS) for the whole group. Results: For the whole group, 135 patients (58.4%) achieved clinical complete response (cCR). The 5-year OS, PFS, and LRFS were 86.19%, 83.30%, and 92.50%, respectively. Patients with cCR acquired better survival than those with non-cCR. In multivariable analysis, it revealed that clinical stage, carcinoembryonic antigen (CEA level) and concurrent chemotherapy were independent predictors of PFS. Conclusion: Definitive radiotherapy or chemoradiotherapy may be feasible in some early-stage distal rectal cancer regarding its favorable efficacy.

Kai-yun You,1,* Hai-hua Peng,2,* Yan-hui Jiang,1,* Zhuo-fei Bi,1 Xing-sheng Qiu11Department of Radiation Oncology, SunYat-Sen Memorial Hospital, SunYat-Sen University; 2Department of Radiation Oncology, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou 510075, People’s Republic of China*These authors contributed equally to this workBackground: Whether concurrent chemotherapy could bring about better oncological outcomes in elderly patients receiving definitive radiotherapy is still unknown. So, the purpose of this study was to find out whether it is essential for elderly patients to undergo concurrent chemotherapy.Methods: We performed a retrospective study of 246 elderly cervical cancer patients who were treated with definitive radiotherapy or chemo-radiation between August 2004 and August 2015. All patients were divided into two groups according to whether they were receiving concurrent chemotherapy or not. Overall survival (OS) and disease-free survival (DFS) were compared between the two groups. Recurrence patterns were also analyzed. Multivariate analysis was performed to explore clinical factors significantly associated with DFS, local recurrence-free survival, and distant metastasis-free survival (DMFS).Results: The 5-year OS in the radiotherapy and chemo-radiation groups were 72.89% and 82.25%, respectively. A significant difference was found between the two groups (P=0.016). The 5-year DFS in the radiotherapy and chemo-radiaton groups were 58.19% and 75.52%, respectively, also with a significant difference between the two groups (P=0.028). Further subgroup analysis showed that in patients with negative lymph nodes, there were no differences in both OS and DFS between patients who did and did not receive concurrent chemotherapy. However, in patients with positive lymph nodes, patients who received concurrent chemotherapy acquired better OS and DFS than those who did not. Multivariable analysis showed that concurrent chemotherapy was an independent predictor of DFS and DMFS.Conclusion: Concurrent chemotherapy could improve oncological outcomes in elderly cervical cancer patients with positive lymph nodes, but not in those with negative lymph nodes.Keywords: cervical cancer, chemotherapy, radiotherapy &nbsp

Background Metabolic memory contributes to the development of diabetic retinopathy (DR), which is the complication of diabetes. But it’s still unknown how to prevent the metabolic memory to treat the DR. In our study, we want to examine the function of Astragalus polysaccharides (APS) in the metabolic memory of retinal pigment epithelium (RPE) pretreated with high glucose (HG). Methods ARPE-19 and PRPE cells were exposed to HG followed by normal glucose (NG) treatment with or without APS. QPCR was used to examine the levels of miR-195 and Bcl-2. MDA and SOD detection assays were used to examine the oxidative stress level. Western blotting and immunostaining were applied to detect the protein level of mitochondrial damage and apoptotic signaling pathway. Flow cytometry and TUNEL staining were used to analyze cell apoptosis. Luciferase assay was used to examine the direct target of miR-195. Results APS treatment significantly decreased the expression of miR-195, while increased the expression of Bcl-2 with optimized dosages which were induced by HG treatment, even after replacing the HG with NG. And we found Bcl-2 was the direct target of miR-195. APS alleviated the oxidative stress, mitochondrial damage and cell apoptosis induced by HG and HG + NG treatments in RPE cells via regulating miR-195. Furthermore, we found overexpression of miR-195 abolished the alleviated effects of APS on the HG-treated RPE cells. Conclusions APS suppressed high glucose-induced metabolic memory in retinal pigment epithelial cells through inhibiting mitochondrial dysfunction-induced apoptosis by regulating miR-195.

Gamma-amino butyric acid (GABA) is the main inhibitory neurotransmitter in the central nervous system, including the retina, and play an important role in both regulating neurogenesis and neural stem cell proliferation. GABAa receptor has been identified in the retina, however, the function of GABAa receptor on retinal progenitor cell (RPC) is unclear. RPCs were cultured to analyze changes in cell proliferation and cell cycle distribution after GABAa receptor activation. The activation of GABAa receptor significantly inhibits RPCs proliferation, cell cycle progress, and self-renewal. Moreover, the activation of GABAa receptor leads to the up-expression of p21 and p27 and down-expression of Nestin, Pax6, Sox2, and Chx10. These results suggest that GABA acts as a negative regulator of RPCs proliferation and self-renewal.

Background Acidic preconditioning (APC) has been demonstrated to protect against ischemia-reperfusion (IR)-induced lung injury, which could occur during lung transplantation or cardiopulmonary bypass. However, the pathophysiological mechanisms underlying IR lung injury and APC protection are not completely understood. The key factors responsible for the protective effects of APC are not clear. In this study, bioinformatics was used to predict the potential key factor in IR lung injury and explore the important mediator of the APC protective effect in IR lung injury. Methods First, we screened GSE6730, which is related to both lung injury and IR in Gene Expression Omnibus, and STRING was used later to select the genes in GSE6730 needed in the future. Animal models were established and classified to validate the effect of matrix metalloproteinase 9 (MMP-9) on lung injury after IR by adding a selective inhibitor (4-phenoxyphenylsulfonyl) methylthiirane, MMP-9 inhibitor. Next, for better understanding of APC inhibition of the expression of MMP-9 in lung injury, assessment of lung tissues, Western blot analysis, and RNA extraction and reverse transcription quantitative polymerase chain reaction were conducted. Results MMP-9 was identified to be overexpressed after IR according to the analysis on GSE67370. MMP-9 was an unknown gene in relation to acute lung injury and found to be associated with interleukin (IL)-1B, IL-6, and IL-8. The expressions of these inflammatory factors, including MMP-9, were all elevated in IR. Furthermore, lung injury was ameliorated, and the level of MMP-9 was lower when an MMP-9 inhibitor, (4-phenoxyphenylsulfonyl) methylthiirane, was added. Compared with group IR, APC reversed the ischemia-induced lung injury, and the level of MMP-9 was lower, and the concentrations of IL-1β, IL-6, and IL-8 were decreased. Conclusions Our findings reveal a novel mechanism indicating that IR induces higher expression of MMP-9 in lung injury by increasing the expression of inflammation-related factors. APC might protect against IR lung injury by inhibiting the expression of MMP-9.

Objective. To investigate the effects of Dendrobium officinale polysaccharides (DOPS) on the expression of inflammatory factors IL-1β and TNF-α and the MKP-1/MAPK signal pathway. Methods. PTZ-induced epileptic rat models were established. The rats were randomly divided into four groups: the control group, the DOPS group, the model group, and the DOPS intervention group. RT-PCR was used to measure the mRNA expression of IL-1β and TNF-α in the hippocampi of all groups; western blot was used to measure the protein expression of IL-1β and TNF-α and phosphorylation of ERK1/2, JNK, p38, and MKP-1 in the hippocampi of all groups at weeks 1, 2, 3, and 4 after modeling. Results. At weeks 1, 2, 3, and 4 after modeling, there were no significant differences between the control group and the DOPS group in the mRNA and protein expression of IL-1β and TNF-α and phosphorylation of ERK1/2, JNK, p38, and MKP-1 (all P>0.05); the mRNA and protein expression of IL-1β and TNF-α and phosphorylation of ERK1/2, JNK, and p38 were significantly increased, while the phosphorylation of MKP-1 was decreased in the model group compared with the control group. The mRNA and protein expression of IL-1β and TNF-α and phosphorylation of ERK1/2, JNK, and p38 were significantly decreased, while the phosphorylation of MKP-1 was increased in the DOPS intervention group compared with the model group. Conclusion. DOPS can reduce PTZ-induced brain inflammation and seizures of epileptic rats by inhibiting IL-1β, TNF-α, and MAPK signal pathways.

Background Maize is one of the primary crops of genetic manipulation, which provides an excellent means of promoting stress resistance and increasing yield. However, the differences in induction and regeneration capacity of embryonic callus (EC) among various genotypes result in genotypic dependence in genetic transformation. Results In this study, embryonic calli of two maize inbred lines with strong redifferentiation capacity and two lines with weak redifferentiation capability were separately subjected to transcriptome sequencing analysis during the early redifferentiation stages (stage I, 1–3 d; stage II, 4–6 d; stage III, 7–9 d) along with their corresponding controls. A total of ~ 654.72 million cDNA clean reads were yielded, and 62.64%~ 69.21% clean reads were mapped to the reference genome for each library. In comparison with the control, the numbers of differentially expressed genes (DEGs) for the four inbred lines identified in the three stages ranged from 1694 to 7193. By analyzing the common and specific DEGs of the four materials, we found that there were 321 upregulated genes and 386 downregulated genes identified in the high-regeneration lines (141 and DH40), whereas 611 upregulated genes and 500 downregulated genes were specifically expressed in the low-regeneration lines (ZYDH381–1 and DH3732). Analysis of the DEG expression patterns indicated a sharp change at stage I in both the high- and low-regeneration lines, which suggested that stage I constitutes a crucial period for EC regeneration. Notably, the specific common DEGs of 141 and DH40 were mainly associated with photosynthesis, porphyrin and chlorophyll metabolism, ribosomes, and plant hormone signal transduction. In contrast, the DEGs in ZYDH381–1 and DH3732 were mainly related to taurine and hypotaurine metabolism, nitrogen metabolism, fatty acid elongation, starch and sucrose metabolism, phenylpropanoid biosynthesis, and plant circadian rhythm. More importantly, WOX genes, which have an ancestral role in embryo development in seed plants and promote the regeneration of transformed calli, were specifically upregulated in the two high-regeneration lines. Conclusions Our research contributes to the elucidation of molecular regulation during early redifferentiation in the maize embryonic callus.

Background The optimal care for pT3N0 rectal cancer remains controversial. And whether tumor location can be used to guide the administration of adjuvant radiotherapy for pT3N0 rectal cancer is not fully confirmed. The current study was designed to identify the benefit of adjuvant radiotherapy for pT3N0 rectal cancer. Methods We performed a retrospective study of 265 pT3N0 rectal cancer patients who were treated by surgery and adjuvant therapy from Mar. 2005 to Sept. 2015. All patients were divided into two groups according to receiving adjuvant radiotherapy or not. Overall survival (OS), disease-free survival (DFS) were compare between patients who did and did not receive adjuvant radiotherapy. Multivariate analysis was performed to explore clinical factors significantly associated with DFS, local recurrence-free survival (LRFS) and distant metastasis-free survival (DMFS). Results For patients with lower tumor, DFS in adjuvant chemo-radiotherapy group was higher than that in adjuvant chemotherapy group. Besides, the rates of local recurrence and distant metastasis were found lower in patients who did receive adjuvant radiotherapy than those who did not. For patients with upper tumor, the 5-year OS and DFS were similar between groups of adjuvant chemotherapy and adjuvant chemo-radiotherapy. Multivariable analysis indicated both the CEA and tumor location were independent predictors of LRFS. And adjuvant radiotherapy predicted the DFS, LRFS and DMFS in lower rectal cancer patients. Conclusion Tumor location can serve as an indication for the administration of adjuvant radiotherapy in pT3N0 rectal cancer patients.

Objectives: To evaluate the prognostic significance of Adult Comorbidity Evaluation-27 (ACE-27) for elderly patients (age ≥70 years) with locoregionally advanced nasopharyngeal carcinoma (NPC) treated with Intensity-Modulated Radiotherapy (IMRT), with or without chemotherapy. Methods: 206 elderly patients with locoregionally advanced NPC treated from December 2006 to December 2016 were involved into analysis as the training cohort. Besides, a separate cohort of 72 patients from the same cancer center collected between January 2003 and October 2006 served as the validation cohort. By using propensity score matching (PSM), we created a balanced cohort by matching patients who received chemoradiotherapy with patients who received IMRT alone. Treatment toxicities were calculated between CRT and RT groups using the χ2 test. The primary endpoint was cancer-specific survival (CSS). Multivariate analysis was performed to assess the relative risk for each factor by using a Cox's proportional hazards regression model. Results: The median follow-up was 39.0 months (range = 3-137 months). In the PSM cohort, patients in the CRT group achieved comparable survival compared with patients in the RT group. The 3-year CSS rate was 64.3% and 65.2%, respectively (P =0.764). In multivariate analysis, the addition of chemotherapy to IMRT was not an independent prognostic factor for CSS, whereas a high ACE-27 score was an independent risk factor. In subgroup analysis with ACE-27 score ≥ 2, the 3-year CSS rate was worse in patients from the CRT group (63.5% vs. 46.3%, P = 0.041). Conclusions: CRT is comparable to IMRT alone for elderly patients with locoregionally advanced NPC. The ACE-27 tool may help to identify high-risk subgroup for poor disease outcome and tailor individualized treatment.

Purpose There are limited therapeutic options for patients with advanced penile squamous cell carcinoma (PSCC) after chemotherapy failure. Thus, we evaluated the feasibility of salvage treatment using the epidermal growth factor receptor (EGFR) mono-antibody nimotuzumab in chemotherapy-failed PSCC patients and explored potential response or resistance biomarkers. Materials and methods Six chemotherapy-failed PSCC patients with locally advanced disease or distant metastasis were enrolled consecutively to nimotuzumab treatment. Clinical responses and side effects were evaluated, and genetic characteristics of cancer specimens were analyzed through the next-generation sequencing of hotspot regions in cancer-related genes. Results Two of 6 patients showed partial responses, one was identified as having stable disease, while the other 3 had disease progression after nimotuzumab therapy. Side effects were all welltolerated. Genetic analysis revealed that TP53, CDKN2A, RB1, SMAD4, FLT3, and PIK3CA were the most frequently mutated genes in PSCC specimens, while altered KRAS, HRAS, EGFR, ERBB2, and FLT3 may be correlated with nimotuzumab resistance. Furthermore, 3 patients that were human papillomavirus-positive each showed clinical response or stable disease. Conclusions EGFR mono-antibody may be a potential modality for locally advanced PSCC patients after chemotherapy failure. Further large-scale clinical studies are needed to elucidate the role of human papillomavirus status and critical gene mutations in the clinical response to EGFR-targeted therapy.

Inspired by human dancers who make a comprehensive aesthetic judgement of their own dance poses by using both visual and non-visual information, this paper presents a novel feature fusion based approach to automatic aesthetics evaluation of robotic dance poses in order to improve the performance of robotic choreography creation. Four kinds of features are extracted, namely kinematic feature, region feature, contour feature, and spatial distribution feature of colour block. Based on different feature combinations, machine learning is deployed to train aesthetics models for the automatic judgement on robotic dance poses. The proposed approach has been implemented on a simulated robot environment, and experimental results are presented to verify its feasibility and good performance.

Syncope belongs to the transient loss of consciousness (TLOC), characterized by a rapid onset, short duration, and spontaneous complete recovery. It is common in children and adolescents, accounting for 1% to 2% of emergency department visits.Recurrent syncope can seriously affect children's physical and mental health, learning ability and quality of life and sometimes cardiac syncope even poses a risk of sudden death. The present guideline for the diagnosis and treatment of syncope in children and adolescents was developed for guiding a better clinical management of pediatric syncope. Based on the globally recent development and the evidence-based data in China, 2018 Chinese Pediatric Cardiology Society (CPCS) guideline for diagnosis and treatment of syncope in children and adolescents was jointly prepared by the Pediatric Cardiology Society, Chinese Pediatric Society, Chinese Medical Association (CMA)/Committee on Pediatric Syncope, Pediatricians Branch, Chinese Medical Doctor Association (CMDA)/Committee on Pediatric Cardiology, Chinese College of Cardiovascular Physicians, Chinese Medical Doctor Association (CMDA)/Pediatric Cardiology Society, Beijing Pediatric Society, Beijing Medical Association (BMA). The present guideline includes the underlying diseases of syncope in children and adolescents, the diagnostic procedures, methodology and clinical significance of standing test and head-up tilt test, the clinical diagnosis vasovagal syncope, postural orthostatic tachycardia syndrome, orthostatic hypotension and orthostatic hypertension, and the treatment of syncope as well as follow-up.

Though lymphotoxin (LT) is highly expressed by type I helper T (Th1) cells, its contribution to CD4+ T cell differentiation during infections and diseases remains a mystery. In HSV-1 infection, we observed that LTβR signaling is required to limit the Th1 response. Using bone marrow chimeric mice, mixed-T-cell chimeric mice, and LTβR in vivo blockades, we unexpectedly observed that LT, especially T cell-derived LT, played an indispensable role in limiting the Th1 response. The LTβR-Ig blockade promoted the Th1 response by increasing infiltration of monocytes and monocyte-derived DCs and up-regulating IL-12 secretion in the lymphoid environment. Our findings identified a novel role for T cell-derived LT in manipulating Th1 differentiation.