Long non-coding RNAs (lncRNAs) are transcripts of a recently discovered class of genes which do not code for proteins. LncRNA genes are approximately as numerous as protein-coding genes in the human genome. However, comparatively little remains known about lncRNA functions. We globally interrogated changes in the lncRNA transcriptome of oestrogen receptor positive human breast cancer cells following treatment with oestrogen, and identified 127 oestrogen-responsive lncRNAs. Consistent with the emerging evidence that most human lncRNA genes lack homologues outside of primates, our evolutionary analysis revealed primate-specific lncRNAs downstream of oestrogen signalling. We demonstrate, using multiple functional assays to probe gain- and loss-of-function phenotypes in two oestrogen receptor positive human breast cancer cell lines, that two primate-specific oestrogen-responsive lncRNAs identified in this study (the oestrogen-repressed lncRNA BC041455, which reduces cell viability, and the oestrogen-induced lncRNA CR593775, which increases cell viability) exert previously unrecognized functions in cell proliferation and growth factor signalling pathways. The results suggest that oestrogen-responsive lncRNAs are capable of altering the proliferation and viability of human breast cancer cells. No effects on cellular phenotypes were associated with control transfections. As heretofore unappreciated components of key signalling pathways in cancers, including the MAP kinase pathway, lncRNAs hence represent a novel mechanism of action for oestrogen effects on cellular proliferation and viability phenotypes. This finding warrants further investigation in basic and translational studies of breast and potentially other types of cancers, has broad relevance to lncRNAs in other nuclear hormone receptor pathways, and should facilitate exploiting and targeting these cell viability modulating lncRNAs in post-genomic therapeutics.

Data from the Encyclopedia of DNA Elements (ENCODE) project show over 9640 human genome loci classified as long noncoding RNAs (lncRNAs), yet only ~100 have been deeply characterized to determine their role in the cell. To measure the protein-coding output from these RNAs, we jointly analyzed two recent data sets produced in the ENCODE project: tandem mass spectrometry (MS/MS) data mapping expressed peptides to their encoding genomic loci, and RNA-seq data generated by ENCODE in long polyA+ and polyA- fractions in the cell lines K562 and GM12878. We used the machine-learning algorithm RuleFit3 to regress the peptide data against RNA expression data. The most important covariate for predicting translation was, surprisingly, the Cytosol polyA- fraction in both cell lines. LncRNAs are ~13-fold less likely to produce detectable peptides than similar mRNAs, indicating that ~92% of GENCODE v7 lncRNAs are not translated in these two ENCODE cell lines. Intersecting 9640 lncRNA loci with 79,333 peptides yielded 85 unique peptides matching 69 lncRNAs. Most cases were due to a coding transcript misannotated as lncRNA. Two exceptions were an unprocessed pseudogene and a bona fide lncRNA gene, both with open reading frames (ORFs) compromised by upstream stop codons. All potentially translatable lncRNA ORFs had only a single peptide match, indicating low protein abundance and/or false-positive peptide matches. We conclude that with very few exceptions, ribosomes are able to distinguish coding from noncoding transcripts and, hence, that ectopic translation and cryptic mRNAs are rare in the human lncRNAome.

Chronic obstructive pulmonary disease (COPD) is a disease caused by cigarette smoke, which has been emerging as a serious health problem worldwide. The aim of this study is to explore the mRNA expression profile of lung tissues from the COPD rats and to characterize the role of Forkhead box C1 (Foxc1) in COPD.

4-Nitrophenol (4-NP) is a priority pollutant in water and is both carcinogenic and genotoxic to humans and wildlife even at very low concentrations. Thus, we herein fabricated a novel molecularly imprinted core-shell nanohybrid as a ratiometric fluorescent sensor for the highly sensitive and selective detection of 4-NP. This sensor was functioned by the transfer of fluorescence resonance energy between photoluminescent carbon dots (CDs) and 4-NP. This sensor was synthesized by linking organosilane-functionalized CDs to silica-coated CdSe quantum dots (CdSe@SiO2) via Si-O bonds. The nanohybrids were further modified by anchoring a molecularly imprinted polymer (MIP) layer on the ratiometric fluorescent sensor through a facile sol-gel polymerization method. The morphology, chemical structure, and optical properties of the resulting molecularly imprinted dual-emission fluorescent probe were characterized by transmission electron microscopy and spectroscopic analysis. The probe was then applied in the detection of 4-NP and exhibited good linearity between 0.051 and 13.7 μg/mL, in addition to a low detection limit of 0.026 μg/mL. Furthermore, the simplicity, reliability, high selectivity, and high sensitivity of the developed sensor demonstrate that the combination of MIPs and ratiometric fluorescence allows the preparation of excellent fluorescent sensors for the detection of trace or ultra-trace analytes.

Understanding the responses of animals to acute heat stress can help to reveal and predict the effect of more frequent extreme hot weather episodes on animal populations and ecosystems in the content of global climate change. Antioxidant defenses can help to protect animals against oxidative stress caused by intense temperature variation. In the present study, systematic antioxidant responses to acute heat stress (Δ15°C and maintained for 12 h) and subsequent recovery were assessed by evaluating gene transcript levels and relative enzyme activities in tissues of Pelodiscus sinensis, a subtropical freshwater turtle. Targets included nuclear factor erythroid 2-related factor 2 (Nrf2, the upstream transcription factor), antioxidant enzymes, and the glutathione (GSH) and ascorbic acid (AA) systems. Results showed three main patterns of expression change among antioxidant genes: (1) gene expression of Mn-superoxide dismutase (Mn-SOD), glutathione peroxidase 4 (GPx 4), and catalase (CAT) increased in response to heat stress or recovery in the liver; (2) transcripts of most genes did not change in brain, liver, and kidney of P. sinensis; and (3) expression of several GST isoforms were affected by heat stress or recovery in brain and kidney. However, relative enzyme activities involved in antioxidant defense were little affected by acute heat stress and recovery, indicating a relatively conservative antioxidant response in P. sinensis. Furthermore, results for malondialdehyde (MDA) levels indicated that acute heat stress and recovery did not cause a net increase in oxidative damage in turtle tissues and, in particular, MDA levels in spleen decreased along with increased splenic ascorbic acid concentration. Overall, the present study revealed a conservative antioxidant response in P. sinensis, which may be indicative of a high basal stress tolerance and relate with adaptation to climate change in freshwater turtles.

To evaluate the effects of different placements of mesial implants and different angles of distant implants in maxillary edentulous jaws on the stress on the implant and the surrounding bone tissue under dynamic loading.

The functions of the protein expressed in the nucleus and cytoplasm were different or opposite. The previous study found that oncogene Klf4 played a role of tumor suppressor in the nasopharyngeal cytoplasm. Cetuximab targeted epidermal growth factor receptor (EGFR) for the treatment of nasopharyngeal carcinoma.

Anti-CTLA-4 monoclonal antibodies (mAbs) confer a cancer immunotherapeutic effect (CITE) but cause severe immunotherapy-related adverse events (irAE). Targeting CTLA-4 has shown remarkable long-term benefit and thus remains a valuable tool for cancer immunotherapy if the irAE can be brought under control. An animal model, which recapitulates clinical irAE and CITE, would be valuable for developing safer CTLA-4-targeting reagents. Here, we report such a model using mice harboring the humanized Ctla4 gene. In this model, the clinically used drug, Ipilimumab, induced severe irAE especially when combined with an anti-PD-1 antibody; whereas another mAb, L3D10, induced comparable CITE with very mild irAE under the same conditions. The irAE corresponded to systemic T cell activation and resulted in reduced ratios of regulatory to effector T cells (Treg/Teff) among autoreactive T cells. Using mice that were either homozygous or heterozygous for the human allele, we found that the irAE required bi-allelic engagement, while CITE only required monoallelic engagement. As with the immunological distinction for monoallelic vs bi-allelic engagement, we found that bi-allelic engagement of the Ctla4 gene was necessary for preventing conversion of autoreactive T cells into Treg cells. Humanization of L3D10, which led to loss of blocking activity, further increased safety without affecting the therapeutic effect. Taken together, our data demonstrate that complete CTLA-4 occupation, systemic T cell activation and preferential expansion of self-reactive T cells are dispensable for tumor rejection but correlate with irAE, while blocking B7-CTLA-4 interaction impacts neither safety nor efficacy of anti-CTLA-4 antibodies. These data provide important insights for the clinical development of safer and potentially more effective CTLA-4-targeting immunotherapy.

During the process of deep decay, when decay approaches the pulp, an immune response is triggered inside the pulp, which activates the complement cascade. The effect of complement component 5a (C5a) on the differentiation of dental pulp mesenchymal stem cells (DPSCs) is related to dentin reparation. The aim of the present study was to stimulate DPSCs with different concentrations of C5a and evaluate the differentiation of odontoblasts using dentin sialoprotein (DSP).

Acetaminophen (APAP) hepatotoxicity is the leading cause of acute liver failure in the western world. Oridonin (OD), which is the major active ingredient of the traditional Chinese medicine Rabdosia rubescens, reportedly exerts anti-inflammatory and antioxidative effects. Here, we first find that OD protects against APAP-induced hepatotoxicity. The results of hepatic tissue-associated RNA-seq and metabolomics showed that the protective effects of OD were dependent upon urea cycle regulation. And such regulation of OD is gut microbiota partly dependent, as demonstrated by fecal microbiota transplantation (FMT). Furthermore, using 16S rRNA sequencing, we determined that OD significantly enriched intestinal Bacteroides vulgatus, which activated the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway to regulate redox homeostasis against APAP by urea cycle. In conclusion, our study suggests that the Bacteroides vulgatus-urea cycle-Nrf2 axis may be a potential target for reducing APAP-induced liver injury, which is altered by OD.

Patients with head and neck squamous cell carcinoma (HNSCC) have poor prognosis and show poor responses to immune checkpoint (IC) inhibitor (ICI) therapy. Competing endogenous RNA (ceRNA) networks, tumor-infiltrating immune cells (TIICs), and ICIs may influence tumor prognosis and response rates to ICI therapy. This study is aimed at identifying prognostic and IC-related biomarkers and key TIIC signatures to improve prognosis and ICI therapy response in HNSCC patients.

The South China Sea (SCS) is an important part of the Indo-Pacific convergence zone, with high biodiversity and abundant marine resources. Traditional methods are primarily used to monitor biodiversity. However, a few studies have used environmental DNA (eDNA) metabarcoding to research the assemblage structure of the SCS. This study used eDNA metabarcoding to survey the SCS assemblage and its relationship with environmental factors over a month-long time-series (August 30th to September 30th, 2020) of seawater samples from the central part of the SCS (9°-20°86' N, 113°-118°47' E). 32 stations were divided into six groups (A, B, C, D, E, F) according to longitude. We collected water samples, extracted eDNA, and amplified 18S rRNA gene V4 region (18S V4), 18S rRNA gene V9 region (18S V9), and 12S rRNA gene (12S). Krona diagrams were used to show species composition. We identified 192 phytoplankton, 104 invertebrate, and 61 fish species from 18S V4, 18S V9, and 12S, respectively. Generally, the three assemblage structures exhibited an increase in species diversity with increasing longitude. Group E had the highest fish diversity. Groups F and C had the highest phytoplankton and invertebrate diversity, respectively. Canonical correspondence analysis showed that four factors (chlorophyll a, depth, salinity, and temperature) were correlated with assemblage structure. Chlorophyll a was the main environmental factor that affected fish, phytoplankton, and invertebrate assemblage structures; salinity was strongly correlated with fish and invertebrate assemblage structures; temperature was a key factor that impacted fish and invertebrate assemblage structures; and depth was strongly correlated with invertebrate assemblage structure. Our results revealed that eDNA metabarcoding is a powerful tool for improving detection rate and using multiple markers is an effective approach for monitoring biodiversity. This study provided information that can be used to enhance biodiversity protection efforts in the SCS.

Esophageal squamous cell carcinoma (ESCC) is a highly prevalent and aggressive cancer with poor treatment outcomes. Despite the critical role of tight junction proteins in tumorigenesis, the involvement of Claudin5 in ESCC remains poorly understood. Thus, this study aimed to investigate the role of Claudin5 in ESCC malignant progression and radioresistance, as well as the underlying regulatory mechanisms.

Germline CTLA-4 deficiency causes severe autoimmune diseases characterized by dysregulation of Foxp3+ Tregs, hyper-activation of effector memory T cells, and variable forms autoimmune cytopenia including gradual loss of B cells. Cancer patients with severe immune-related adverse events (irAE) after receiving anti-CTLA-4/PD-1 combination immunotherapy also have markedly reduced peripheral B cells. The immunological basis for B cell loss remains unexplained. Here, we probe the decline of B cells in human CTLA-4 knock-in mice by using anti-human CTLA-4 antibody Ipilimumab conjugated to a drug payload emtansine (Anti-CTLA-4 ADC). The anti-CTLA-4 ADC-treated mice have T cell hyper-proliferation and their differentiation into effector cells which results in B cell depletion. B cell depletion is mediated by both CD4 and CD8 T cells and at least partially rescued by anti-TNF-alpha antibody. These data revealed an unexpected antagonism between T and B cells and the importance of regulatory T cells in preserving B cells.

Hematopoietic neoplasms with chromosomal translocations involving JAK2 are rare, and most of them show myeloproliferative neoplasm-associated features, followed by B-acute lymphoblastic leukemia (B-ALL). De novo B-ALL cases with JAK2 rearrangements are suggested to be appropriately considered as BCR-ABL1-like B-ALL, but its partners varied.

Type A trichothecene neosolaniol (NEO) is considered a potential risk to human and animal health by the European Food Safety Authority (EFSA). To date, available data do not allow making conclusions about the toxicological properties of this toxin. Trichothecenes have been previously demonstrated to induce emetic responses in mink, and this response has been associated with neurotransmitter peptide YY (PYY) and serotonin (5-hydroxytryptamine, 5-HT). The goal of this study was to compare emetic effects of NEO administered by intraperitoneal and oral routes and relate these effects to PYY and 5-HT. The effective doses resulting in emetic events in 50% of the animals following intraperitoneal and oral exposure to NEO were 0.4 and 0.09 mg/kg bw, respectively. This emetic response corresponded to elevated PYY and 5-HT levels. Blocking the neuropeptide Y2 receptor diminished emesis induction by PYY and NEO. The 5-HT3 receptor inhibitor granisetron completely restrained the induction of emesis by 5-HT and NEO. To summarize, our findings demonstrate that PYY and 5-HT play important roles in the NEO-induced emetic response.

Root-knot nematodes (RKN; Meloidogyne spp.) cause a significant decrease in the yield of cucumber crops every year. Cucumis metuliferus is an important wild germplasm that has resistance to RKN in which plant root volatiles are thought to play a role. However, the underlying molecular mechanism is unclear. To investigate it, we used the resistant C. metuliferus line CM3 and the susceptible cucumber line Xintaimici (XTMC). CM3 roots repelled Meloidogyne incognita second-stage larvae (J2s), while the roots of XTMC plants attracted the larvae. CM3 and XTMC were found to contain similar amounts of root volatiles, but many volatiles, including nine hydrocarbons, three alcohols, two aldehydes, two ketones, one ester, and one phenol, were only detected in CM3 roots. It was found that one of these, (methoxymethyl)-benzene, could repel M. incognita, while creosol and (Z)-2-penten-1-ol could attract M. incognita. Interestingly, creosol and (Z)-2-penten-1-ol effectively killed M. incognita at high concentrations. Furthermore, we found that a mixture of CM3 root volatiles increased cucumber resistance to M. incognita. The results provide insights into the interaction between the host and plant-parasitic nematodes in the soil, with some compounds possibly acting as nematode biofumigation, which can be used to manage nematodes.

The PI3K/AKT pathway plays a central role in human cancers, aberrant activation of this pathway is associated with tumorigenesis, cancer progression and angiogenesis. Based on the importance of the PI3K/AKT pathway in malignancies, we developed a 4-aminoquinazoline derivative, ZDQ-0620, initially envisioned as a novel pan-PI3K inhibitor. This study aimed to evaluate the potential target of ZDQ-0620 and its anticancer effect in human colorectal carcinoma (CRC). PI3K-kinase activity test showed IC50 of ZDQ-0620 against PI3Ka was 0.5 nM; molecular docking, CETSA assay and western blotting was further performed to predict ZDQ-0620 was a PI3K/AKT pathway inhibitor by targeting PI3K. To identify the effect of ZDQ-0620 on CRC cells, Sulforhodamine B (SRB) assay, flow cytometry, and Cell morphology analysis were conducted. The results showed that ZDQ-0620 inhibited the proliferation, migration and invasion of CRC cells, induced apoptosis through G0/G1 cell cycle arrest and mitochondrial pathway. Additionally, ZDQ-0620 inhibited the migration and tube formation of human umbilical vein endothelial cells (HUVECs). In vivo, neovascularization of rat aortic ring and chick chorioallantoic membrane (CAM) induced by VEGF was diminished when treated with ZDQ-0620. These results indicate that ZDQ-0620 induce apoptosis and anti-angiogenesis via inhibits the PI3K/AKT pathway. We suggest that the great potential of ZDQ-0620 as an effective treatment candidate against CRC.

Hutchinson-Gilford progeria syndrome (HGPS) is a lethal premature aging disorder without an effective therapeutic regimen. Because of their targetability and influence on gene expression, microRNAs (miRNAs) are attractive therapeutic tools to treat diseases. Here we identified that hsa-miR-59 (miR-59) was markedly upregulated in HGPS patient cells and in multiple tissues of an HGPS mouse model (LmnaG609G/G609G ), which disturbed the interaction between RNAPII and TFIIH, resulting in abnormal expression of cell cycle genes by targeting high-mobility group A family HMGA1 and HMGA2. Functional inhibition of miR-59 alleviated the cellular senescence phenotype of HGPS cells. Treatment with AAV9-mediated anti-miR-59 reduced fibrosis in the quadriceps muscle, heart, and aorta, suppressed epidermal thinning and dermal fat loss, and yielded a 25.5% increase in longevity of LmnaG609G/G609G mice. These results identify a new strategy for the treatment of HGPS and provide insight into the etiology of HGPS disease.

Objective This study aimed to investigate the mechanism by which Chinese herbal medicine ulcer oil (UO) accelerates ulcer healing in a diabetic ulcer rat model. Methods Sprague Dawley rats were allocated at random into four groups: a control group, a positive control group (PC), a UO treatment group and an ethacridine lactate solution treatment group. Subcutaneous tissue was surgically removed from the rats on days 3, 7 and 14. The levels of protein phosphotyrosine phosphatase 1B (PTP1B), vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF) and advanced glycation end products (AGEs) were detected using western blot analysis. Results PTP1B protein expression was significantly lower in the UO group compared with the PC group. VEGF protein expression was significantly higher in the UO group than in the control group on day 3. PDGF protein expression in the UO group was significantly higher than in the PC group on day 3. AGE expression was significantly lower in the UO group than in the PC group. Conclusions UO may downregulate PTP1B and AGEs and upregulate VEGF and PDGF, which may contribute to the inhibition of the inflammatory response and promote the healing of diabetic foot ulcers.