Cancer, a complex disease which involves abnormalities of multiple cellular pathways, is one of the most serious threatens to human health across the world. Chemotherapy with a single agent or a ...combined regimen is a standardized strategy for the treatment of almost all human cancers, and the cure rate of cancer increases with the continuous discovery of anticancer agents and the optimization of chemotherapy options. However, drug resistance, especially multidrug resistance, remains an obstacle in the effective treatment of cancer. Hence, it is urgent to develop novel agents with potential activity against cancers, especially drug-resistant forms. Acridine, which bears three fused rings, could intercalate into DNA and interfere with metabolic processes. Recently, acridines have been found with anticancer activity in a variety of malignancies through suppressing cell proliferation, stimulating apoptosis, and inducing cell cycle arrest, retarding migration, invasion and metastasis. Thus, acridines are useful scaffolds for the discovery of novel drug candidates with potent anticancer activity. This review focused on the current scenario of acridine hybrids with potential activity against cancers reported from Jan, 2015 to Feb, 2021. The mechanisms of action, the criteria of compound design as well as structure-activity relationships were also summarized to pave the way for a further rational design of novel anticancer agents.
Supercritical CO2 has wide application in enhancing oil recovery, but the low viscosity of liquid CO2 can lead to issues such as poor proppant-carrying ability and high filtration loss. Therefore, ...the addition of thickening agents to CO2 is vital. Hydrocarbon polymers, as a class of green and sustainable materials, hold tremendous potential for acting as thickeners in supercritical CO2 systems, and PVAc is one of the best-performing hydrocarbon thickeners. To further improve the viscosity enhancement and solubility of PVAc, here we designed a novel polymer structure, PVAO, by introducing CO2-affine functional groups to PVAc. Molecular dynamics simulations were adopted to analyze viscosity and relevant solubility parameters systematically. We found that PVAO exhibits superior performance, with a viscosity enhancement of 1.5 times that of PVAc in supercritical CO2. While in the meantime, PVAO maintains better solubility characteristics than PVAc. Our findings offer insights for the future design of other high-performance polymers.
Little is known about how stony corals build their calcareous skeletons. There are two prevailing hypotheses: that it is a physicochemically dominated process and that it is a biologically mediated ...one. Using a combination of ultrahigh-resolution three-dimensional imaging and two-dimensional solid-state nuclear magnetic resonance (NMR) spectroscopy, we show that mineral deposition is biologically driven. Randomly arranged, amorphous nanoparticles are initially deposited in microenvironments enriched in organic material; they then aggregate and form ordered aragonitic structures through crystal growth by particle attachment. Our NMR results are consistent with heterogeneous nucleation of the solid mineral phase driven by coral acid-rich proteins. Such a mechanism suggests that stony corals may be able to sustain calcification even under lower pH conditions that do not favor the inorganic precipitation of aragonite.
There are numerous genes for which loss-of-function mutations do not produce apparent phenotypes even though statistically significant quantitative changes to biological pathways are observed. To ...evaluate the biological meaning of small effects is challenging. Bardet-Biedl syndrome (BBS) is a heterogeneous autosomal recessive disorder characterized by obesity, retinopathy, polydactyly, renal malformations, learning disabilities and hypogenitalism, as well as secondary phenotypes including diabetes and hypertension. BBS knockout mice recapitulate most human phenotypes including obesity, retinal degeneration and male infertility. However, BBS knockout mice do not develop polydacyly. Here we showed that the loss of BBS genes in mice result in accumulation of Smoothened and Patched 1 in cilia and have a decreased Shh response. Knockout of Bbs7 combined with a hypomorphic Ift88 allele (orpk as a model for Shh dysfuction) results in embryonic lethality with e12.5 embryos having exencephaly, pericardial edema, cleft palate and abnormal limb development, phenotypes not observed in Bbs7(-/-) mice. Our results indicate that BBS genes modulate Shh pathway activity and interact genetically with the intraflagellar transport (IFT) pathway to play a role in mammalian development. This study illustrates an effective approach to appreciate the biological significance of a small effect.
Papillary thyroid carcinoma (PTC) is the most common malignancy of the thyroid gland, with a relatively high cure rate. Distant metastasis (DM) of PTC is uncommon, but when it occurs, it ...significantly decreases the survival of PTC patients. The molecular mechanisms of DM in PTC have not been systematically studied. We performed whole exome sequencing and GeneseeqPrime (425 genes) panel sequencing of the primary tumor, plasma and matched white blood cell samples from 20 PTC with DM and 46 PTC without DM. We identified somatic mutations, gene fusions and copy number alterations and analyzed their relationships with DM of PTC. BRAF‐V600E was identified in 73% of PTC, followed by RET fusions (14%) in a mutually exclusive manner (P < 0.0001). We found that gene fusions (RET, ALK or NTRK1) (P < 0.01) and chromosome 22q loss (P < 0.01) were independently associated with DM in both univariate and multivariate analyses. A nomogram model consisting of chromosome 22q loss, gene fusions and three clinical variables was built for predicting DM in PTC (C‐index = 0.89). The plasma circulating tumor DNA (ctDNA) detection rate in PTC was only 38.9%; however, it was significantly associated with the metastatic status (P = 0.04), tumor size (P = 0.001) and invasiveness (P = 0.01). In conclusion, gene fusions and chromosome 22q loss were independently associated with DM in PTC and could serve as molecular biomarkers for predicting DM. The ctDNA detection rate was low in non–DM PTC but significantly higher in PTC with DM.
The study identified gene fusion and somatic copy number alterations, particularly chromosome 22q loss, to be risk factors for distance metastasis (DM) of PTC and provided a convenient tool for the prediction of PTC DM.
J subgroup avian leukosis virus (ALV-J) infection causes serious immunosuppression problems, leading to hematopoietic malignancy tumors in chicken. It has been demonstrated that interferon-stimulated ...genes (ISGs) could limit ALV-J replication; nevertheless, the underlying mechanisms remain obscure. Here, we demonstrate that Long-chain Acyl-CoA synthetase 1 (ACSL1) is an interferon (IFN)-stimulated gene that specifically restricts the replication of ALV-J due to the higher IFN-I production. More importantly, ACSL1 induces primary monocyte-derived macrophages (MDMs) to pro-inflammatory phenotypic states during ALV-J infection, and ACSL1 mediates apoptosis through the PI3K/Akt signaling pathway in ALV-J-infected primary monocyte-derived macrophages (MDMs). Overall, these results provide evidence that ACSL1 contributes to the antiviral response against ALV-J.
The sharp increase in the total installed capacity of natural gas generators has intensified the dynamic interaction between the electricity and natural gas systems, which could induce cascading ...failure propagation across the two systems that deserves intensive research. Considering the distinct time response behaviors of the two systems, this paper discusses an integrated simulation approach to simulate the cascading failure propagation process of integrated electricity and natural gas systems (IEGSs). On one hand, considering instantaneous re-distribution of power flows after the occurrence of disturbance or failure, the steady-state AC power flow model is employed. On the other hand, gas transmission dynamics are represented by dynamic model to capture the details of its transition process. The interactions between the two systems, intensified by energy coupling components (such as gas-fired generator and electricity-driven gas compressor) as well as the switching among the operation modes of compressors during the cascading failure propagation process, are studied. An IEGS composed of the IEEE 30-bus electricity system and a 14-node 15-pipeline gas system is established to illustrate the effectiveness of the proposed simulation approach, in which two energy sub-systems are coupled by compressor and gas-fired generator. Numerical results clearly demonstrate that heterogeneous interactions between electricity and gas systems would trigger the cascading failure propagation between the two coupling systems.
An amorphous solid dispersion (SD) of curcumin (Cur) with disodium glycyrrhizin (Na
2
GA) was prepared by mechanical ball milling. Curcumin loaded micelles were self-formed by Na
2
GA when SD ...dissolved in water. The physical properties of Cur SD in solid state were characterized by differential scanning calorimetry, X-ray diffraction studies, and scanning electron microscope. The characteristics of the sample solutions were analyzed by reverse phase HPLC, UV-visible spectroscopy,
1
H NMR spectroscopy, gel permeation LC, and transmission electron microscopy. In vitro cytotoxic tests demonstrated that Cur SD induced higher cytotoxicity against glioblastoma U-87 MG cells than free Cur. Besides, an improvement of membrane permeability of Cur SD was confirmed by parallel artificial membrane permeability assay. Further pharmacokinetic study of this SD formulation in rat showed a significant ∼19-fold increase of bioavailability as comparing to free Cur. Thus, Cur SD provide a more potent and efficacious formulation for Cur oral delivery.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
The pleiotropic features of obesity, retinal degeneration, polydactyly, kidney abnormalities, cognitive impairment, hypertension, and diabetes found in Bardet-Biedl syndrome (BBS) make this disorder ...an important model disorder for identifying molecular mechanisms involved in common human diseases. To date, 16 BBS genes have been reported, seven of which (BBS1, 2, 4, 5, 7, 8, and 9) code for proteins that form a complex known as the BBSome. The function of the BBSome involves ciliary membrane biogenesis. Three additional BBS genes (BBS6, BBS10, and BBS12) have homology to type II chaperonins and interact with CCT/TRiC proteins and BBS7 to form a complex termed the BBS-chaperonin complex. This complex is required for BBSome assembly. Little is known about the process and the regulation of BBSome formation. We utilized point mutations and null alleles of BBS proteins to disrupt assembly of the BBSome leading to the accumulation of BBSome assembly intermediates. By characterizing BBSome assembly intermediates, we show that the BBS-chaperonin complex plays a role in BBS7 stability. BBS7 interacts with BBS2 and becomes part of a BBS7-BBS2-BBS9 assembly intermediate referred to as the BBSome core complex because it forms the core of the BBSome. BBS1, BBS5, BBS8, and finally BBS4 are added to the BBSome core to form the complete BBSome.
Bardet-Biedl syndrome proteins form a complex known as the BBSome. The details of BBSome assembly are unknown.
The BBSome is assembled via intrinsic protein-protein interactions, some of which involve cytoplasmic chaperonins.
BBSome assembly is a regulated stepwise process.
Understanding the assembly process of the BBSome might help to better understand the molecular mechanisms involved in cilia-related diseases.
The aim of this study was to better understand the sequence characteristics and immune responses in avian leukosis virus subgroup J (ALV-J) infected yellow chicken flocks in South China. We isolated ...four strains of ALV-J virus from these flocks, which were then identified by several methods, including subtype-specific polymerase chain reaction (PCR), enzyme-linked immunosorbent assay (ELISA), and immunofluorescence assay (IFA). All four viruses were sequenced for their complete genomes and named GD19GZ01, GD19GZ02, GD19GZ03, and GD19GZ04. In comparison with the reference sequence, the homology analysis showed that the gag and pol genes were relatively conserved, whereas env contained much variation. Both GD19GZ01 and GD19GZ02 almost entirely lacked the rTM region and E element, while the latter was retained in GD19GZ03 and GD19GZ04. Moreover, the virus replication levels in GD19GZ03 and GD19GZ04were much higher than those in GD19GZ01 and GD19GZ02. And three virus recombination events in GD19GZ01 and GD19GZ02 were revealed by the results of PDR5 and SimPlot software analysis. Additionally, we found that some interferon-stimulating genes (CH25H, MX, PKR, OAS, and ZAP) and inflammatory mediators (IL-4, IL-6, IL-10, IL-12, 1L-18, and TNF-α) were significantly upregulated in the immune system organs of clinical chickens. Taken together, these findings clarify and reveal the sequence characteristics and trends in the variation of ALV-J infection in yellow chicken flocks of South China.
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