Ependymal tumors across age groups are currently classified and graded solely by histopathology. It is, however, commonly accepted that this classification scheme has limited clinical utility based ...on its lack of reproducibility in predicting patients’ outcome. We aimed at establishing a uniform molecular classification using DNA methylation profiling. Nine molecular subgroups were identified in a large cohort of 500 tumors, 3 in each anatomical compartment of the CNS, spine, posterior fossa, supratentorial. Two supratentorial subgroups are characterized by prototypic fusion genes involving RELA and YAP1, respectively. Regarding clinical associations, the molecular classification proposed herein outperforms the current histopathological classification and thus might serve as a basis for the next World Health Organization classification of CNS tumors.
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•DNA methylation profiling of ependymomas identifies nine molecular subgroups•YAP1 and RELA fusions characterize two distinct groups of supratentorial ependymoma•Patients with PFA or supratentorial RELA-positive ependymoma show dismal prognosis•Risk stratification by molecular subgrouping is superior to histological grading
Pajtler et al. classify 500 ependymal tumors using DNA methylation profiling into nine molecular subgroups. This molecular classification outperforms the current histopathological grading in the risk stratification of patients.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Ferrocene is a stable metallocene complex with aromatic high-electron π-conjugated system and sandwich structures. We first prepared and characterized a novel ferrocenediamide bridged
bis
...(β-cyclodextrin) chiral stationary phase (FeCDP) to explore its chiral separation function. Its HPLC performance was systematically evaluated by basic, acidic, amphoteric and neutral chiral probes, including triazoles, profens, flavanones, amino acids and β-blocker drugs in reversed-phase and polar organic modes, respectively. The results showed that FeCDP successfully resolved 44 kinds of tested analytes (
R
s = 0.66–4.38), of which 36 were completely separated (
R
s ≥ 1.5). The best resolutions of different types, such as hexaconazole, ketoprofen, 3'-hydroxyflavanone, phenylalanine and arotinolol on FeCDP were reached at 3.06, 1.90, 4.38, 1.89 and 2.12 in a short time, respectively. Especially, FeCDP could completely resolve imazalil (
R
s = 1.97), ketoprofen (
R
s = 1.90), dansylated arginine (Dns-Arg,
R
s = 1.50), pindolol (
R
s = 1.42), bevantolol (
R
s = 1.41), which were very difficult to be resolved on the conventional CDCSPs. However, under optimal condition, the ordinary CDCSP could only separate 19 analytes with low resolutions (
R
s = 0.29–1.27). Compared with the reported similar stationary phases, the HPLC performance of FeCDP was also further improved. Based on the above comparison results, the satisfactory enantioselectivity of FeCDP may be mainly due to the fact that the “
pseudo
-cavity” composed of two CDs and a ferrocene diamide, could provide cooperative inclusion for analytes. Meanwhile, the large π-conjugated ferrocenediamide bridging group could also provide hydrogen bonding, π–π stacking, dipole–dipole and hydrophobic interactions, which may promote the chiral recognition effect of FeCDP. Bridge CD-CSP was a versatile chiral separation material in drugs analysis.
Graphical Abstract
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Background Diabetic kidney disease (DKD) has become a major cause of chronic kidney disease. However, early diagnosis of DKD is challenging. Trimethylamine oxide (TMAO) is an intestinal microbial ...metabolite which might be associated with diabetes complications. The aim of this study was to investigate the correlation between TMAO and DKD. Methods A cross-sectional study was conducted. A total of 108 T2DM patients and 33 healthy subjects were enrolled in this study. Multiple logistic regression analyses and area under receiver operating characteristic curves (AUROC) were performed to evaluate the correlation between serum TMAO and DKD. Results Serum TMAO levels were significantly higher in DKD patients than healthy control group and the NDKD (T2DM without combined DKD) group (P < 0.05). TMAO levels were negatively correlated with eGFR and positively correlated with urea nitrogen, ACR and DKD (P < 0.05). Logistic regression analysis indicated that serum TMAO was one of the independent risk factors for DKD patients (P < 0.05). In the diagnostic model, the AUROC of TMAO for the diagnosis of DKD was 0.691. Conclusion Elevated levels of serum TMAO levels were positively associated with the risk of DKD in T2DM patients, which might be a potential biomarker for DKD.
Task allocation of unmanned surface vehicles (USVs) with low task cost is an important research area which assigns USVs from starting points to different target points to complete tasks. Most of the ...research lines of task allocation are using heuristic algorithms to obtain suboptimal solutions to reduce both the max task cost and total task cost. In practice, reducing the maximum is more important to task time, which is from the departure of USVs to the last USV arriving at the designated position. In this paper, an exact algorithm is proposed to minimize the max task time and reduce the total task time based on the Hungarian algorithm. In this algorithm, task time is composed of the travel time along the planned path and the turning time at initial and target points. The fast marching square method (FMS) is used to plan the travel path with obstacle avoidance. The effectiveness and practicability of the proposed algorithm are verified by comparing it with the Hungarian algorithm (HA), the auction algorithm (AA), the genetic algorithm (GA) and the ant colony optimization algorithm (ACO). The results of path planning and task allocation are displayed in the simulation.
In this paper, we developed an organic solvent-free, eco-friendly, simple and efficient one-pot approach for the preparation of amphiphilic conjugates (Ugi-OSAOcT) by grafting octylamine (OCA) to ...oxidized sodium alginate (OSA). The optimum reaction parameters that were obtained based on the degree of substitution (DS) of Ugi-OSAOcT were a reaction time of 12 h, a reaction temperature of 25 °C and a molar ratio of 1:2.4:3:3.3 (OSA:OCA:HAc:TOSMIC), respectively. The chemical structure and composition were characterized by Fourier transform infrared spectroscopy (FTIR),
H nuclear magnetic resonance (
H NMR), X-ray diffraction (XRD), thermogravimetry analyser (TGA), gel permeation chromatography (GPC) and elemental analysis (EA). It was found that the Ugi-OSAOcT conjugates with a CMC value in the range of 0.30-0.085 mg/mL could self-assemble into stable and spherical micelles with a particle size of 135.7 ± 2.4-196.5 ± 3.8 nm and negative surface potentials of -32.8 ± 0.4--38.2 ± 0.8 mV. Furthermore, ibuprofen (IBU), which served as a model poorly water-soluble drug, was successfully incorporated into the Ugi-OSAOcT micelles by dialysis method. The drug loading capacity (%DL) and encapsulation efficiency (%EE) of the IBU-loaded Ugi-OSAOcT micelles (IBU/Ugi-OSAOcT = 3:10) reached as much as 10.9 ± 0.4-14.6 ± 0.3% and 40.8 ± 1.6-57.2 ± 1.3%, respectively. The in vitro release study demonstrated that the IBU-loaded micelles had a sustained and pH-responsive drug release behavior. In addition, the DS of the hydrophobic segment on an OSA backbone was demonstrated to have an important effect on IBU loading and drug release behavior. Finally, the in vitro cytotoxicity assay demonstrated that the Ugi-OSAOcT conjugates exhibited no significant cytotoxicity against RAW 264.7 cells up to 1000 µg/mL. Therefore, the amphiphilic Ugi-OSAOcT conjugates synthesized by the green method exhibited great potential to load hydrophobic drugs, acting as a promising nanocarrier capable of responding to pH for sustained release of hydrophobic drugs.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
This paper reports the improvement of a bitterness sensor based on a lipid polymer membrane consisting of phosphoric acid di-n-decyl ester (PADE) as a lipid and bis(1-butylpentyl) adipate (BBPA) and ...tributyl o-acetylcitrate (TBAC) as plasticizers. Although the commercialized bitterness sensor (BT0) has high sensitivity and selectivity to the bitterness of medicines, the sensor response gradually decreases to almost zero after two years at room temperature and humidity in a laboratory. To reveal the reason for the deterioration of the response, we investigated sensor membranes by measuring the membrane potential, contact angle, and adsorption amount, as well as by performing gas chromatography-mass spectrometry (GC-MS), liquid chromatography-tandem mass spectrometry (LC-MS/MS). We found that the change in the surface charge density caused by the hydrolysis of TBAC led to the deterioration of the response. The acidic environment generated by PADE promoted TBAC hydrolysis. Finally, we succeeded in fabricating a new membrane for sensing the bitterness of medicines with higher durability and sensitivity by adjusting the proportions of the lipid and plasticizers.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Mutations in the
gene cause inherited retinal disease; however, the pathogenic mechanisms associated with RCBTB1 deficiency remain poorly understood. Here, we investigated the effect of RCBTB1 ...deficiency on mitochondria and oxidative stress responses in induced pluripotent stem cell (iPSC)-derived retinal pigment epithelial (RPE) cells from control subjects and a patient with
-associated retinopathy. Oxidative stress was induced with tert-butyl hydroperoxide (tBHP). RPE cells were characterized by immunostaining, transmission electron microscopy (TEM), CellROX assay, MitoTracker assay, quantitative PCR and immunoprecipitation assay. Patient-derived RPE cells displayed abnormal mitochondrial ultrastructure and reduced MitoTracker fluorescence compared with controls. Patient RPE cells displayed increased levels of reactive oxygen species (ROS) and were more sensitive to tBHP-induced ROS generation than control RPE. Control RPE upregulated
and
expression in response to tBHP treatment; however, this response was highly attenuated in patient RPE. RCBTB1 was co-immunoprecipitated from control RPE protein lysates by antibodies for either UBE2E3 or CUL3. Together, these results demonstrate that
deficiency in patient-derived RPE cells is associated with mitochondrial damage, increased oxidative stress and an attenuated oxidative stress response.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Variants in RCBTB1 have been implicated in inherited retinal disease (IRD). Here, we generated induced pluripotent stem cells (iPSCs) from a 45-year-old female IRD patient harbouring compound ...heterozygous mutations in the RCBTB1 gene. Episomal plasmids containing OCT4, SOX2, KLF4, MYCL, LIN28, shRNA for TP53 and mir302/367 microRNA were employed to conduct the reprogramming of primary dermal fibroblasts. These iPSC lines provide a useful model for further investigations on the pathophysiological role of mutations in the RCBTB1 gene in IRD.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Retinitis pigmentosa 11 (RP11) is caused by dominant mutations in
, however a significant proportion of mutation carriers do not develop retinopathy. Here, we investigated the relationship between
...polymorphism,
repeat copy number and disease penetrance in RP11 patients and non-penetrant carriers (NPCs). We further characterized
and
expression in fibroblasts from eight RP11 patients and one NPC from a family carrying the c.1205C>T variant. Retinal organoids (ROs) and retinal pigment epithelium (RPE) were differentiated from induced pluripotent stem cells derived from RP11 patients, an NPC and a control subject. All RP11 patients were homozygous for the 3-copy
repeat in the
promoter, while 3/5 NPCs carried a 4-copy
repeat. The
rs4806718 genotype did not correlate with disease penetrance.
expression declined with age in adult cadaveric retina.
and
expression was reduced in RP11 fibroblasts, RO and RPE compared with controls. Both RP11 and NPC RPE displayed shortened primary cilia compared with controls, however a subpopulation of cells with normal cilia lengths was present in NPC RPE monolayers. Our results indicate that RP11 non-penetrance is associated with the inheritance of a 4-copy
repeat, but not with
polymorphisms.
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