Datasets:
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5,363,900 | 25023634 | 30,825 | The GCKR rs780094 polymorphism is associated with elevated fasting serum triacylglycerol, reduced fasting and OGTT-related insulinaemia, and reduced risk of type 2 diabetes | [
4,
9
] | [
4,
8
] | [
4,
3
] |
933,912 | 27336035 | 7,485 | The present results suggest an interaction between DRD2 rs1076560 and AKT1 rs2494732 genotypes on psychosis risk among cannabis users. Individuals carrying the DRD2 T allele or the AKT1 C allele have an increased psychosis risk in the context of cannabis use; however, the risk is especially increased in subjects who carry 'risk' alleles from both genes. In line with previous findings, the psychosis risk in cannabis users depends on the frequency of use, with the highest probability of psychotic disorder among daily users carrying both the risk variants. Our results indicate a model of interaction known as 'qualitative GxE interaction' with a crossover pattern: carriers of risk allele(s) for one of the two genes (DRD2 rs1076560 T or AKT1 rs2494732 C allele), compared with individuals carrying no 'risk' alleles (DRD2 rs1076560 GG/AKT1 rs2494732 TT), have a lower probability of psychotic disorder if they never used cannabis but a higher probability if they have a history of cannabis use, especially of daily use. Similarly, carriers of both the 'risk' alleles (DRD2 rs1076560 T allele and AKT1 rs2494732 C allele), compared with the other groups, have the lowest probability of psychotic disorder if they never used cannabis but the highest probability if they have a history of cannabis use, especially of daily use. Our findings are in line with previous results in the field and indicate that specific minor alleles may prevent or promote the risk for psychosis depending on the presence and degree of cannabis use. Such findings require validation in experimental designs and animal studies where both changes in the exposure and in the genotype can be modeled. | [
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209,805 | 20156327 | 7,985 | Impact of the MDM2 SNP309 and p53 Arg72Pro polymorphism on age of tumour onset in Li-Fraumeni syndrome | [
30,
14,
34
] | [
3,
4,
8
] | [
4,
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2,307,113 | 35998911 | 9,826 | Genotyping of A2748G mutant mtDNA | [
14
] | [
6
] | [
1
] |
2,054,301 | 22504937 | 125 | Diaminoterephthalates with a maleimide moiety were synthesized and used as fluorescence dyes for sensing thiols. Whereas these "NiWa Blue" dyes showed no emission, the conjugate addition of a thiol to the maleimide group turned on a fluorescence at about 400 nm when irradiating the dye at 338 nm. The neuronal-calcium sensor protein recoverin possesses a single cysteine residue at position 39, which reacts with NiWa Blue, and is therefore labeled by a fluorophore with an emission at about 440 nm. In the absence of Ca(2+), irradiation at 280 nm of a tryptophan residue in close proximity to Cys-bound NiWa Blue lead to strong FRET, which was detected by emission of the dye at 440 nm. In the presence of Ca(2+), the protein holds a conformation with distal Trp and Cys residues, thus FRET of irradiated Trp to Cys-bound NiWa Blue was significantly weakened. | [
334,
363
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31
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1,872,427 | 35897799 | 17,831 | FTO (rs9939609), GHRL (rs34911341), LEPR (rs1137101), polymorphisms which affect the amount of food consumed and the feeling of satiety; | [
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23
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1,170,528 | 31223424 | 7,401 | Animal experiments were approved by the Committee of Medical Ethics and Welfare for Experimental Animals of Henan University School of Medicine (HUSOM-2017-189) in compliance with the Experimental Animal Regulations formulated by the National Science and Technology Commission, China. Animal studies were conducted as previously described with slight modifications. Forty-eight 4-week-old male BALB/C nude mice (n = 8 per group) were purchased from Beijing HFK Bioscience Co. Ltd. (Certificate No. SCXK (Jing) 2014-0004, Beijing, China). TPC-1, TT, and ARO cells (5 x 106 cells in 200 mul PBS) were implanted by subcutaneous injection into the right flanks of mice. Then, the mice were randomly divided into six groups (n = 8 per group). NaHS (0.56, 1.4, 2.8, 5.6, and 11.2 mg/kg/day) was administered subcutaneously (near the implanted tumor) for 4 weeks. The control group was treated with PBS. Body weight and tumor volume were daily measured. Tumor volume was calculated as volume = L x W2/2, where L is the longest dimension and W is the dimension perpendicular to L. The tumor volume doubling time (TVDT) was calculated as TVDT = log2/log(V2/V1) x (T - T0), where V2 and V1 are tumor volumes and (T - T0) is the time interval. Then, the mice were sacrificed and tumors were excised and weighted. The inhibition rate (IR) of tumor growth was calculated as IR = [(A - B)/A] x 100%, where A is the average tumor weight of the control group and B is that of the treatment group. | [
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859,791 | 32566830 | 23,306 | Optical rotations were measured on a Jasco P-2000 polarimeter (Easton, MD, USA) at 25 C in CHCl3. FTIR spectra were acquired on Bruker Vertex 70 (Bruker, Billerica, MA, USA) and PerkinElmer Frontier (Waltham, MA, USA) spectrometers. 1D- and 2D-NMR spectra were recorded on a Bruker AVANCE III HD 800 MHz spectrometer (800 and 200 MHz for 1H and 13C, respectively), Varian NMR spectrometer (500 and 125 MHz for 1H and 13C, respectively), and Bruker AVANCE III HD spectrometer (400 and 100 MHz for 1H and 13C, respectively) using CHCl3 (deltaH 7.24 and deltaC 77.0), the residual solvent, as an internal standard. High-resolution electrospray ionization mass spectrometry (HRESIMS) and tandem (MSn) analyses were carried out using Bruker spectrometers of models micrOTOFII and Ion Trap-amaZonX (Billerica, MA, USA), respectively, both operating in the positive mode. Column chromatography (CC) was performed on a silica gel 60 (60-200 mum, 70-230 mesh, SiliaCycle, Quebec, Canada), and medium-pressure liquid chromatography (MPLC) was performed on a silica gel 60 (40-63 mum, 230-400 mesh, SiliCycle). Thin-layer chromatography (TLC) was carried out using precoated silica gel F-254 aluminum sheets (SiliCycle), and the compound spots were observed under UV light at 254 and 366 nm, staining with iodine vapor. Analytical high-performance liquid chromatography (HPLC) was performed on a Prominence Shimadzu instrument equipped with a SPD-M20A diode array detector and a reversed-phase Phenomenex Gemini C18 column (250 mm x 4.6 mm ID filled with 5 mum particles). For preparative HPLC, a Shimadzu apparatus with an SPD-M10A VP diode array detector and an ACE C18 column (250 mm x 21.2 mm and 5 mum particles) was used with a flow rate of 8.0 mL/min. | [
1619,
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4,574,866 | 27170758 | 35,174 | In addition to their role in AAV DNA replication, the Rep proteins coordinate the temporal regulation of transcription of the viral genome during the AAV life cycle. In the absence of helper virus, the Rep proteins participate in repressing transcription from the three viral promoters, p5, p19, and p40, ensuring minute levels of expression of the viral proteins. In the presence of helper virus, i.e., during a productive infection, repression of the p5 promoter is lifted by the adenoviral E1A protein, and binding of Rep to the p5 promoter or the ITRs leads to transactivation of the p19 and p40 promoters. The p5 promoter itself is also controlled by Rep, which can act both as a repressor and as an activator through binding at the p5 or ITR RBS, respectively. The net result is a self-regulatory loop that generates protein levels that are tightly controlled and are optimal for AAV replication and packaging. Two mechanisms of Rep-mediated repression have been identified: direct repression through binding at the RBS in the p5 promoter and indirect repression that requires the ATPase activity of Rep. In light of the dependence of transcriptional regulation on Rep binding to the p5 promoter and ITR, we assessed whether the oligomerization mutants also displayed defects in transcriptional activity resulting in altered protein expression levels. As a control, we again used the K340H ATPase mutant, which has been shown to lead to the expression of exceedingly high Rep protein levels under conditions permissive for AAV replication. Cells were transfected with the various AAV infectious plasmids, and Rep and Cap protein levels were determined in the presence and absence of adenovirus coinfection. In the presence of WT Rep and the absence of adenovirus, we expected low levels of both Rep and Cap proteins. In the presence of adenovirus, Rep protein levels peaked at about 30 h after infection and then slowly decreased, while Cap levels increased with viral DNA replication. Because we harvested the cells at 72 h posttransfection, we expected to see only slightly higher levels of the Rep proteins but significantly higher Cap expression levels compared to those in cells that were not coinfected with adenovirus. As shown in Fig. 7A, we observed strikingly high Rep protein levels in cells transfected with the mutated Rep proteins, including the control K340H mutant. Once more, we observed that the Y224F mutant showed an intermediate phenotype represented by a very modest increase in Rep protein expression levels (Fig. 7A). The Cap protein levels, on the other hand, were found to be lower in cells expressing the mutant proteins; we detected high Cap levels only in the presence of Rep proteins that support the AAV life cycle, with the sole exception being the K340H mutant (Fig. 7A). The same trend was observed both in the presence and in the absence of adenovirus infection, although the Cap levels were significantly lower in the absence of helper virus. These results suggest that the oligomerization mutants failed to regulate the expression levels of the AAV proteins, most likely by failing to autoregulate the p5 promoter through RBS binding. In view of these important differences in protein amounts, we assessed the levels of AAV transcripts by RT-qPCR (Fig. 6C). Because all AAV RNAs use the same polyadenylation signal, we were not able to quantify the p19 and p40 transcripts separately from the p5 transcripts. As expected, with all primer sets used, which targeted p5, p5+p19, and p5+p19+p40, we observed an increase in mRNA levels in response to adenovirus coinfection in the presence of Rep proteins that support AAV replication. In the presence of the Y224F mutant, the response to adenovirus was still present but was nevertheless reduced compared to that in the presence of WT Rep. The oligomerization-deficient Y224, I251, and Y224-I251 mutants, which were unable to bind the RBS at the p5 promoter, had higher basal mRNA levels, varying between 2- and 10-fold compared with those of the WT, and did not respond to adenovirus infection. In the context of adenovirus coinfection, however, the differences in mRNA levels did not correlate with those observed for the protein levels, suggesting that changes in posttranscriptional regulation also contribute to the altered protein expression levels. Rep-mediated posttranscriptional regulation has been observed before, but its mechanism remains unknown. The K340H mutant, which oligomerized but failed to support AAV replication, had considerably higher basal mRNA levels than WT Rep, possibly explaining the very high Rep and Cap protein amounts observed, and the presence of adenovirus did not lead to a clear change in mRNA levels. Taken together, our data support a model in which Rep oligomerization is important for the gene regulatory function of Rep, potentially through p5 RBS binding, which is necessary to achieve an appropriate transcription profile. | [
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729,295 | 37074909 | 10,218 | Cross Math1-Cre/Ptch1loxp/wt mice with Ptch1loxp/wt/R26R-GFP mice to obtain MPG mice. | [
6,
52
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5,
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] | [
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4,953,410 | 35626123 | 26,682 | Compound EGFR mutations were identified in 40 patients in the afatinib uncommon EGFR mutation database. Among these patients, 26 out of 40 had at least 1 major uncommon EGFR mutation. Patients were treated with afatinib as a first-line treatment, and in assessable patients, the ORR was 77%. The median duration of response (DoR) was 16.6 months. In patients harboring a major uncommon EGFR mutation, the ORR was 78%, and the median DoR was 17.1 months. With osimertinib, four patients had compound EGFR mutations (two harboring G719X th L861Q and two with S768I th G719X) in the KCSG-LU15-09 trial, and three out of four patients showed a response. Some real-world data have suggested that patients harboring compound EGFR mutations exhibit a fair response to first-generation EGFR-TKIs. | [
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3,539,336 | 39722885 | 28,040 | (A) Dynamic cross-correlation analysis (DCCA) of WT EFE. Differential DCCA (d-DCCA) comparison of the WT enzyme versus (B) A198V, (C) D191E, (D) E215A, and (E) R171A variants of EFE. The positive values shown in cyan represent the positively correlated motions. The negative values in pink represent anticorrelated motions. The identified flexible regions in the WT EFE are shown in circles. | [
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266,612 | 34680476 | 42,359 | Finally, even variants that alter FFA fluxes into the liver or their catabolism, such as the rs56225452 in fatty acid transport proteins (FATP5) or the rs13412852 in Lipin1 (LPIN1), may leverage IR and steatosis. | [
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249,957 | 35661827 | 15,717 | We identified significant (P < 5 x 10-8) rare variant (MAF < 0.01) associations in 25 genes, 15 of which had nonsynonymous variant or gene burden associations (Fig. 1b, Table 2, Supplementary Data 6 & 7). Five of the 15 genes also had significant common variant associations within 1 Mb (KLHDC7B, SYNJ2, GJB2, EYA4, and CDH23). After conditioning on independent common variants at each locus (Supplementary Data 6, 7 & 8), the rare variant and gene burdens remained associated with hearing loss (maximum conditional P <= 3 x 10-5) except for the CDH23 Asn1103Ser association (conditional P = 0.79). Of note, the lead common variant in CDH23 is also a missense (Ala371Thr) variant (MAF = 0.01) and is pinpointed by FINEMAP as the only causal variant at that locus with high confidence. Overall, our conditional analyses suggest that rare variant association signals are usually independent of nearby common variant associations. | [
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785,972 | 36569427 | 9,816 | The 10S structure consisted of residues 2-528 in chain A and residues 2-529 in chain B with the loop between residues 451-455 omitted in both chains. Although density is observed within this region, the main chain cannot be reliably modeled within this density. Numerous attempts were made to soak tryptamine into 10S crystals; however, even with high concentrations of tryptamine (>10 mM), no clear density for tryptamine was observed within the active site. Overlaying the structures of 10S and RebH containing L-Trp substrate shows a steric clash between H52 in 10S and L-Trp, suggesting that the combination of H52 and C465 must significantly alter substrate binding (Figure 3B). | [
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1,834,068 | 20480039 | 18,259 | As Asn9 is already able to interact with the 3'-hydroxy and 2'-phosphate group of the cofactors adenine ribose moiety in the wild-type enzyme, it is reasonable that changing the properties of this amino acids side chain from polar but uncharged (Asn) to charged (Asp, Glu) brings about the electrostatic repulsion needed to decrease binding of NADPH and permits formation of hydrogen bonds between the 2'- and 3'-ribose hydroxyl groups and the side chain carboxyl group (Figure 9). | [
3
] | [
4
] | [
2
] |
1,951,701 | 30944684 | 22,737 | Envelope protein mutations L107F and E138K are important for neurovirulence attenuation for Japanese encephalitis virus SA14-14-2 strain | [
37,
27
] | [
5,
5
] | [
2,
2
] |
4,239,227 | 35156780 | 68,069 | CFBE mCherry-Flag-CFTR cells (WT or F508del variants) were cultured in DMEM high glucose (Corning 10-013-CV) supplemented with 10% fetal bovine serum (Gibco 10270), 10 mug/ml of blasticidin (Invivogen #ant-bl) and 2 mug/ml of puromycin (Invivogen #ant-pr-1) at 37 C and 5% CO2. CFBE cells constitutively expressing WT-/F508del-CFTR were cultured in equivalent conditions but excluding blasticidin. When seeded to siRNA coated multi-well plates culture media was DMEM supplemented with FBS (0.1% when using VX-661, 10% elsewhere). | [
18,
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5,050,099 | 36155857 | 19,344 | However, the LEP gene had one variation (G281A) in intron 2 when compared with GenBank (acc. no. EU220012.1) and was submitted to GenBank with accession number OM418855 (Fig. 5B, C). On the other hand, exon 3 did not have any variation from the sequence on GenBank (acc. no. MH716185.1). All previous mutations have been recorded for the first time in this study and submitted to GenBank as indicated previously. | [
13,
41
] | [
3,
5
] | [
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1
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222,599 | 36232890 | 30,109 | Plasmid coding for HA-CDH1 was obtained from Dr Michele Pagano, and those coding for GFP-Ubi-K11 and GFP-Ubi-K11R from Dr Michel Bouvier. Plasmids coding for Stau155-HA3, STAU1Delta37-HA3, STAU1Delta46-HA3, STAU1Delta60-HA3, and STAU1Delta88-HA3 were previously described. RBD2-YFP, RBD2Delta51-YFP, RBD2Delta46-YFP, and RBD2Delta37-YFP were generated by PCR amplification of the N-terminal end of STAU155- HA3 using sense and antisense oligonucleotide primers (Supplementary Table S7). PCR products were digested with the endonucleases EcoRI and AgeI and inserted into a YFP CMV Topaz vector. For the alanine scanning of amino acids 37 to 51, STAU155-HA3 was PCR-amplified using the PfuUltra II polymerase (Agilent Technologies, Toronto, ON, Canada) and oligonucleotide primers (Integrated DNA Technologies, Coralville, IA, USA) (Supplementary Table S7). MAP4K1 was cloned in the pcDNA-RSV vector by PCR amplification from pDONR223-MAP4K1 (Supplementary Table S7). pDONR223-MAP4K1 was a gift from Drs Hahn and Root (Addgene plasmid #23484; accessed on 30 October 2019; RRID: Addgene_23484). The PCR product was cloned at the XhoI and NotI sites. An HA3 tag was then inserted at the Not1 site as described. The MAP4K1F651A-HA3 mutant was generated using the PfuUltra II polymerase and specific oligonucleotide primes (Supplementary Table S7). | [
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4,708,064 | 36116149 | 18,868 | Clade Genomic Frequency Nucleotide Protein Protein Mapped with Coding and Position Change Change Coordinate Non-Coding Region 19A 11083 425 GA, GT Synonymous, LF 37 NSP6 13730 374 CT AV 97 RdRp 28311 364 CT PL 13 Nucleocapsid 23929 360 CT Synonymous 789 Spike 6312 359 CT, CA TI, TK 1198 NSP3 19524 111 CT Synonymous 495 Exon 6310 98 CA, CT SR, Synonymous 1197 NSP3 1397 77 GA VI 198 NSP2 29742 77 GA,GC, GT Not Present Not Present 3' UTR 28688 74 TC Synonymous 139 Nucleocapsid 19B 28144 87 TC LS 84 ORF8 8782 86 CT Synonymous 76 NSP4 28878 83 GA,GT, GC SN, SI, ST 202 Nucleocapsid 29742 81 GA,GC, GT Not Present Not Present 3' UTR 22468 62 GT,GA Synonymous, Synonymous 302 Spike 11230 19 GT MI 86 NSP6 7945 16 CT Synonymous 1742 NSP3 28167 15 GA EK 92 ORF8 2705 9 AG TA 634 NSP2 14500 9 GT VL 354 RdRp 20A 23403 2472 AG DG 614 Spike 241 2458 CT Not Present Not Present 5' UTR 3037 2455 CT Synonymous 106 NSP3 14408 2377 CT PL 323 RdRp 26735 1432 CT Synonymous 71 Membrane 18877 1427 CT Synonymous 280 Exon 25563 1418 GA, GT, GC Synonymous, QH, QH 57 ORF3a 28854 1230 CT SL 194 Nucleocapsid 22444 1191 CT Synonymous 294 Spike 2836 557 CT Synonymous 39 NSP3 20B 3037 1923 CT Synonymous 106 NSP3 241 1922 CT Not Present Not Present 5' UTR 23403 1922 AG DG 614 Spike 14408 1912 CT PL 323 RdRp 28881 1868 GA, GT RK, RM 203 Nucleocapsid 28882 1868 GA Synonymous 203 Nucleocapsid 28883 1867 GA, GC GR, GR 204 Nucleocapsid 313 1120 CT Synonymous 16 Leader protein 5700 1106 CA AD 994 NSP3 4354 281 GA Synonymous 545 NSP3 20C 241 18 CT Not Present Not Present 5' UTR 1059 18 CT TI 85 NSP2 3037 18 CT Synonymous 106 NSP3 14408 18 CT PL 323 RdRp 23403 18 AG DG 614 Spike 25563 18 GA, GT, GC Synonymous, QH, QH 57 ORF3a 16260 9 CT Synonymous 8 Helicase 28821 9 CA SY 183 Nucleocapsid 28221 4 GT, GC E-, EQ 110 ORF8 28371 4 GT SI 33 Nucleocapsid | [
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1,667,971 | 24196318 | 17,017 | (a) Schematic illustration of the device structure. The device includes a 20 nm thick permalloy film separated from the striplines by 50 nm of SiO2. The striplines are in an asymmetric coplanar waveguide configuration made of Cr (5 nm)/Ag (150 nm)/Pt (5 nm) with a signal width (S) of 3 mum and ground width (W) of 9 mum. The bias magnetic field is applied in the y-direction and propagating spin wave in the x-direction is detected by the antenna using an inductive technique. (b) The optical microscope picture of a device. (c) Scanning electron micrograph (SEM) of a device. | [
308,
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5,451,625 | 26438795 | 72 | Helicobacter pylori exhibits a high level of intraspecies genetic diversity. In this study, we investigated whether the diversification of H. pylori is influenced by the composition of the diet. Specifically, we investigated the effect of a high-salt diet (a known risk factor for gastric adenocarcinoma) on H. pylori diversification within a host. We analyzed H. pylori strains isolated from Mongolian gerbils fed either a high-salt diet or a regular diet for 4 months by proteomic and whole-genome sequencing methods. Compared to the input strain and output strains from animals fed a regular diet, the output strains from animals fed a high-salt diet produced higher levels of proteins involved in iron acquisition and oxidative-stress resistance. Several of these changes were attributable to a nonsynonymous mutation in fur (fur-R88H). Further experiments indicated that this mutation conferred increased resistance to high-salt conditions and oxidative stress. We propose a model in which a high-salt diet leads to high levels of gastric inflammation and associated oxidative stress in H. pylori-infected animals and that these conditions, along with the high intraluminal concentrations of sodium chloride, lead to selection of H. pylori strains that are most fit for growth in this environment. | [
825,
830,
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] | [
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4
] | [
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2
] |
4,571,300 | 32708184 | 0 | The Lipid Receptor G2A (GPR132) Mediates Macrophage Migration in Nerve Injury-Induced Neuropathic Pain | [
24,
19
] | [
6,
3
] | [
4,
1
] |
3,519,187 | 39268259 | 21,360 | Thrombophilia, hypofibrinolysis, the eNOS T-786C polymorphism, and multifocal osteonecrosis | [
42
] | [
6
] | [
1
] |
1,849,189 | 19040733 | 7,666 | The genetic selection model was calculated for the evolution of the 677C>T genotypes. The genetic selection could be classified as codominant or incompletely dominant and directional with the heterozygous genotype having an intermediate fitness. For this kind of selection, the most appropriate mathematical model is dq = [spq(2hp+q-h)]/[p2 + 2pq(1-hs) + q2 x (1-s)], where dq is the change of frequency of the allele with lower fitness, s is the fraction of that genotype lost to selection, h is the degree of dominance (between 0, for no dominance and 1, for complete dominance), and p is the frequency of the allele with higher fitness. | [
68
] | [
6
] | [
1
] |
3,768,238 | 34203356 | 7,197 | The inverse-variance weighted method with random-effects was used as the main analysis. This method provides the most accurate estimate but is sensitivity to pleiotropy. Thus, we employed the weighted median approach and MR-Egger regression as sensitivity analyses. The weighted median method can generate consistent causal estimates assuming >50% of the weight comes from valid SNPs. The MR-Egger regression can detect possible pleiotropic effects and provide estimates after correction for pleiotropy. The I2 statistic was calculated to assess the degree of heterogeneity across estimates of instruments in one analysis. We used the p-value for intercept in MR-Egger to detect the directional pleiotropic effect. To minimize pleiotropy, we performed a sensitivity analysis using rs2472297 in CYP1A1/2 and rs4410790 in AHR as instrumental variables. Considering positive genetic correlations of coffee consumption with BMI and smoking, we obtained causal estimates of associations of coffee consumption with cardiovascular disease using the multivariable inverse-variance weighted model with adjustment for BMI and smoking initiation. Given a small overlap (~23%) between exposure and outcome samples, we calculated the F-statistic to assess the strength of the instruments assuming ~0.48% variance in coffee consumption explained by the 12 SNPs. We used the Bonferroni method to adjust for multiple-testing and associations were considered statistically significant at a p-value < 0.003 (0.05/15 outcomes). The statistical analyses were conducted using the packages mrrobust in Stata/SE (version 15.0, StataCorp, College Station, TX, USA) and TwoSampleMR in R Software (version 3.6.0, R Core Team, Vienna, Austria). | [
820,
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4,943,118 | 28720660 | 39,942 | Because the WMD bears resemblance to PX domains, we finally tested whether residues predicted to be part of this domain were required for PI(3)P binding in vitro and for membrane localization in cells. We generated a R29A/F30A mutant version of the WMD fused to MBP and purified it alongside the wild-type MBP-WMD (Figure 10A). To compare the affinity of the WMD(RF/AA) mutant and WMD(WT) for PI(3)P, we used the MBP-tagged constructs to probe arrays containing different amounts of this phospholipid. As predicted, based on the conservation of R29 and F30 in the PX consensus sequence, mutation of these residues to alanine resulted in a dramatically lower degree of WMD binding to PI(3)P (Figure 10B). Even when PI(3)P was present at its highest amount (100 pmol), it bound approximately fourfold less WMD(RF/AA) than WMD(WT) (Figure 10B and Supplemental Figure S5E), further demonstrating that R29 and F30 are crucial for the interaction with PI(3)P. | [
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2,333,632 | 34960755 | 25,056 | Similarly, GMTs against B.1.1.7 (955 for Pfizer and 1917 for Moderna) and B.1.429 variant with the L452R substitution (1063 for Pfizer and 1799 for Moderna) were comparable to those against WT(D614G). Consistent with previous observations, the B.1.351 variant (GMT 169 for Pfizer and 306 for Moderna) displayed ~7-fold lower titers compared to WT(D614G), whereas C.37, P.1, R.1, and B.1.526 variants displayed modestly reduced titers that are similar to the titers against B.1.617 pseudoviruses (GMT 452-707 for Pfizer and GMT 824-1332 for Moderna). Overall, the trends in neutralization titers for the vaccine-elicited sera against a large panel of variant pseudoviruses were similar to those for convalescent sera, though the GMTs were approximately 3- to 5-fold higher for vaccine-elicited sera. | [
193,
347,
99
] | [
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5,
5
] | [
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2
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54,515 | 38000896 | 57,908 | Overlapping of translated uORFs. A to C) Translational profiles of 3 CPuORF genes showing the overlapping of translated uORFs. The positions of CPuORFs (red boxes) and other uORFs (blue or teal boxes, depending on their reading frame) are indicated. In B) and C), zoom-ins of the overlapping region between the CPuORF and the stacking uORF (suORF) are shown. Note that bZIP11 in A) is also shown in Fig. 7B as an example of periodic ribosome stalling upstream of the CPuORF stop codon. | [
369,
33
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6,
6
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1,339,319 | 39940106 | 18,338 | Pre-assembled signalling complexes are an emerging general feature of signal transduction. cAMP signalling is organised in nanodomains, with close coordination of cyclases, phosphodiesterases and cAMP receptors in complexes often nucleated by AKAPs. However, given that cyclases are the source of all cAMP signals, it might be expected that these enzymes would play a more prominent role in coordinating multiprotein complexes for precise spatiotemporal regulation of cAMP signalling. Given that many important channels and transporters:in addition to all ~ 800 GPCRs :feature bundles of TM helices, there is tremendous scope for interactions between these elements and AC TM helices (Fig. 2D). Multiple tmACs interact with AKAPs including Yotiao, AKAP79 and mAKAPbeta but these interactions typically involve the cytosolic N-terminal regulatory regions of the cyclases. There are a few reports of cyclase interactions involving the TM domain. Bioluminescence resonance energy transfer (BRET) and bimolecular fluorescence complementation show that AC5 interacts with both adenosine 2A (A2A) and type-2 dopamine (D2R) receptors. Furthermore, disruption experiments with peptides derived from specific TM helices suggest that the interface between AC5 and these receptors depends on the receptor activation state. For example, in the presence of the A2AR agonist CGS21680, peptides corresponding to any of the first six TM helices from AC5 disrupt AC5-A2AR interactions, whereas helices 1 and 12 are the most effective disruptors prior to receptor activation. AC9 interacts with POPDC1/2 in the heart through an interaction that involves both TM and cytosolic elements in POPDC. POPDC is thought to bridge AC9 to TREK-1 channels in this context , although the details of the membrane interface have not been established. | [
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3,545,146 | PMC12897130 | 33,622 | Frequent carriage of pESI-like megaplasmids among S. Infantis supports the global pattern of MDR S. Infantis lineages reported across the Americas, Europe, and the Eastern Mediterranean. The pESI-like features observed in this study, including ESBL-associated determinants (e.g., blaCTX-M-65), IncFIB(K) replicons, and QRDR mutations such as gyrA D87Y, are consistent with prior descriptions of emerging S. Infantis lineages. Moreover, detection of qacEDelta1, a marker associated with tolerance to quaternary ammonium disinfectants, mirrors early pESI characterizations and suggests a potential contribution to persistence under hygiene practices relying on QAC-based disinfectants. The presence of class I integrons (intI genes with attI/attC regions) within IncFIB(K) plasmid backbones is consistent with prior reports, and supports the role of pESI-like elements as platforms for the acquisition and dissemination of AMR-associated gene cassettes across diverse reservoirs. The representative pESI-like plasmid sequence also contained multiple mobile genetic element signatures (e.g., transposons and prophage-related regions) and genes associated with metal tolerance, including tellurite resistance determinants, which have been described in other Enterobacterales such as E. coli. Together, these features are compatible with ongoing horizontal gene transfer and adaptive processes in environmental interfaces. In addition, detection of less common plasmid replicons (e.g., IncFIB(pHCM2)_1_pHCM2 and ColpVC_1) in a small subset of poultry-meat S. Infantis isolates suggests occasional acquisition of plasmid backbones more frequently reported in other serovars. IncFIB(pHCM2)-like replicons have been described in S. Tennessee recovered from dead chick embryos in Henan Province, China, during 2014-2015 (2139 embryos sampled across 28 hatcheries) Additionally, a USA surveillance dataset from North Carolina (2018-2019) reported IncF-family virulence plasmid replicons (IncFII(S)_1 and/or IncFIB(S)_1) in poultry-associated serovars, including chicken-derived S. Enteritidis. | [
347
] | [
4
] | [
2
] |
2,854,228 | PMC12841848 | 91,920 | Whole-Exome Sequencing and Experimental Validation Unveil the Roles of TMEM229A Q200del Mutation in Lung Adenocarcinoma | [
71,
80
] | [
8,
7
] | [
4,
2
] |
2,330,953 | 29315345 | 3,122 | Interestingly, SOX10 expression is required for efficient therapeutic targeting of the activating BRAFV600E mutation in melanoma. This BRAF mutation is found in approximately 50% of patients with advanced melanoma and causes constitutive activation of the Mitogen Activated Protein Kinase (MAPK) pathway. Targeted inhibition of the BRAFV600E mutation with the small molecule inhibitor PLX4032 (Vemurafinib) decreases MAPK pathway signaling and has shown rapid responses in patients. However, this agent is rarely curative, due to acquired resistance through several mechanisms employed by tumor cells to increase MAPK signaling in the presence of inhibitor. Loss of SOX10 was shown to increase inhibitor resistance via elevated expression of the receptor tyrosine kinase EGFR. This suggests SOX10 can regulate EGFR levels in melanoma, and that reducing SOX10 protein may play an important role in acquired resistance. | [
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1,304,256 | 31877994 | 30,405 | The signals comprising both potential and current traces were stored online and sampled at 10 kHz using an ASUS VivoBook Flip-14 touchscreen laptop computer (TP412U; Taipei City, Taiwan), which was equipped with a Digidata 1440A interface (Molecular Devices) for analog-to-digital/digital-to-analog conversion. During the recordings, the latter device was driven by pCLAMP 10.7 software (Molecular Device) running on Windows 10 (Redmond, WA, USA), and the signals were simultaneously monitored on an MB169B+ monitor (ASUS, Taipei, Taiwan) through a USB type-C connection. When current signals were acquired, they were low-pass filtered at 2 kHz with a FL-4 four-pole Bessel filter (Dagan, Minneapolis, MN, USA) to minimize background noise. Through digital-to-analog conversion, various voltage-clamp profiles with either rectangular or ramp waveforms were created from pCLAMP and then applied to evaluate either the current versus voltage (I-V) relationship or the steady-state activation curve for the different types of ionic currents. As high-frequency stimuli needed to be delivered, an Astro-med Grass S88X dual output pulse stimulator was used (Grass Technologies, West Warwick, RI, USA). After the data were digitally collected, they were then analyzed using different analytical tools including the LabChart 7.0 program (AD Instruments, Castle Hill, Australia), 64-bit OriginPro 2016 (Microcal, Northampton, MA, USA), or custom-made macros built under Microsoft Excel 2013 (Redmond). | [
1108
] | [
4
] | [
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] |
1,806,182 | 22787448 | 66,555 | Role of the S6 C-terminus in KCNQ1 channel gating | [
29,
12
] | [
5,
2
] | [
4,
2
] |
2,823,559 | 39114506 | 18,215 | SNP PP.H0.abf PP.H1.abf PP.H2.abf PP.H3.abf PP.H4.abf rs1959910 0.04808632 0.9048905 0.001337023 0.025139612 0.02054654 rs34292801 0.46447663 0.4899215 0.006157673 0.006462019 0.03298217 rs4814813 0.01312701 0.956298 0.000171904 0.012505231 0.01789786 rs73088610 0.45102883 0.4911956 0.015389112 0.01673395 0.02565252 | [
56,
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10
] | [
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857,401 | 28401144 | 21,021 | The conservation of the [4Fe-4S] cluster in these mutant proteins indicates that these mutants may actively conduct the SP TpT repair. Considering that an alanine is only slight bigger than a glycine residue and position 168 is located at a flexible junction of a beta-strand and a peptide loop, we expect that the SPL G168A mutant may exhibit a similar activity as the WT enzyme. A careful examination of the G168A mutant activity reveals that SP TpT was repaired to TpT at 0.09 +- 0.01 min-1 (Figure 6A), suggesting that the G A mutation retains the enzyme activity. However, comparing with the repair efficiency of 0.35 +- 0.05 min-1 exhibited by the WT SPL (Yang et al.,), the activity of the G168A mutant is reduced by 3~4-fold. | [
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778,008 | 37485173 | 5,942 | ECD is driven by somatic mutations of BRAF and/or other signaling molecules. No infectious or environmental cause of ECD has been identified in the literature, and there is no evidence to suggest that it is inherited. BRAF V600E mutation has been detected in approximately half of ECD patients. As a result, symptomatic patients presenting with evidence of organ dysfunction or CNS involvement are often treated with BRAF inhibitors like vemurafenib. Other therapies include MEK inhibitors, interferon alfa, glucocorticoids, or systemic chemotherapy. Asymptomatic patients who have no evidence of organ dysfunction or CNS involvement are usually observed relative to being treated immediately. | [
38,
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] | [
4,
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5
] | [
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2
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3,187,061 | 33069768 | 30,224 | In summary, here we describe a new tumor suppressor protein function of AGGF1 and we propose a novel signaling mechanism of tumor suppression. We show, using in vivo, in vitro, and human cancer mutations, that AGGF1 is a potent inhibitor of proliferation of multiple types of tumor cells. Importantly, we show that three somatic mutations in the FHA domain of AGGF1 identified in human cancers (p.Q467H, p. Y469 N, and p.N483T) are functional pathogenic variants that attenuate the tumor suppressing activity of AGGF1. An interesting aspect of AGGF1-mediated tumor suppression is its cell type-specific activity in tumor cells with the presence of p53, but not in cells without p53 expression. An unexpected finding of this study is that an angiogenic factor can function as a tumor suppressor, which may act as a braking system to minimize the effects of angiogenic factors in the stroma to stimulate tumor growth. As angiogenic factor AGGF1 is currently being developed into therapies to treat human diseases such as CAD and MI, cardiac hypertrophy and heart failure, ischemia-reperfusion, peripheral vascular disease, and restenosis after vascular injury, the finding that AGGF1 acts as a tumor suppressor when overexpressed in tumor cells may minimize some concerns regarding stimulation of tumor growth by angiogenic factors, which may be advantageous for AGGF1 during evolution. | [
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811,315 | 41560006 | 8,080 | Time node Critical incident Laboratory/Imaging results Treatment measures 0 h after admission Emergency visit, ECG: STEMI Platelet 784 x 109/L troponin I normal BP 98/62 mm Hg Aspirin 300 mg,Clopidogrel 300 mg heparin 2 h after admission TroponinI:4.75 ng/mLECG: STEMI Thrombus in the distal middle segment of the right coronary artery (Fig. 2A) intraoperative electrical storm Implantation of a 3.0 x 29 mm stent and temporary pacemaker (Fig. 2B), followed by 4 defibrillation procedures Admitted ICU BP: 83/51 mm Hg Blood gas analysis: PH 7.201Lac 5.19 mmol/LEF 60% Norepinephrine 0.8 mug/kg/min, multimodal monitoring 24 h after admission (ICU day 1) Bellyache White blood cell 36.92 x 109/Lprocalcitonin 6.26 ng/mLcreatinine 204 micromol/Lplatelet count of 1357 x 109/Labdominal CT showed pancreatic blurring + retroperitoneal effusion (Fig. 3A and B) Piperacillin tazobactam 4.5 g q12hmonitored fluid resuscitationaspirin 100 mg + clopidogrel 75 mgenoxaparin 1 mg/kg q12h 72 h after admission (ICU day 3) Cyclic stability WBC 19.18 x 109/LPCT 1.26 ng/mLcreatinine 90 micromol/L,platelet count of 747 x 109/L Disable norepinephrine, restricted fluid (1500-1800 mL)enoxaparin 1 mg/kg qdtransferred out of ICU 1 wk after admission Infection control platelets remain high WBC 14.96 x 109/LPCT 0.13 ng/mL,platelet count of 874 x 109/LAbdominal CT scan shows normal results (Fig. 3C and D) Discontinue enoxaparin ticagrelor 90 mg bid, complete bone marrow smear bone marrow proliferative tumor-related gene mutation test 2 wk after admission Remission Platelet count of 680 x 109/L80% mutation in the JAK2 V617F gene of the bone marrow Hydroxyurea 1 g qd ticagrelor 90 mg bid Follow-up 1 mo No complaints Platelet count of 439 x 109/L Hydroxyurea 0.5 g qd | [
1614
] | [
10
] | [
2
] |
3,011,337 | 16738139 | 14,331 | The PS1betaH and hydrophobic loop form a ringed array in the central channel of T-antigen, through which DNA is proposed to thread as it is unwound. Wild-type E1HD bound ssDNA to a greater extent in the presence of ATP (ATP/Mg2+; herein referred to simply as ATP) compared with its absence (Figure 5a, lanes 2-4, top compared with bottom). R505E did not bind DNA without ATP but was active in its presence (lanes 5-7, top compared with bottom). K506E and K506A were inactive for DNA binding (lanes 8-13, top and bottom), with or without ATP, except for formation of a fast-migrating species for K506A with ATP (lane 13, bottom). For the H507 substitutions (lanes 14-22), ssDNA binding was dependent on the bulk of the amino acid side chain (HF > wild-type > HL > HA), and in each case augmented in the presence of ATP. The gel-shift pattern for H507L and H507A with ATP indicated a level of complex instability, judged by some partial retardation of probe (lanes 15 and 16, 18 and 19). | [
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2,885,309 | 34191960 | 48,362 | Communication from the Commission Temporary Framework for State Aid Measures to Support the Economy in the Current COVID-19 Outbreak 2020/C 91 I/01, C/2020/1863 [2020] OJ C 91I/1-9. | [
171,
138
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5,064,421 | 26748988 | 4,455 | Patient# Gender Age Inheritance Genetic mutation BCVAa (decimal) fERGa (mV) 1 M 38 Autosomal recessive CERKL R257X (homozygous) 0.39 0.30 2 M 28 Autosomal recessive Unknown 0.17 0.09 3 M 59 Autosomal dominant Unknown 0.85 0.58 4 M 69 Autosomal recessive CRX V242M (heterozygous) 0.32 0.12 5 F 48 Autosomal dominant RHO R135W 0.10 0.41 6 F 62 Autosomal recessive Unknown 0.05 0.30 7 M 57 Autosomal dominant Unknown 0.57 0.16 8 M 37 X-linked Unknown 0.10 0.27 | [
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2,218,961 | 32575418 | 2,837 | Pancreatic neuroendocrine neoplasms (pNENs) are the second most common malignancies of the pancreas and mainly occur in elderly patients. Their incidence of currently 1-2/100000 inhabitants in the United States and Europe is steadily increasing. A recent multicenter study in Austria has shown 5 and 10 year survival rates after surgical resection of around 81% and 50%, respectively. A large international cohort study validated the pNEN grading system to distinguish well differentiated pNET (G1, G2, G3) and poorly differentiated pNEC (only G3 by definition). Based on the secretion of peptide hormones, pNENs can be classified as functional and non-functional, with the majority of 60-85% being non-functional. Moreover, pNENs can be associated with familial syndromes in approximately 10% of cases, while most pNENs are sporadic. TPMs in pNETs were recently found to be mainly associated to patients with hereditary syndromes, but not to sporadic cases. In detail, 4 of 55 (7%) pNET patients showed exclusive single TPMs with C228T, but no C250T alteration and 3 of 4 (75%) TPM cases occurred in patients with hereditary syndromes, such as multiple endocrine type 1 (MEN1) and Von Hippel-Lindau (VHL). | [
1031,
1045
] | [
5,
5
] | [
1,
1
] |
364,488 | 29330839 | 39,772 | Association between smoking, nicotine dependence, and BDNF Val66Met polymorphism with BDNF concentrations in serum | [
86,
54,
59
] | [
4,
4,
8
] | [
4,
4,
2
] |
3,853,935 | 34857772 | 22,643 | Using two-sample MR, we confirm a significant causal association between serum CD33 (myeloid cell surface antigen CD33) and Alzheimer's disease (AD; BETA = 0.0091; SE = 0.0017; inverse variance-weighted [IVW] Padj = 3.62 x 10-4) (Figs. 3 and 4a). The role of CD33 in AD is further affirmed by positive colocalisation between the cis-pQTL with the causal variant rs2455069 (MAF = 0.3967; P = 2.03 x 10-1580; BETA = 1.2092; SE = 0.0142), and a known AD-associated locus (CLPP4 = 0.82). CD33 is upregulated in the AD brain and is positively correlated with disease severity, while knockout mice have been shown to have reduced amyloid plaque formation. Additionally, the cis-pQTL for CD33 colocalises with an eQTL for the CD33 gene in whole blood (CLPP4 = 0.95) and in the brain (cerebellar hemisphere CLPP4 = 0.62), indicating a shared regulatory pathway for gene and protein expression. | [
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4,498,207 | 38439078 | 86,575 | Depletion of mast cells and macrophages impairs heterotopic ossification in an Acvr 1(R206H) mouse model of fibrodysplasia ossificans progressiva | [
86
] | [
5
] | [
2
] |
1,047,117 | 35055209 | 14,086 | Figure 4a,b represent the current-voltage (I-V) curves of the different types of devices under dark and light illumination of 0.1 mWcm-2, respectively. In addition to the single layer (D1) and trilyer (D4) devices, we added two more devices for comparison, i.e., the bilayer perovskite devices with glass/GO/Perovskite (D2) and another bilayer device with glass/TiO2/Perovskite (D3). The D1 device shows the highest dark current of 9.03 x 10-11 A, at a bias voltage (V) of 5 V, while the D4 device with graphene oxide exhibits the lowest dark current of 1.55 x 10-11 A. The significant reduction in the dark current of the D4 device can be attributed to the presence of depletion region (caused by the addition of GO layer in our case) It is consistent with the fact that the dark current measured in the two bilayer perovskite devices reaches 4.35 x 10-11 A and 3.39 x 10-11 A, for D2 (GO/Perovskite) and D3 (TiO2/Perovskite), respectively, which are higher than that of D4 photodetector device. In other words, the low dark current in the D4 photodetector is caused by the extra depletion regions at the two interfaces introduced by GO layer, which leads to the narrowing of the conducting region. | [
466
] | [
8
] | [
2
] |
3,175,376 | 32064097 | 23,787 | IL-1alpha and IL-1beta, two members of IL-1, have a common receptor with shared SNPs (IL-1alpha-889C>T and IL-1beta-3737C>T). Our results show that C:T polymorphisms of the IL-1alpha-889C>T and IL-1beta-3737C>T were associated with MM risk. IL-10 is one of the well-investigated pro-inflammatory cytokines. It is documented that IL-10-592G/A and IL-10-1,082G>A SNPs are located in the negative and positive regulatory sequence of the promoter region, respectively. The IL-10 gene with -592 (C) or -1,082 (G) is associated with a high expression of IL-10, and it has a low expression with -592 (A) or -1,082 (A). Our results indicate that the C allele of IL-10-592 has no significant association with MM susceptibility under the three allele model, CC/AA, CC/AC and AC/AA18. In contrast, our cumulative results indicate that IL-10-1082G>A is found to be associated with MM risk (R=1.18, 95% CI, 0.94-1.3). | [
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661,023 | 19877176 | 105 | 3-M syndrome is an autosomal recessive disorder characterized by severe pre- and postnatal growth retardation and minor skeletal changes. We have previously identified CUL7 as a disease-causing gene but we have also provided evidence of genetic heterogeneity in the 3-M syndrome. By homozygosity mapping in two inbred families, we found a second disease locus on chromosome 2q35-36.1 in a 5.2-Mb interval that encompasses 60 genes. To select candidate genes, we performed microarray analysis of cultured skin fibroblast RNA from one patient, looking for genes with altered expression; we found decreased expression of IGFBP2 and increased expression of IGFBP5. However, direct sequencing of these two genes failed to detect any anomaly. We then considered other candidate genes by their function/location and found nine distinct mutations in the OBSL1 gene in 13 families including eight nonsense and one missense mutations. To further understand the links between OBSL1, CUL7, and insulin-like growth factor binding proteins (IGFBPs), we performed real-time quantitative PCR (RT-PCR) analysis for OBSL1, CUL7, IGFBP2, and IGFBP5, using cultured fibroblast RNAs from two patients with distinct OBSL1 mutations (p.F697G; p.H814RfsX15). We found normal CUL7 mRNA levels but abnormal IGFBP2 and IGFBP5 mRNA levels in the two patients, suggesting that OBSL1 modulates the expression of IGFBP proteins. | [
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4,630,852 | 20339440 | 3,329 | The HA-tagged NUP98-DDX10 cDNA was generated by PCR and subcloned into EcoRI/XbaI sites of pTracer-CMV/Bsd. The NUP98-DDX10/3Q mutant was created by replacing an EagI/HindIIII fragment with a synthetic fragment containing 3 arginine to glutamine mutations in the YIHRAGRTAR motif. HA-tagged NUP98-DDX10 and NUP98-DDX10/3Q were subcloned upstream of IRES into the HpaI site of MSCV-IRES-GFP. PCR products and mutations were confirmed by sequencing. The KBTBD10 and PLN luciferase constructs were previously described. | [
14,
112,
291,
307,
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313,
297,
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452,
222
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23
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2,459,357 | 30105048 | 25,122 | HIV Gene Position (amino acid residue) SNP (Chromosome: bp) P-value PR 35(E) rs2596477 (6:31327723) 8.503e-28 35(D) rs17199328 (6:31322395) 4.083e-25 12(T) rs75344417 (6:31429439) 1.559e-15 12(A) rs116855165 (6:31059097) 1.266e-11 37(N) rs2596477 (6:31327723) 3.370e-14 93(I) rs9378249 (6:31327701) 1.953e-13 93(L) rs9378249 (6:31327701) 1.953e-13 67(Y) rs9391775 (6:31427948) 3.394e-12 RT 135(I) rs2844527 (6:31367636) 3.444e-35 135(T) rs79556279 (6:31329846) 1.114e-29 165(T) rs2442724 (6:31319907) 1.557e-13 165(I) rs92647589 (6:31248434) 1.919e-12 123(E) rs114773933 (6:31148349) 1.917e-12 138(A) rs114073761 (6:31336749) 1.929e-11 | [
70,
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3
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5,273,412 | 22771212 | 25,240 | While our studies revealed an unexpected role for Sgf11 in maintaining the overall folding of the DUBm into a compact complex, it is possible that the Sgf11-ZnF also contributes to Ubp8 activity by stabilizing the catalytically competent configuration of the active site through interactions with loops L2. We were unable to obtain crystals of the monomeric form of the DUBm lacking the Sgf11-ZnF and containing the Ubp8 S149N mutation or the S149N/S144N mutations, so this question could not be addressed directly in our study. The activated double mutant is still 10-fold less active than the wild-type intact DUBm, indicating that Sgf11 makes an additional contribution to full enzymatic activity besides its role in maintaining the properly folded monomeric DUBm. | [
50,
151,
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416,
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421,
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5,188,519 | 34680268 | 23,383 | Sarcomatous transformation of a conventional GCTB (secondary malignant GCTB) is a rather uncommon phenomenon accounting for an incidence of 2.4% of all GCTB cases. Most cases occur after radiotherapy, although occasionally malignancy may arise subsequent to denosumab treatment. The malignant part of the otherwise conventional type GCTB does not have specific morphological features. This transformation may be into an undifferentiated sarcoma or into several types of osteosarcoma. (1,5) Primary malignant GCTB is even more rare and accounts for 1.6% of all GCTB cases. In some of these cases the H3.3-G34W mutation is retained. When dealing with a giant-cell-rich osteosarcoma the differential diagnosis with primary or secondary maligant GCTB can be very challenging. Next to histological examination, interpretation of the radiological features may be of major help in distinguishing both entities. Molecularly, a recent publication reported that maligant bone tumours with a H3.3-G34W mutation possess features resembling osteosarcoma. More specifically, they carry an increased burden of somatic mutation variants. Of major interest in view of the differential diagnosis with (giant cell rich) osteosarcomas, and more specifically concerning the relation between H3.3-G34W and telomere biology in GCTB, is that H3.3-G34W mutated maligant bone tumours are enriched with a variety of alterations involving TERT suggesting telomere dysfunction in the transformation of benign to malignant GCTB. This finding is in line with the above-stated hypothesis of a delicate balanced telomere stability in GCTB. Once instable, futher cytogenetical abberations are needed in order to transform into malignancy where the H3.3-G34W mutation itself may become nonessential in this process. Moreover, the authors found that hypermethylation of the CCND1 promotor is specific for GCTB and therefore cyclin D1 is a plausible cancer-driver gene. This finding is in line with the earlier-mentioned accelerated cell cycle in GCTB where its progression is linked to increased risk of disease progression. | [
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3,033,614 | 28224001 | 17,410 | Gene name Gene ID* Nucleotide level Protein level PmLEA8 Pm026682 r.135A > C r.292_396dup r.646_699dup Q45H D98_T132dup P216_T233dup PmLEA10 Pm026684 r.93G > C r.461A > G r.513G > C D154G PmLEA19 Pm020945 No No PmLEA20 Pm021811 r.266A > G r.416C > A r.537T > C r.609T > G N89S T139K PmLEA29 Pm006114 r.336C > T No | [
280,
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114
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4,843,180 | 39766603 | 66,325 | Substitution of lysine for isoleucine at the center of the nonpolar face of the antimicrobial peptide, piscidin-1, leads to an increase in the rapidity of bactericidal activity and a reduction in toxicity | [
16
] | [
21
] | [
2
] |
1,613,033 | 28607813 | 104 | Bone morphogenetic proteins (Bmp) are well-known to induce bone formation following chondrogenesis, but the direct role of Bmp signaling in the osteoblast lineage is not completely understood. We have recently shown that deletion of the receptor Bmpr1a in the osteoblast lineage with Dmp1-Cre reduces osteoblast activity in general but stimulates proliferation of preosteoblasts specifically in the cancellous bone region, resulting in diminished periosteal bone growth juxtaposed with excessive cancellous bone formation. Because expression of sclerostin (SOST), a secreted Wnt antagonist, is notably reduced in the Bmpr1a-deficient osteocytes, we have genetically tested the hypothesis that increased Wnt signaling might mediate the increase in cancellous bone formation in response to Bmpr1a deletion. Forced expression of human SOST from a Dmp1 promoter fragment partially rescues preosteoblast hyperproliferation and cancellous bone overgrowth in the Bmpr1a mutant mice, demonstrating functional interaction between Bmp and Wnt signaling in the cancellous bone compartment. To test whether increased Wnt signaling can compensate for the defect in periosteal growth caused by Bmpr1a deletion, we have generated compound mutants harboring a hyperactive mutation (A214V) in the Wnt receptor Lrp5. However, the mutant Lrp5 does not restore periosteal bone growth in the Bmpr1a-deficient mice. Thus, Bmp signaling restricts cancellous bone accrual partly through induction of SOST that limits preosteoblast proliferation, but promotes periosteal bone growth apparently independently of Wnt activation. | [
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583,470 | 36032194 | 21,459 | TRPA1 is a heat-sensitive ion channel and contributes to thermal detection and thermotaxis behavior in reptiles. We performed electrophysiological and laser irradiation experiments to examine divergence between wild-type and mutant TRPA1 (ie, with three T. baileyi-specific replacements) in response to heat. Figure 5A shows the temperature responses of the two types of TRPA1 after repeated stimulation with different temperatures produced by laser irradiation. The TRPA1 agonist (4-aminodiphe-nylamine) is potent against reptile TRPA1 orthologs, activating the channel with a high probability of opening in the absence of heat (Figure 5A). Whole-cell recordings indicated that heat activation of TRPA1 was normalized to agonist-induced currents (Figure 5A). We found that the temperature threshold (~29 C-30 C) was comparable between the wild-type and mutated TRPA1 (Figure 5B). Subsequently, the peak currents of the wild-type and mutant channels significantly increased upon heating (Figure 5B). We then compared the current amplitudes at the end of each stimulus. Results showed that heat sensitivity of the TRPA1 mutant was higher than that of the wild type (Figure 5C). Functional analysis showed that the three T. baileyi-specific replacements in the TRPA1 did not alter the temperature-response threshold values but increased heat sensitivity to some extent. | [
805
] | [
6
] | [
1
] |
384,402 | 21773006 | 48,901 | To identify common polymorphisms, extensive sequencing of the Apo A5 interval in humans has been performed. A set of 4 common polymorphisms (SNPs1 through 4; also named 259T/C, IVS3+476G/A, -1131T/C, and -12,238T/C, resp.) were first identified within the human Apo A5. Statistical analysis indicated that the minor alleles SNPs 1 through 3 formed a relatively common haplotype that is found in approximately 15% of Whites. | [
62,
262,
190,
177,
169,
208
] | [
6,
6,
8,
11,
6,
6
] | [
4,
4,
1,
1,
1,
1
] |
1,911,749 | 34324310 | 33,294 | In previous studies, we attributed the inability of the Y75H holo-HasAp to activate the CSS cascade to the potential of a stronger bis-His ligation. In an effort to further understand the significance of the His-Tyr motif in controlling the release of heme to HasR, we performed spectroscopic and structural analysis of the Y75H holo-HasAp variant. SPR analysis of the interaction of Y75H holo-HasAp with HasR confirmed the inability to trigger the CSS cascade was not due to disruption of the protein-protein interaction (Figure 1). Moreover, despite the retention of the protein-protein interaction, supplementation of the DeltahasAp strain with [13C]heme-loaded Y75H HasAp showed a growth defect consistent with the lack of [13C]heme-derived biliverdin metabolites compared to WT holo-HasAp supplementation (Figure 2). Taken together, the data are consistent with a stronger heme ligation inhibiting heme sensing and uptake by preventing the release of heme to the receptor. | [
66,
334,
394,
670,
788,
56,
384,
208,
665,
324
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4
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2,
2
] |
2,427,562 | 24207128 | 37,832 | Reexamination of the role of the leucine/isoleucine zipper residues of phospholamban in inhibition of the Ca2+ pump of cardiac sarcoplasmic reticulum | [
33
] | [
18
] | [
2
] |
669,343 | 11500821 | 80 | The ability of specific virally encoded proteins to down-regulate MHC class I molecules may enable infected cells to elude killing by CTL. In the case of HIV-1, Nef appears to be responsible for this effect. Thus, interfering with Nef-induced MHC class I down-regulation would be a strategy for increasing HIV-1-specific CTL activity, particularly towards long-lived T cell populations such as memory T cells that harbor replication-competent virus. Here, using two Nef-expressing human cell model systems, we show that a dominant-negative mutant derived from the Hck protein-tyrosine kinase, composed of the Hck N-terminal region, as well as the SH3 and SH2 domains, was able to inhibit Nef-induced MHC class I molecule down-regulation. This effect was SH3 domain dependent as it was not evident when the cells were transfected with DN-Hck-W93F, an SH3 domain mutant. The inhibitory effect of dominant-negative-Hck (DN-Hck) on Nef-induced class I down-regulation suggests that this Nef-mediated effect requires an interaction between the Nef polyproline site and an SH3-containing cellular protein that is involved in MHC class I molecule turnover. Interfering with the function of the Nef SH3 binding site in this way represents a strategy for assisting the host CTL response to clear HIV-1-infected cells. | [
161,
231,
466,
564,
568,
609,
688,
841,
912,
928,
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1039,
1187
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4
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1,952,791 | 19905033 | 32,337 | Channel activity was assayed by TEVC for A/M2 channels expressed in Xenopus oocytes. Responses in the presence of various concentrations of an inhibitor (I) were normalized to the current evoked by application of the activating (pH 5.5) solution without inhibitor (I0). The experimental data are the average of three independent experiments. Each point is the mean (+-SD) of 5-8 oocytes. IC50 values in muM: A/M2 with amantadine IC50=15.76+-1.24; with BL-1743 IC50=46.25+-3.56; with spiran amine 8 IC50=12.59+-1.11. A/M2-L26F with amantadine IC50=164.46+-14.40; with BL-1743 IC50>10 mM; with spiran amine 8 IC50=30.62+-8.13. A/M2-V27A with amantadine IC50=1840; with BL-1743 IC50>10 mM; with spiran amine 8 IC50=84.92+-13.61. A/M2- S31N with amantadine IC50=237.01+-22.14; with BL-1743 IC50>10 mM; with spiran amine 8 IC50>10 mM. | [
521,
732,
630
] | [
4,
4,
4
] | [
2,
2,
2
] |
847,261 | 38813459 | 7,565 | The total fat of Zhenba Bacon was extracted to measuring the peroxide value (POV) and acid value (AV). Take 5 g samples of Zhenba bacon from different periods (M, S8D, F16D and F32D), homogenize the tissue with a 2:1 chloroform-methanol mixture, and extracts were washed with 0.2 volumes of water or the appropriate salt solution to it. The resulting solution was mixed by a vortex mixer (Coroic, Shanghai, China) for 30 s and then centrifuged at 2500 rpm for 10 min at 4 C (Centrifuge 5702 R, Eppendorf, Germany). The resulting mixture underwent layering, with the lower layer being the total pure lipid extract. | [
168,
177
] | [
4,
4
] | [
2,
2
] |
3,188,729 | 31921875 | 23,776 | Associations of TM6SF2 167K allele with liver enzymes and lipid profile in children: the PANIC Study | [
16,
23
] | [
6,
4
] | [
4,
2
] |
2,331,811 | 33597243 | 1,336 | Wnt/beta-catenin signaling is required for many cell fate decisions in animal development and adult tissue homeostasis. Misregulation of the pathway has been linked to many cancers and other human pathologies. This pathway is centered around the stability of beta-catenin. In the absence of Wnt stimulation, beta-catenin is targeted for degradation by a "destruction complex" containing the scaffolding proteins Axin and APC, the protein kinases glycogen synthase kinase 3 (GSK3) and casein kinase I (CKI), and the SCF (Skp1/Cullin/F-box)-betaTrCP E3-ubiquitin ligase. Axin and APC recruit beta-catenin, and after sequential phosphorylation of specific Ser/Thr residues in its N terminus, beta-catenin is polyubiquitinated by betaTrCP and degraded by the proteasome. Wnt stimulation disrupts the function of the destruction complex, leading to stabilization and nuclear accumulation of beta-catenin protein where it acts as a transcriptional coactivator with T cell factor (TCF) family transcription factors. | [
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515,
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525,
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548,
569,
578,
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726,
767,
886,
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3,803,481 | 19245693 | 20,967 | To investigate the effect on a population-based level, analyses of obesity-related traits were moreover performed in the population-based Inter99 cohort. The association with body weight and height remained significant for CTNNBL1 rs6020846, while no associations were demonstrated for FDFT1 rs7001819, Additional file 2. | [
223,
286,
231,
292
] | [
7,
5,
9,
9
] | [
4,
4,
3,
3
] |
5,332,507 | 32341402 | 28,092 | Single Nucleotide Polymorphism (SNP) genotyping was used on all included human samples. Allelic discrimination method was performed using TaqMan assays on an ABI Step-One Plus (Applied Biosystems, Foster City, CA) real-time PCR instrument according to manufacturer's instruction. Pre-designed SNP Genotyping Assay probes were purchased from Applied Biosystems. PiS allele, rs1758 (assay ID: C_594695_20); PiZ allele, rs28929474 (assay ID: C_34508510_10); PiM2/M4 allele, rs709932 (assay ID: C_2895146_20) PiNull allele, rs28929473 (assay ID: C_63321235_20). Total RNA was extracted from mouse liver tissue with the TRIzol reagent (Invitrogen, Carlsbad, CA) and was reverse-transcribed using the high-capacity cDNA reverse transcription kit (Applied Biosystems, Thermo Fisher Scientific, Carlsbad, CA) into cDNA according to manufacturer's instructions. Specific TaqMan assays specific for housekeeping gene mouse Cyclophilin A (assay ID Mm02342429_g1) and human AAT gene SERPINA1 (assay ID Hs01097800_m1) containing primers and hydrolysis probes. Quantitative real-time PCR was performed on an ABI Step-One Plus instrument. | [
456,
916,
974,
965,
521,
418,
374,
472
] | [
4,
13,
8,
3,
10,
10,
6,
8
] | [
4,
4,
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4,
3,
3,
3,
3
] |
3,060,434 | 28594932 | 28,192 | Slower kinetics of RNA synthesis inhibition by an NS5A inhibitor for H77S.3 compared to H77D. | [
88
] | [
4
] | [
2
] |
1,364,441 | 40564901 | 29,058 | L-ASNase TsAI (GenBank accession No. WP_015849943.1) was heterologously expressed in E. coli cells using synthetic gene tsA_mod (GenBank accession No. MW981255) inserted into the pET-28a(+) vector. TsAID54G/T56Q mutant was designed and constructed as previously described. | [
207
] | [
4
] | [
2
] |
3,105,303 | 36506180 | 44,607 | Sequence alignment between KirBac1.1 and other Kir channels is shown in Figure 6. Many residues examined above are partially or completely conserved, implying relevance to hKir channels (Figure 6B-D). Q92 and D115 are not conserved in other channels. Since activity upon mutation to alanine was not significantly impacted, the role of Q92 and D115 may not be directly important for channel conductance, but they may act as hinges to accommodate motions of residues in direct allosteric contact. S104 and E106 are almost fully conserved across all channels. E130 is conserved in bacterial but not hKir channels. This position in hKir channels is typically glutamine, which could fulfill many of the same roles if E130 is protonated. V72, 73, and 133 are not perfectly conserved, but this position is always a branched hydrophobic residue in hKir channels. R181 is fully conserved across the Kir channels, highlighting the different modes of activation between channel types. F149 seems to be conserved in bacterial Kir channels, but most residues at this position are isoleucine or methionine in hKir channels. L140, when aligned with the other channels, is typically replaced with phenylalanine, suggesting a preference for larger side chains. The secondary glycine hinge G137 is not as conserved in hKir channels but seems to be more conserved as a bacterial specialty may stress that the importance of smaller hydrophobic residues is more favorable for TM helix motion across channels. In general, sequence alignments presented herein indicate that many of the observations and accompanying rationale we have presented could be widely applicable to hKir channel physiology. | [
495,
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557,
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2,
2,
1
] |
2,980,226 | 31363383 | 52,957 | (a) Reaction scheme of pairwise addition of p-H2 to allyl 1-13C-pyruvate in CD3OD followed by polarization transfer to 13C nuclei (HA and HB are two atoms from the same p-H2 molecule, cat. = [Rh(NBD)(dppb)]BF4). (b) Reaction scheme of the competing process of norbornadiene hydrogenation with p-H2. (c) 1H NMR spectrum acquired after 1H ALTADENA hyperpolarization of propyl 1-13C-pyruvate with 15 s p-H2 bubbling duration. (d) Corresponding thermal 1H NMR spectrum acquired after relaxation of hyperpolarization (multiplied by a factor of 32). epsilon1H = 480, P1H = 1.5% (2.0% at 85% p-H2 fraction) (calculated using signal 16b+17b). (e) 13C NMR spectrum acquired after 13C hyperpolarization of propyl 1-13C-pyruvate using MFC at 0.015 muT magnetic field with RG = 1. (f) Corresponding thermal 13C NMR spectrum acquired after relaxation of hyperpolarization with RG = 203. epsilon13C = 610, P13C = 0.47% (0.49% at 85% p-H2 fraction). (g) Dependence of conversion of allyl pyruvate to propyl pyruvate on p-H2 bubbling duration (estimated pseudo-first order rate constant k = 0.0031 +- 0.0002 s-1). (h) Dependence of 1H ALTADENA signal (absolute value) of HP propyl pyruvate (signal 16b+17b, red squares), norbornene (signal 19b, blue circles) and norbornane (signal 20b+20d, black triangles) on p-H2 bubbling duration. (i) Dependence of P1H (at 85% p-H2 fraction) of allyl acetate (signal 16b+17b, red squares), norbornene (signal 19b, blue circles) and norbornane (signal 20b+20d, black triangles) on p-H2 bubbling duration. (j) Dependence of P13C (at 85% p-H2 fraction) of propyl 1-13C-pyruvate on magnetic field used in MFC experiments (red squares - data points obtained with the 98% 13C-enriched precursor, blue circles - data points obtained with the 1.1% 13C-enriched precursor). | [
1762,
881,
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892
] | [
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2,
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2
] |
1,757,472 | 36457028 | 26,515 | To test this hypothesis, we first demonstrated the direct relationship between HPV16 early genes and the expression of c-Rel, p65, p50 coding genes Rel,Rela and Nfkappab1. Overexpression and shRNA vectors were constructed respectively to modulate HPV16 E5, E6,and E7 which expressed separately from the corresponding ectopic vector(named E5OE, E6OE, E7OE; shE5, shE6, shE7 respectively). P2K7 and H1 were transfected as empty control vectors (negative control)of overexpression and shRNA vector respectively. The expression of HPV16 E5, E6,and E7 after transfection are shown in Additional file 1: Fig. S3. After that, the effect on Rel,Rela and Nfkappab1 expression were examined by qRT-PCR independently (Fig. 2). When SiHa cells were transfected by shE5 vector, the expression of Rel,Rela and Nfkappab1 were all decreased compared with negative control(All P values are less than 0.05), while when E5OE vectors were transfected into C33-A cells, the expression of Rel,Rela and Nfkappab1 were all increased compared with negative control(All P values are less than 0.05). Differently, although shE6 and shE7 vectors infection could decrease Rel and Nfkappab1 expression of SiHa cells(these two P values are less than 0.05), E6OE and E7OE vector could not correspondingly increase the Rel and Nfkappab1 expression in C33-A cells. So the data showed that Rel,Rela and Nfkappab1 were regulated by HPV16 E5, but not sure be modulated by HPV16 E6 and E7. | [
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2,239,572 | 32520643 | 36,662 | The CRM1(E571K) mutation has been found in a variety of cancer types, with enrichment in advanced hematologic diseases. We examined the subcellular localization of 4E-T in tumor cells from CLL patients with and without a heterozygous E571K CRM1 mutation (Supplemental Figure 5). Patient samples across a range of cytogenetic profiles were selected (Supplemental Table 4). Patient samples WT-5 and K-5 are the only ones with normal cytogenetics. Patient cells were thawed and immunostained for endogenous 4E-T as was done for HEK 293 cells. Confocal microscopy imaging of immunostained CLL cells showed significantly lower C/N ratios of 4E-T (more nuclear) in patient cells with CRM1(E571K) compared with patient cells with WT CRM1: average C/N values for 4E-T in WT-1, WT-2, WT-3, and WT-4 cells range from 1.2 to 2.6 compared with average C/N values for K-1, K-2, K-3, and K-4 cells that range from 0.3 to 0.9 (p < 0.0001). Patient cells with normal cytogenetics, WT-5 and K-5, show an average C/N of 8.6 in WT-5 versus 3.0 in K-5 cells (p = 0.0017; Figure 7, C and D). | [
4,
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5,436,114 | 19290710 | 49,896 | Nutrition stage PCa Cb Pc Ad Me M(SD) M(SD) M(SD) M(SD) M(SD) Pair comparisons Linear termF = Quadratic termF = Cubic termF = Fourth-orderterm F = Behavior: Portions of Fruit and vegetables per day 2.95 (1.77) 3.10 (3.14) 3.80 (2.65) 5.14 (2.49) 6.79 (10.12) PC = C = P < A < M 125.46** 10.14** 0.03 0.03 Intention 1.27 (0.53) 2.12 (0.83) 2.88 (0.87) 3.31 (0.75) 3.37 (0.94) PC < C < P < A = M 1138.00** 124.00** 4.01* 0.36 Plans 1.48 (0.65) 1.75 (0.73) 2.08 (0.76) 2.55 (0.75) 2.70 (0.97) PC < C < P < A = M 534.59** 0.13 4.62* 2.44 Maintenance Easiness (R) 1.53 (0.74) 1.85 (0.90) 2.11 (0.95) 2.56 (0.88) 1.66 (0.86) PC < C < P < A > M 3.46 131.57** 46.27** 20.37** Habit 3.88 (1.06) 3.68 (0.99) 3.53 (0.98) 3.06 (0.80) 4.20 (0.85) PC = C = P < A < M 21.62** 124.70** 56.70** 30.16** Duration of behavior pattern performance (yrs) 14.19 (12.85) 10.94 (11.42) 8.16 (10.46) 1.86 (6.26) 8.61 (9.13) PC > C > P > A < M 60.34** 47.90** 29.70** 17.41** Social-cognitive variables Pros 2.65 (0.78) 3.15 (0.60) 3.39 (0.55) 3.54 (0.47) 3.54 (0.49) PC < C < P < A = M 334.20** 79.04** 1.99 0.87 Cons 2.32 (0.69) 2.22 (0.67) 2.06 (0.66) 1.95 (0.62) 1.60 (0.59) PC = C < P = A > M 265.29** 8.76** 0.78 2.28 | [
927,
1197,
651
] | [
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5,
5
] | [
1,
1,
1
] |
598,967 | 31551747 | 14,210 | A ball-screw type linear motion module (RS-075N-Z05PR, Robostar, South Korea) was combined to a 100 W AC servo motor (APM-SA01ACN2, LS Mecapion, South Korea) to build the linear actuator. The motor includes an electromagnetic brake to fix the position of the handle. The maximum stroke of the module was 400 mm, which was a sufficient length to test the reach of the upper limb. The motor was controlled by a commercial motor driver (XSJ-230-06, Copley Controls, United States). The gross weight of the linear actuator including the load cell and the gimbaled handle was 10.3 kg. To reduce the gravitational load on the linear actuator positioner mechanism due to the weight of the links and the linear actuator, a gravity compensation mechanism based on passive springs was added to the RRRR mechanism. For the detail of gravity compensation, we recommend referring to Kim and Song's study. | [
96
] | [
5
] | [
2
] |
5,109,761 | 36477686 | 19,301 | Histological and immunohistochemical features of xenotransplanted tumor, inoculated cloned cells with V595E ( +) or V595E ( -) | [
102,
116
] | [
5,
5
] | [
2,
2
] |
5,326,583 | 35153790 | 9,494 | Total protein was extracted from samples using RIPA buffer (P0013C, Beyotime) containing 1% phosphatase and protease inhibitors (P1206, Applygen) following the instructions. The nuclear and cytoplasm protein fractions were isolated using the NE-PER Nuclear and Cytoplasmic Extraction Reagents (78,835, Thermo Scientific) following the instructions. Using BCA Protein Assay Kit (9S8K-29538-413, Thermo Scientific) normalized the total protein for the follow-up experiments. Quantified samples were separated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and transferred to polyvinylidene fluoride (PVDF) membranes (IPYH00010, Merck Millipore). 5% skimmed milk is slowly shaken at room temperature to block the membrane for 1 h and then primary antibodies incubate these membranes overnight at 4 C. The next day membranes were incubated by the species-specific secondary antibody at room temperature for 1 h and exposed by Immobilon Western Chemiluminescent HRP Substrate (WBKLS0500, Merck Millipore). The antibodies used in the experiment are as follows: GAPDH (1:2,000; 60004-1-Ig, Proteintech), ss-Tubulin (1:2,000; 10094-1-AP, Proteintech), Lamin B1 (1:2,000; 12987-1-AP, Proteintech), IL-1beta (1:1,000; 216,995, Abcam), cleaved IL-1beta (1:1,000; 83,186, CST), NF-kappaB p65 (1:1,000; 8,242, CST), phospho-NF-kappaB p65 (Ser536) (1:1,000; 3,033, CST), cleaved caspase-1 (1:1,000; 4,199, CST) and caspase-1 (1:1,000; 179,515, Abcam) for HaCaT cells samples; IL-1beta (1:1,000; 234,437, Abcam), cleaved IL-1beta (1:1,000; 63,124, CST), caspase-1 (1:1,000; 24,232, CST) and cleaved caspase-1 (1:1,000; 89,332, CST) for mice samples. GAPDH and ss-Tubulin were shown as housekeeping proteins for the normalization of total protein or cytoplasmic protein; Lamin B1 as the loading control for nuclear protein. | [
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1,435,615 | 38510292 | 27,056 | The initial treatment primarily focuses on weight reduction through lifestyle modifications and has a hemoglobin A1C target of <7%. When pharmacotherapy is initiated, metformin is typically first line for both children and adults, with alternative or additional medications considered based on comorbidities, response, and severity of the disease. | [
113
] | [
3
] | [
1
] |
4,480,690 | 39091725 | 42,955 | UU2612 transformant colonies carrying mutant pRR53 derivatives were transferred with toothpicks to T swim plates and incubated at 32.5 C for 6-7 hours. | [
135
] | [
9
] | [
1
] |
2,053,622 | 38658600 | 3,143 | Two of the most distinct SBS signatures with respect to their trinucleotide contexts are signatures SBS2 and SBS13. These signatures were identified already in the breast cancer study by Nik-Zainal et al. and have been associated with the activity of APOBEC cytidine deaminases (APOBEC mutagenesis). APOBEC mutagenesis has, in turn, been linked to a mutational phenomenon referred to as kataegis, which is characterized by clusters of SBS hypermutation biased towards a single DNA strand shown to co-localize with specific rearrangement signatures (typically signatures 4 and 6) at the vicinity of structural rearrangements, specifically those in the 10-25 kilobase (kb) range. Kataegis hypermutation typically comprises C>N mutations in a TpC context, although a T>N conversion in a TpT or CpT process attributed to error-prone polymerases has also been reported as well as rare occurrences of an alternative kataegis form with a base substitution pattern most closely matching SBS signature 9. Kataegis is proposed to be due to the dominant acting apolipoprotein B editing catalytic subunit 3b (APOBEC3B) enzyme that deaminates genomic DNA cytosines and promotes mutation rates higher than normal. Kataegis is typically defined by an intermutation distance between adjacent SBSs, e.g., as six or more consecutive mutations with an average intermutation distance of <=1000 bp. In a recent pan-cancer whole genome sequence (WGS) based study, kataegis events were found in 60.5% of all cancers, with particularly high abundance in lung squamous cell carcinoma, bladder cancer, acral melanoma, and sarcomas. The APOBEC signature accounted for 81.7% of these kataegis events, while 5.7% of kataegis events involved the T>N error-prone polymerase signature, and 2.3% of events showed cytidine deamination in an alternative GpC or CpC context. | [
25,
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1,370,719 | 21482677 | 0 | Luminal expression of PIK3CA mutant H1047R in the mammary gland induces heterogeneous tumors. | [
22,
36
] | [
6,
6
] | [
4,
2
] |
3,877,719 | 27279750 | 16,781 | Allelic and genotypic distributions of rs3024974 in the study population are shown in Table 2. The genotype distribution of the rs3024974 was in Hardy-Weinberg equilibrium in the controls (P = 0.43) but not in the malaria cases (P = 0.00018). | [
39,
128
] | [
9,
9
] | [
3,
3
] |
3,183,102 | 28773413 | 11,258 | A combination of analytical techniques was used allowing the full characterization of the g-C3N4-TiO2 samples produced. These techniques included XRD using a Siemens D 500 X-ray diffractometer (Siemens, Germany) with the diffraction angles scanning from 2theta = 20 -80 , using a Cu Kalpha radiation source. XRD was utilized in phase identification and the measurement of particle size and the anatase to rutile transition. The crystallite size for each sample was calculated using the Scherrer equation (Equation (1)). where D is the crystalline size, lambda is the X-ray radiation wavelength (0.154 nm), beta is the full line width at half-maximum height of the main intensity peak, and theta is Bragg's angle. | [
166
] | [
7
] | [
2
] |
2,264,486 | 35236987 | 31,329 | ESI-MS experiments were performed using Elite hybrid linear ion trap-orbitrap mass spectrometer equipped with a heated-electrospray ionization (HESI) source (Thermo). All solutions for ESI-MS samples were prepared using LC-MS grade water (JT Baker). The concentrations of (AB)2 dimers were adjusted to 5 muM in 20 mM NH4HCO3. Protein solutions were exchanged using 20 mM to remove non-specifically bound metal ions. The capillary voltage was adjusted to 2.5 kV, the flow rate was set to 3-10 muL/min, the source temperature was set to 100 C, and the gas flow rates (sheath and aux) were set to 12. For each sample, 200 spectra were obtained for 3-4 min and averaged for further analysis using Xcalibur software. To prevent cross-contamination of metal ions, peek tubing and steel capillary were flushed out using 0.1% formic acid and 20 mM NH4HCO3 in each measurement. High mass mode at 240,000 resolution was applied to obtain the best resolution limit. Estimated resolution (m/Deltam) of the mass spectrometer was ~80,000 around +11 charge state of (AB)2. To assure reproducibility of ESI-MS results, two independent experiments were performed with the interval of 1-2 weeks. Theoretical and experimental m/z values of (AB)2 and H100A(AB)2 complexes are tabulated in Supplementary Tables 2-5. | [
1232,
535
] | [
5,
6
] | [
2,
2
] |
5,368,707 | 36831384 | 57,116 | Interaction of E3 Arkadia with wt UbcH7 and UbcH7 K96S mutant. (a) Diagram of the total CSPs measured at a 1:2 molar ratio (saturation point) for 15N Ark RING/14N wt UbcH7, *: represents disappeared residues, +: represents residues with no information. (b) Ark RING mapping (PDBid: 2KIZ) after the addition of UbcH7 (residues that disappeared during the interaction are colored red, whereas residues that exhibited 'fast exchange' interaction are colored coral). (c) Diagram of the total CSPs measured at a 1:1.5 molar ratio for 15N UbcH7/14N Ark RING. (d) UbcH7 mapping (PDBid: 6XXU) after the addition of Ark RING. (e) Diagram of the total CSPs measured at a 1:1.5 molar ratio for 15N UbcH7 K96S/14N Ark RING. (f) ITC data for the titration of wt UbcH7 into Ark RING and (g) UbcH7 K96S into Ark RING. (h) In vitro auto-ubiquitylation assays of Ark LONG using wt UbcH7 and UbcH7 K96S, respectively. | [
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4,672,033 | 34953453 | 27,876 | The GABAA agonistic activity of MG has also been reported to have antiepileptic and alcohol detoxification effects, such as benzodiazepine. Pretreatment with MG attenuated picrotoxin- and pilocarpine-induced seizures at both behavioral and electroencephalogram levels. Pretreatment with a GLO1 inhibitor also alleviated pilocarpine-induced seizures, whereas Glo1 overexpression exacerbated seizures and decreased the MG concentration in the brain. Likewise, GLO1 inhibitors reduced alcohol consumption and handling-induced convulsion after alcohol injection, whereas Glo1 overexpression exacerbated these effects. In addition, alcohol consumption was reduced in Glo1 hemizygous-knockdown mice. Although there are no clinical reports showing an association between alcoholism/sleep disorder and GLO1, a clinical study reported that rs1049346 T>C SNP in 5'-UTR of GLO1 was associated with late-onset epilepsy and drug-resistant epilepsy. The C allele increases GLO1 enzymatic activity in whole blood cells. These findings are consistent with the results of rodent studies. | [
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1
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1,842,265 | 37863881 | 21,947 | We further employed hydrogen-deuterium exchange mass spectrometry (HDX-MS) to elucidate the protein conformation of GuApiGT, and L369/H373Q and I136T/L369/H373Q mutants in the solution state. The peptide coverage was 90.1% (Supplementary Figs. 133, 134). Compared with the wild type, peptide L363-D372 of the mutants showed decreased deuterium uptake, indicating the R368L369G370S371 loop became compact and rigid after mutagenesis, and thus may be able to interact with xylose or glucose (Fig. 5d, e and Supplementary Figs. 135, 136). The L135-E156 peptide of I136T/L369/H373Q mutant exhibited noticeable increase of deuterium uptake, verifying the significance of T136 in recognizing UDP-Glc (Supplementary Fig.137). For the PSPG box, the R316-M334 and I335-F344 peptides only showed minor changes, while I345-Q362 and L363-D372 changed significantly upon mutagenesis. This result indicated the R316-F344 and I345-H373 parts were responsible for the binding with UDP and the sugar moiety, respectively. | [
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2,720,280 | 39043961 | 32,437 | RCP analysis of two independent Hi-C experiments revealed consistent alterations in chromatin interactions in K202R mutant cells compared to WT cells, though these alterations were less pronounced than those observed in K202Q mutant cells. Notably, no evident changes were consistently observed in the aggregate intensity of TADs and chromatin loops between K202R and WT cells. Gene expression is intricately regulated, and the spatiotemporal aspects of genomic structure are increasingly recognized as pivotal for understanding eukaryotic gene expression. While the mechanistic underpinnings and causal links between structure and gene expression remain poorly understood, the development and application of Hi-C technology have provided valuable insights into such studies (Nollmann et al,). In this study, we found that the normalized contact frequency of interactions showed a significant correlation with gene expression levels at distal elements of promoters. Upon comparing the promoter-centered interactions among the K202Q and K202R mutants and the WT cells, we observed that differences in the number of interactions for each promoter exhibited a positive correlation with the corresponding changes in gene expression (Figs. 4G and EV4F), as illustrated in individual maps (Fig. 4H) and corresponding gene expression levels (Fig. 4I). Importantly, this correlation was more pronounced between the K202Q mutants and the WT cells. In sum, both K202Q and K202R mutations have the capacity to influence chromatin interactions, while K202Q mutation exhibits a considerably more pronounced impact. Furthermore, the K202Q mutation prominently promotes the formation of chromatin loops, which are potentially associated with regulating the expression of related genes. | [
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] |
469,241 | 21752155 | 24,524 | Is there an association between GNbeta3 C825T genotype and lower functional gastrointestinal disorders? | [
40
] | [
5
] | [
1
] |
1,921,394 | 26060510 | 22,691 | Recent studies have demonstrated the power of combining the CRISPR-Cas9 system with well-studied conditional mouse models of cancer. Notably, a somatic genome engineering approach that combines Cre-dependent somatic activation of KrasG12D with CRISPR-Cas9-mediated genome editing of tumor suppressor genes has been shown to enable the rapid functional characterization of putative lung cancer genes using mouse models. In this study, a pSECC lentiviral system was used to deliver both the CRISPR system and Cre recombinase, thus allowing for the examination of CRISPR-meditated mutations of genes in the context of well-studied Cre-LoxP lung cancer models. For instance, it was demonstrated that in KrasLSL-G12D/+ and KrasLSL-G12D/+; p53fl/fl lung tumor models, loss of NK2 homeobox1 (Nkx2-1) or Pten accelerated tumorigenesis. Furthermore, this system has also been used to characterize the functional role of a novel lung tumor suppressor gene, adenomatous polyposis coli (Apc). Thus, combining CRISPR and Cre-LoxP models bypasses the laborious breeding of mouse alleles and significantly accelerates the pace of generation of complex mouse models. | [
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269,276 | 18662000 | 6,950 | Calculations are based on the crystal-lographic structure of Bacillus halodurans RNase H complexed with the hybrid RNA DNA substrate as in the D192N mutated conformation (pdb code 1ZBL, 2.2 A resolution). Although the mutant enzyme is completely inactive, D192N substitution supposedly does not significantly affect the active site architecture. Furthermore, D192N mutation affects the active site much less than D132N mutation, which perturbs the coordination shell of the A-site Mg2+. For this reason, in the molecular model employed herein, N192 is replaced by D192 to reproduce the wild-type conformation. The remaining structural details of the molecular model are retained as in the crystallographic structure. This includes the Mg2+ ions coordination sphere in the active configuration of the enzyme upon DNA RNA substrate binding (Figure 1). | [
359,
564,
413,
544,
256,
143
] | [
5,
4,
5,
4,
5,
5
] | [
2,
2,
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2,
2,
2
] |
2,646,211 | 33746731 | 86,989 | Mutation-specific strategies would require new drugs that are capable of reversing some or all of the gating changes of Ca2+-channel GOF mutations. As a proof-of-concept it has already been shown that the tert-butyl dihydroquinone (BHQ) can modulate Cav2.1 channels in a manner that oppose altered channel gating of the FHM-1 mutation S218L (type 2, Figures 1D, 4). BHQ inhibited voltage-dependent activation thereby also reducing the enhanced current amplitudes in the mutant channel at negative voltages. At the Drosophila neuromuscular junctions expressing the S218L channel, BHQ largely restored the abnormally elevated evoked postsynaptic potentials and the impaired synaptic plasticity to the wildtype phenotypes. | [
250,
120,
564,
335
] | [
6,
4,
5,
5
] | [
4,
4,
2,
2
] |
3,365,214 | 34677122 | 16,640 | The C2 vs C4 plot enables visualization of all possible evolutionary paths by joining the stepwise mutations from DmelIr75a to DmelIr75aT289S,Q536K,F538L. Most receptor variants are plotted close to the straight line (i.e., the shortest path) that joins the initial and final state, with the DmelIr75aF538L single mutant showing the largest individual 'step' along this line (Figure 3E). If we assume that all steps along this line would be favored by selection, this observation suggests the hypothesis that the F538L change might have been the first one of the three substitutions to occur, as de novo mutations with larger effect are typically substituted first followed by those with smaller effect. An alternative hypothesis is that T289S variant already existed, perhaps as standing variation in the population (despite the lack of evidence from sequences of extant populations): T289S has little phenotypic consequence by itself (Figure 3C and E), but it greatly augments the effect of the F538L substitution (Figure 3C and E). In this case, T289S and F538L would have reached fixation together in the same genetic background because their combined effect allows for a large adaptive leap from one peak (C2) to the other (C4).The Q536K change alone has an intermediate phenotype, but we suspect is unlikely to have been the first to occur, as combination with either other amino acid change leads to a less specific receptor (DmelIr75aQ536K,F538L, lying above-right of the line), or a receptor with overall weak sensitivity (DmelIr75aT289S,Q536K, lying below-left of the line) (Figure 3C and E). | [
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2
] |
2,245,973 | 33473249 | 12,674 | Ripretinib has been studied preclinically across a broad range of models, including transfected CHO or Ba/F3 cells expressing KIT or PDGFRA mutants, primary human GIST cell lines and sublines, GIST xenografts and patient-derived xenografts (PDX). Overall, ripretinib and ripretinib active metabolite DP-5439 showed significant anti-tumor effects regardless the type of primary or secondary KIT mutation, as assessed mainly by viability, proliferation and phosphorylation inhibition assays. In addition, ripretinib showed preliminary proof-of-concept activity in two TKI-refractory KIT-mutant metastatic GIST patients harboring secondary mutations in the circulating tumor (ct)DNA across exons 13, 17 and 18, further confirming the encouraging preclinical activity observed in the laboratory (Figure 2). Ripretinib also appeared to be effective against the multi-resistant PDGFRA D842V in transfected mutant models, although no primary human cell lines or PDX exist for this specific subset of GIST patients. | [
126,
133,
390,
581,
872,
879
] | [
3,
6,
3,
3,
6,
5
] | [
4,
4,
4,
4,
4,
2
] |
555,230 | 33342090 | 7,115 | To generate GD1 patient-derived iPSCs, skin fibroblasts of the patient (29 years, male, GM00372) were obtained from the NIGMS Human Genetic Cell Repository at the Coriell Institute for Medical Research. The donor subject is a compound heterozygote for the following mutations: one allele carries a single-base mutation (1226A>G) in the GBA gene, which results in the amino acid substitution of serine for asparagine (N370S); the second allele carries an insertion of a second guanine at cDNA nucleotide 84 (84GG). Three iPSC clones (clones 1, 2, 3) from the same donor were generated with StemRNA-NM reprogramming kit (Stemgent) at ReproCELL, Japan. As the healthy control, 201B7 iPSCs were obtained from CiRA (Kyoto, Japan). 28 To rescue the enzymatic defect of GBA1, wild-type GBA1 cDNA was cloned into the PiggyBac expression vector and the tet-inducible iPSC line was generated as described previously. 29 Undifferentiated iPSCs were maintained in StemFit AK-02 medium (Ajinomoto, Tokyo, Japan) on iMatrix-511 (Nippi, Tokyo, Japan)-coated plates. | [
336,
764,
780,
320,
394,
417,
476
] | [
3,
4,
4,
7,
21,
5,
29
] | [
4,
4,
4,
1,
2,
2,
1
] |
1,769,852 | 33372419 | 5,227 | A total of 99 p53-mutated and 99 EGFR-mutated NSCLC patients were selected from our database to explore whether hOGG1 Ser326Cys polymorphism might be associated with the occurrence of p53 and EGFR deletion mutations. The selection procedure is outlined in Fig. 1. The hOGG1 Ser326Cys polymorphisms in adjacent normal lung tissues of this study population were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The EGFR-mutated patients in this study were divided into deletion and nondeletion mutation subgroups based on the presence of an exon 19 deletion mutation and exon 21 L858R point mutation of the EGFR gene for this study. | [
14,
33,
112,
184,
192,
268,
457,
649,
621,
118,
274
] | [
3,
4,
5,
3,
4,
5,
4,
4,
5,
9,
9
] | [
4,
4,
4,
4,
4,
4,
4,
4,
2,
2,
2
] |
4,757,851 | 40259053 | 14,461 | a Afatinib decreases the level of GTP-bound Rheb in PC9 and HCC827 cells. PC9 and HCC827 cells treated with or without 25 nM erlotinib or 25 nM afatinib for 12 h, were subjected to immunoprecipitation using Rheb-GTP agarose and analyzed by western blotting. b The Rheb-D60V mutant preferentially interacts with endogenous WT EGFR. HEK-293T cells were transfected with empty vector, 3x FLAG-Rheb-WT, -D60V, or -Q64L as indicated, subjected to immunoprecipitation, and analyzed by western blotting. c EDTA increases the interaction between EGFR and Rheb at endogenous levels. HeLa cells were lysed in the absence or presence of EDTA, subjected to immunoprecipitation, and analyzed by western blotting. d EGFR preferentially interacts with nucleotide-free or GDP-bound Rheb in vitro. Purified EGFR-TKD was incubated with GST, nucleotide-free GST-Rheb, GST-Rheb with GDP, or GST-Rheb with GTP as indicated, and then precipitated with GST beads and subjected to SDS-PAGE analysis. Coomassie blue staining is shown. e Top, the reconstitution peaks in the size-exclusion chromatography analysis of the purified EGFR-TKD-WT and Rheb-D60V complex. The reconstitution peak for the complex is shown by a dotted line and observed at 10.22 mL. Bottom, SDS-PAGE analysis of each reconstitution sample. The peak for the complex of EGFR-TKD and Rheb is indicated. f EGFR induces Rheb nucleotide exchange from the GDP-bound to the GTP-bound state. A guanine nucleotide exchange assay was performed in vitro using purified EGFR-TKD and Rheb. The relative fluorescence reflects the guanine nucleotide exchange activity. The initial fluorescence intensity was set to 1. Human RhoGEF Dbs (hDbs) and RhoA were used as positive controls. Curves are representative of three independent experiments. Data are presented as means +- SEM. g EGFR induces Rheb nucleotide exchange in a dose-dependent manner. An in vitro guanine nucleotide exchange assay was performed using purified Rheb and a concentration gradient of EGFR-TKD-WT as indicated. h LAMP2-V5-HER2-ICD, LAMP2-V5-IGF1R-ICD, or LAMP2-V5-c-MET-ICD failed to activate mTORC1. HEK-293T cells stably expressing LAMP2-V5-EGFR-TKD-WT, LAMP2-V5-HER2-ICD, LAMP2-V5-IGF1R-ICD, or LAMP2-V5-c-MET-ICD were serum-starved for 24 h and analyzed by western blotting. | [
44,
207,
264,
325,
390,
538,
547,
702,
766,
790,
843,
853,
875,
1104,
1120,
1316,
1329,
1350,
1363,
1505,
1518,
1678,
1813,
1826,
1954,
1991,
2019,
2028,
2038,
2047,
2061,
2070,
2140,
2149,
2162,
2171,
2181,
2190,
2204,
2213,
1663,
11... | [
4,
4,
4,
4,
4,
4,
4,
4,
4,
4,
4,
4,
4,
4,
4,
4,
4,
4,
4,
4,
4,
4,
4,
4,
4,
4,
5,
4,
5,
5,
5,
5,
5,
4,
5,
4,
5,
5,
5,
5,
3,
4,
4,
4,
4
] | [
4,
4,
4,
4,
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4,
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4,
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4,
4,
4,
4,
4,
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4,
4,
4,
4,
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4,
4,
4,
4,
4,
4,
4,
4,
4,
4,
4,
4,
4,
4,
4,
4,
2,
2,
2,
2
] |
2,639,709 | 29848757 | 7,389 | Detection of tumour EGFR mutations in plasma. EGFR mutation status in tumour samples was documented in the clinical record for 43 patients (Appendix Table S1), of which 38 had verified hotspot activating mutations (deletion in exon 19 for 23 patients and the L858R mutation for 15 patients), three patients had other mutations in EGFR (one of these patients had two different mutations detected in the tumour sample), and two patients were wild-type for EGFR according to tumour analysis and confirmed by plasma analysis. | [
20,
46,
330,
454,
259
] | [
4,
4,
4,
4,
5
] | [
4,
4,
4,
4,
2
] |
End of preview. Expand in Data Studio
Seed NER Dataset
This dataset was derived from Pubtator3 and verified for correctness by GPT 5.2. It contains close to 1,000 rows of text with entity annotations. The dataset is intended for research and development in protein and DNA mutations, SNP identifiers and other genetic variants.
Source
dataset_path:data/Seed Dataset/pubtator3_mutations_10k.jsonlpatch_responses_path:data/Seed Dataset/responses_gpt5.2_10k.jsonlgenerated_at_utc:2026-02-26 23:27:36Z
Schema
id(int64)text(string)offsets(list[int32])lenghts(list[int32])entity_types(ClassLabel sequence)
Entity Labels
CopyNumberVariant, DNAMutation, ProteinMutation, SNP
Size
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