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3,494,860 | 38254628 | 25,003 | 3494860 | It appears that noncrossover recombination is an intrinsic feature of the Rad51-Rad54-dependent recombination. An amino acid substitution of the evolutionally conserved lysine in the ATP-binding domain P-loop, rad54-K300A, does not abolish yeast two-hybrid interaction between Rad51 and Rad54. The rad54-K300A mutation accumulates spontaneous Rad54 foci in a Rad51-dependent manner, suggesting that the mutant Rad54 protein binds and stays at recombination sites. The rad54-K300A mutation increases isochromosome formation to the same extent as the rad54 deletion, showing that Rad54 ATP-dependent activity is vital in suppressing isochromosome formation. After DNA strand invasion, Rad54 ATPase dissociates Rad51 from D-loops and allows DNA polymerase to bind the 3'-OH end of the invading strand to initiate DNA repair synthesis. ATP-dependent Rad54 motor facilitates Rad51-mediated D-loop formation but can also dissociate D-loops. These reactions mediated by Rad51 and Rad54 are essential steps of synthesis-dependent strand annealing (SDSA) that result only in noncrossover recombination. In contrast to other types of homologous recombination, noncrossover recombination does not result in changes in chromosomal structure. Homologous recombination mediated by Rad51 and Rad54 preferentially promotes noncrossover and maintains genome integrity. | [
216,
304,
474
] | [
5,
5,
5
] | [
2,
2,
2
] |
85,305 | 40309404 | 6,296 | 85305 | The biological and toxicological dataset available to the Panel for the re-evaluation of acesulfame K (E 950) comprised evidence from animal toxicological studies and human data, both published and unpublished, made available to EFSA in response to calls for data and related clarification requests and/or also identified from the published literature. The selection, appraisal and integration of the evidence was performed according to the principles outlined in the revised protocol on hazard identification and characterisation of sweeteners. | [
103
] | [
5
] | [
2
] |
2,505,172 | 20157015 | 30,600 | 2505172 | A 58-year-old woman was referred by her optometrist following a routine eye test with suspected bilateral optic atrophy (UK-6). She had no visual complaints (6/9, both eyes) but on examination her colour vision was severely reduced, with bilateral small caeco-central scotomas on Goldmann field perimetry. She had mild gait ataxia and a comprehensive neurological assessment revealed periventricular white matter lesions on MRI, and unmatched oligoclonal bands in her CSF, both supportive of an underlying demyelinating process clinically indistinguishable from multiple sclerosis (Fig. 3). Two of her brothers, aged 61 and 63 years old, had previously been investigated for poor vision and a label of Leber hereditary optic neuropathy was given, even though a screen for the three primary Leber hereditary optic neuropathy mtDNA point mutations (m.3460G > A, m.11778G > A and m.14484T > C) was negative. The family history was also consistent with an autosomal dominant pattern of inheritance and this prompted OPA1 genetic screening, which uncovered a c.2613 + 1g>a splice-site mutation within intron 25 segregating with affected disease status in both the proband and her two brothers. | [
847,
860,
877,
1054
] | [
11,
12,
12,
13
] | [
1,
1,
1,
1
] |
3,090,461 | 21931560 | 5,211 | 3090461 | A key regulatory element in TLS is the monoubiquitination of PCNA at lysine 164 in response to treatment with DNA damaging agents. In S. cerevisiae this reaction is carried out by the Rad6-Rad18 E2-E3 ubiquitinating enzymes (Figure 1A), and is critical for the activity of TLS, functioning to recruit TLS polymerases through their ubiquitin-binding domain, and thereby switching from replicative to TLS polymerases. In higher organisms the involvement of ubiquitinated PCNA (PCNA-Ub) in TLS is less clear. Analysis of replication of damaged DNA in chicken DT40 cells suggested that PCNA ubiquitination is involved in filling in of post-replication gaps. However when measured using a plasmid system in DT40 cells carrying the PcnaK164R/K164R mutation which prevent ubiquitination of PCNA, TLS was normal across a TT 6-4 photoproduct (TT 6-4 PP), a common UV DNA lesion. As for mammals, a common model suggests that similar to S. cerevisiae, PCNA-Ub recruits TLS polymerases to the site of DNA damage mediated via their ubiquitin-binding domain. This model was challenged by studies reporting that mutations in the ubiquitin-binding domain of poleta had no effect on its activities, and it is the direct binding of poleta to PCNA which is critically important for its activities. In response it was argued that these results can be explained by an effect of artificial overproduction of the mutant polymerase, which suppressed its lower binding affinity. However, later studies reported that complete deletion of the UBZ ubiquitin-binding domain from poleta had no effect on its activities, including TLS across a site specific TT cyclobutane pyrimidine dimer (CPD) in a replicative plasmid assay system, leaving the controversy unsettled. | [
69,
736
] | [
10,
5
] | [
2,
2
] |
1,624,549 | 22805110 | 13,658 | 1624549 | Patients with poorly controlled diabetes at baseline (A1C >=9%, N=127 controls, 135 cases) had a significant A1C rate change of -0.10%/month ([95% CI -0.18, -0.022], p=0.012), after adjusting for CHF, depression, type of insurance and loyalty to PCP. Hospitalization, CHF, and depression did not significantly alter the rate of A1C change. Higher patient-PCP connectedness was associated with a steeper decline in A1C in this poorly controlled sub-group (p=0.023). | [
54,
109,
328,
414
] | [
3,
3,
3,
3
] | [
1,
1,
1,
1
] |
2,266,978 | 22566560 | 30,762 | 2266978 | rs489693 genotype and antipsychotic-induced weight gain in four cohorts of subjects. | [
0
] | [
8
] | [
3
] |
4,748,020 | 22500634 | 12,648 | 4748020 | So what might be the kinase that phosphorylates PlexA at Ser1794? Interestingly, PlexA and 14-3-3epsilon interact in yeast indicating that a serine/threonine kinase present in yeast is sufficient to phosphorylate PlexA. We also noticed that PlexA's 14-3-3epsilon binding site contained a consensus phosphorylation site (R/KxxS; Figures 6A, S5A) for several kinases well-conserved from yeast to humans including PKA, the Ca2+-dependent protein kinase (PKC), and the cGMP-dependent protein kinase (PKG). Therefore, we conducted in vitro kinase assays with purified proteins and found that PlexA (PlexACyto2) is specifically phosphorylated by two kinases, PKA and Cdk5 (Figures 6A, S5A-B). Mutating the PlexASer1794 residue significantly decreased this PKA-, but not Cdk5-, dependent phosphorylation (Figures 6B, S5C), revealing that the PlexA Ser1794 residue that is critical for 14-3-3epsilon binding is selectively phosphorylated by PKA. Likewise, our results indicated that PKA is sufficient to mediate this PlexASer1794-14-3-3epsilon interaction, since activating PKA signaling with forskolin significantly enhanced the association between FLAG14-3-3epsilon and HAPlexA in a Ser1794-dependent manner (Figure 6C). We thus wondered if PKA was necessary for phosphorylating PlexASer1794 in vivo. Employing a rabbit polyclonal antibody that we generated that selectively recognized the phosphorylated form of PlexASer1794 (phospho-PlexAS1794) (Figures 6D-E, S5D-E), we found that decreasing the levels of PKA in vivo significantly reduced the levels of phospho-PlexAS1794 (Figure 6F). Therefore, our results indicate that PlexASer1794 is phosphorylated by PKA, which mediates the interaction between PlexA and 14-3-3epsilon (Figure 6H). | [
141,
1625
] | [
16,
7
] | [
2,
2
] |
3,659,349 | 38971757 | 7,910 | 3659349 | Total Pre-epilepsy Non-epilepsy P value N = 35 N = 21 N = 14 GFAP, N (%) (i)(-) 0 (0) 0 (0) 0 (0) (ii)(+) 35 (100%) 21 (100%) 14 (100%) IDH-1, N (%) 0.122 (i)(-) 18 (51%) 8 (38%) 10 (71%) (ii)(+) 14 (40%) 10 (48%) 4 (29%) Missing 3 (9%) 3 (14%) 0 (0) Olig-2, N (%) (i)(-) 0 (0) 0 (0) 0 (0) (ii)(+) 35 (100%) 21 (95%) 14 (100%) P53,N (%) 0.185 (i)(-) 10 (28.5%) 8 (38%) 2 (14%) (ii)(+) 24 (68.5%) 12 (57%) 12 (86%) Missing 1(3%) 1(5%) 0(0) ATRX, N (%) 0.776 (i)(-) 4 (11%) 3 (14%) 1 (7%) (ii)(+) 30 (86%) 17 (81%) 13 (93%) Missing 1(3%) 1(5%) 0(0) H3K27ME3, N (%) 0.714 (i)(-) 1 (4.5%) 1 (8%) 0 (0) (ii)(+) 20 (91%) 11 (92%) 9 (90%) Missing 1 (4.5%) 0 (0) 1 (10%) Ki-67, N (%) <0.001 (i)Low 22 (63%) 18 (85.7%) 4 (29%) (ii)Medium 9 (26%) 1 (4.8%) 8 (57%) (iii)High 4 (11%) 2 (9.5%) 2 (14%) FuBP1, N (%) 1.000 (i)(-) 1 (3%) 1 (5%) 0 (0) (ii)(+) 29 (83%) 17 (81%) 12 (86%) Missing 5 (14%) 3 (14%) 2 (14%) BRAFV600E, N (%) 0.019 (i)(-) 26 (74%) 19 (90%) 7 (50%) (ii)(+) 6 (17%) 1 (5%) 5 (36%) Missing 3 (9%) 1 (5%) 2 (14%) Nestin, N (%) 0.122 (i)(-) 8 (23%) 7 (33.3%) 1 (7%) (ii)(+) 23 (66%) 11 (52.4%) 12 (86%) Missing 4 (11%) 3 (14.3%) 1 (7%) | [
1015
] | [
9
] | [
2
] |
1,356,335 | 39320041 | 28,165 | 1356335 | Molecular modeling of TBX3 missense variants. (a) Structural effect of p.N277S mutation. Asparagine 277 is responsible for a key hydrogen-bond interaction between the C-terminal domain helix of TBX3 and DNA. The p.N277S mutant is not able to engage the same interaction. (b) Movements and flexibility of the C-terminal DNA binding region of (i.) WT and p.P134S (ii.) WT and p.N277S mutants of TBX3. The RMSF Plot shows a significant increase of flexibility of TBX3 upon p.P134S and p.N277S mutations. | [
71,
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212,
353,
374,
470,
482
] | [
7,
14,
7,
7,
7,
7,
7
] | [
2,
2,
2,
2,
2,
2,
2
] |
3,129,486 | 24427120 | 32,843 | 3129486 | Several hypotheses can explain this down-regulation. The first concerns the presynaptic histamine H3 autoreceptors and heteroreceptors in the VN complex. The changes found 1 week after UVN can be explained by the bilateral anatomical connections between the VN complexes and the posterior hypothalamus strengthening the idea of vestibulo-hypothalamic loop activation due to VNC electrical asymmetry. Indeed, the MVN project bilaterally to the posterior hypothalamus but direct and predominantly contralateral projections from the MVN to the HPA have been found in the monkey. While the posterior hypothalamus sends histaminergic fibers to the ipsilateral MVN. The asymmetrical firing rate of the VN cells in acute UVN cats (1 week), with reduced activity on the lesioned side and increased activity on the intact side for both the MVN and the LVN can therefore account for the HDC mRNA up-regulation, particularly pronounced in the TMN at 1 week post-lesion on the lesioned side. The time-course of HDC mRNA expression in the TMN of the UVN cats correlates with electrophysiological data. Electrophysiological investigations in the UVN cat still revealed, 3 weeks post-lesion, asymmetrical spontaneous firing rates between the bilateral VNCs, but the imbalance was attenuated. This attenuated imbalance may account for the lower asymmetry in HDC mRNA expression observed between the two TMN at this stage. Therefore, and as previously discussed, the autoradiographic [3H]N-alpha-methylhistamine binding reduction very likely results from a down-regulation of the histamine H3 receptors. One week after UVN, the high level of histamine synthesis in the ipsilateral TMN and release in the ipsilateral VN due to vestibular lesion very likely leads to a high desensitization of the histamine H3 receptor, its internalization and degradation in the deafferented VN. Based on the data obtained by in situ hybridization and electrophysiology, this reduction was observed bilaterally 3 weeks after UVN, with an ipsilateral predominance in the same brainstem structures. Such molecular mechanisms have been demonstrated in the guinea pig ileum for the histamine H3R and in a specific cell line for the histamine H2R. | [
1573,
1788,
2153
] | [
2,
2,
2
] | [
2,
2,
2
] |
1,042,426 | 30653310 | 18,785 | 1042426 | Our finding that H3K36 is a preferential SIRT7-targeted lysine site for defatty-acylation led us to ask if SIRT7 is also catalytically active in removing acetylation at H3K36 both in in vitro biochemical assays and in cells. We assumed changing the modification type wouldn't change SIRT7 site-specificity, since the residues surrounding the modified lysine are the major contributing factors. We assembled two in vitro nu-H3K36ac nucleosomes using 147bp 601 DNA with or without a 20 bp linker DNA. We then incubated these two acetyl-nucleosomes with SIRT7 and subsequently detected acetylation levels of the reaction products by Western blotting with an anti-H3K36ac antibody. This analysis revealed that SIRT7 deacetylated H3K36 in the context of nucleosomes, and appending a linker DNA significantly improved this deacetylation activity (Figure 6A). To test SIRT7 activity on other nucleosomal H3 lysine sites, we also reconstituted several other acetyl-nucleosomes including nu-H3K4ac, nu-H3K9ac, nu-H3K14ac, nu-H3K18ac, nu-H3K23ac, nu-H3K27ac, and nu-H3K56ac (Figure S6) for use as substrates in SIRT7 deacetylation assays. All acetyl-nucleosomes contained a 20 bp linker DNA for improving SIRT7 activities. Our data confirmed that SIRT7 is also catalytically active to deacetylate H3K18 but inert toward all other tested lysine acetylation sites, and the deacetylation activity of SIRT7 on H3K18 is much weaker than that on H3K36. The relative deacetylation activity of SIRT7 on different H3 lysine sites matches exactly the relative deacylation activity on these sites that we obtained using AzHeK-containing nucleosomes as substrates. We also used nu-H3K36ac and nu-H3K18ac to carry out time-based deacetylation by SIRT7. Our determined results showed that AzHeK-containing nucleosomes mimic acetyl-nucleosomes in not only SIRT7-targeted lysine deacylation sites but also SIRT7-catalyzed deacylation activity (Figure S7). To examine the deacetylase activity of SIRT7 on H3K18 and H3K36 in cells, we constructed two plasmids, one coding a SIRT7-EGFP fusion gene and the other a SIRT7-EGFP fusion gene with a H187Y mutation to inactivate the SIRT7 activity, from a mammalian pEGFP vector. Together with the original pEGFP vector, we transiently transfected 293T cells separately with all three plasmids. We separated cell lysates from these three transiently transfected cells using SDS-PAGE and then analyzed different histone acetylation levels using antibodies that recognize acetylation at K9, K14, K23, K27, and K36 of H3, respectively. These assays revealed significantly decreased acetylation levels at H3K18 and H3K36 in cells with overexpressed SIRT7-EGFP but not in cells transfected with the empty control vector or expressing the inactive SIRT7-H187Y-EGFP fusion protein. These data demonstrate that SIRT7 is catalytically active in deacetylating both H3K18 and H3K36 in cells. Although our in vitro analysis indicates that SIRT7 is four-fold more active to deacetylate H3K36 than H3K18, our cell based assay showed similar acetylation decrease at both sites when SIRT7 was transiently expressed (Figure S8). It is likely that numerous cellular factors influence the overall effects of SIRT7 over-expression on cellular H3K36 or H3K18ac levels, including SIRT7 regulatory factors, acetyltransferase enzymes, or compensatory deacetylase enzymes. | [
2115,
2763
] | [
5,
5
] | [
2,
2
] |
3,631,732 | 30366425 | 16,045 | 3631732 | Total experiment duration per participant was 23 min. Images were presented using a NEC-M420X projector (NEC Display Solutions, Ltd., Tokyo, Japan) on a white screen (165 x 225 cm; see Figure 3c). | [
88
] | [
5
] | [
2
] |
2,190,181 | 33852844 | 79,955 | 2190181 | Interaction with PRMT6 and R118 methylation are preserved in mHTT | [
27
] | [
4
] | [
2
] |
4,715,056 | 29145399 | 3,025 | 4715056 | It has now been fairly well established that THP/uromodulin-associated diseases (UAKD) belong to endoplasmic reticulum (ER)-storage diseases. Like other proteins in this family, mutations of THP cause the protein to mis-fold and aggregate precociously, reducing its ability to exit the ER and translocate to the cell surface. The mutated THP can also exert cytotoxic effects on the TAL cells and adversely affect the biosynthesis and functions of the host cell proteins. Preliminary evidence, based on clinical observations and expression of THP mutants in various cultured cells, suggests that the deleterious effects of THP mutations could be site-dependent, i.e., some mutations might cause more severe phenotypic alterations than others. Of particular interest are the mutations within the so-called "domain of 8 cysteines" (D8C). D8C contains a stretch of 130 amino acid residues in THP and is highly homologous to the same domain present in liver-specific zona pellucida protein (LZP), pancreas-specific glycoprotein 2 (GP-2) and several uncharacterized proteins. The 8 highly conserved cysteines are predicted to form 4 pairs of disulfide bridges that are believed to be crucial for maintaining the correct conformational structures of the proteins. Experimental verification to this prediction remains scare. When we previously compared a cysteine-altering mutation outside D8C (C126R) of THP with another inside it (C217G) in MDCK cells, we observed significantly greater deleterious effects of the latter in terms of ER-retention, reduced apical surface translocation, reduced release into culture media, apoptosis induction and entrapment of co-expressed wild-type THP. Nonetheless, one could still argue that the phenotype could vary in intact animals as compared to cell-culture systems. | [
1387,
1425
] | [
5,
5
] | [
2,
2
] |
5,261,458 | 27134679 | 22,402 | 5261458 | H3 K122A results in decreased nucleosome reassembly and disassembly | [
3
] | [
5
] | [
2
] |
1,462,499 | 41039211 | 237,918 | 1462499 | The G1246A polymorphism in the hypocretin receptor 2 gene is not associated with treatment response in cluster headache | [
4
] | [
6
] | [
1
] |
5,131,893 | 22786724 | 17,611 | 5131893 | The N-terminal region of human SLP-76 contains three tyrosine residues (Tyr113, Tyr128, and Tyr145) that become phosphorylated upon TCR ligation. Phosphorylation of SLP-76 at Tyr113 was clearly detected in NKL cells after crosslinking of 2B4, but not NKG2D, and was further increased in extent by crosslinking both receptors (Fig. 3B). In contrast, SLP-76 phosphorylation at Tyr128 was observed after crosslinking of NKG2D, but not 2B4 (Fig. 3B). The basal extent of SLP-76 phosphorylation at Tyr145 was not increased by engagement of NKG2D, 2B4, or both. Therefore, NKG2D and 2B4 induced distinct signals for the tyrosine phosphorylation of SLP-76. An important question was whether complementary phosphorylation of SLP-76 also occurred during the synergistic activation of primary, resting NK cells. Thus, we stimulated NKG2D and 2B4 on resting NK cells by ligating the receptors with specific mAbs, either individually or together. Similar to the experiments with NKL cells, we found selective phosphorylation of Tyr113 by crosslinking 2B4 and of Tyr128 by crosslinking NKG2D in primary, resting NK cells (Fig. 3C). To confirm this finding in the context of physiological receptor-ligand interactions, we incubated S2 cells that stably expressed either ULBP1, CD48, or both with NKL cells that had been rested in the absence of IL-2 for 24 h (Fig. 3D) or primary, resting NK cells (Fig. 3E). Similar to the results observed after crosslinking the receptors with mAbs, we saw that SLP-76 phosphorylation at Tyr113 and Tyr128 was obtained by mixing NK cells with S2 cells expressing both ligands but not by mixing NK cells with S2 cells expressing either ligand alone (Fig. 3D and E). Therefore, co-engagement of NKG2D and 2B4 is required to induce tyrosine phosphorylation of SLP-76 at both tyrosine residues. | [
72,
80,
92,
175,
375,
493,
1016,
1050,
1509,
1520
] | [
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6,
6,
6,
6,
6,
6,
6,
6,
6
] | [
2,
2,
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2,
2,
2,
2,
2,
2
] |
4,640,754 | 24363615 | 25,987 | 4640754 | Treatment Genotype 38 DAS, 3 days in stress 41 DAS, 6 days in stress 44 DAS, 9 days in stress 47 DAS, 12 days in stress Mean of treatments Control CU 52 0.80 +- 0.2q-u 0.75 +- 0.1e 0.79 +- 0.02s-u 0.99 +- 0.1l-s 0.85 CU 94 0.74 +- 0.1u 0.77 +- 0.1tu 0.78 +- 0.01r-u 0.97 +- 0.1f CU 196 0.85 +- 0.1q-u 0.85 +- 0.1p-u 0.90 +- 0.02o-u 0.93 +- 0.5f CU 280 0.86 +- 0.1p-u 0.83 +- 0.2q-u 0.87 +- 0.1o-u 0.95 +- 0.3m-u Salt CU 52 1.37 +- 0.4fg 1.78 +- 0.1de 1.86 +- 0.1c-e 1.87 +- 0.2c-e 1.52 CU 94 1.19 +- 0.2g-l 2.15 +- 0.2b 2.01 +- 0.1bc 2.46 +- 0.7a CU 196 1.15 +- 0.1g-n 1.09 +- 0.2j-p 1.24 +- 0.2f-k 1.27 +- 0.2f-j CU 280 1.18 +- 0.2g-m 1.08 +- 0.2j-p 1.33 +- 0.2f-h 1.33 +- 0.1f-h Drought CU 52 1.01 +- 0.2k-r 1.10 +- 0.1h-o 1.87 +- 0.1c-e 2.03 +- 0.0bc 1.45 CU 94 0.84 +- 0.0q-u 1.41 +- 0.2f 1.32 +- 0.0f-i 2.16 +- 0.2b CU 196 1.02 +- 0.1k-q 1.09 +- 0.2i-p 1.95 +- 0.1b-d 1.69 +- 0.1e CU 280 1.02 +- 0.2k-q 1.08 +- 0.1j-p 1.74 +- 0.0de 1.92 +- 0.1c-e Mean of times 1.00 1.16 1.39 1.54 Mean of genotypes CU 52 CU 94 CU 196 CU 280 1.35 1.40 1.17 1.18 | [
1046,
1058
] | [
8,
9
] | [
1,
1
] |
1,567,067 | 38002939 | 14,483 | 1567067 | A preliminary power analysis was executed with the G*Power 3.1.9.7 software to determine the sample size for the study. Results indicated that a sample comprising 80 participants divided into two groups would be adequate to detect a relationship between SNPs and obesity, with a statistical significance level set at 0.05, an odds ratio (OR) of 2, and a power of 0.80. Descriptive statistics were presented as percentages for categorical variables, while continuous variables were displayed as mean +- standard deviation (SD). Differences between the two groups for continuous variables were tested using an independent sample t-test when data were normally distributed and a Mann-Whitney U test for non-normally distributed data. A Chi-squared test was applied to test for differences in categorical variables between the two groups. Logistic regression models adjusting for age, sex, type 1 diabetes mellitus (T1DM), and type 2 diabetes mellitus (T2DM) were performed to assess the association between MC4R rs17782313 with obesity risk. A logistic regression model was constructed to examine the interactions between the MC4R rs17782313 risk allele homozygous genotype in females and various eating behaviors in relation to obesity. This model was particularly focused on the female cohort due to the observed sex-specific associations. The model incorporated the dichotomized eating behavior variables and controlled for potential confounders: age, T1DM, and T2DM. ORs and 95% CI were calculated to quantify the strength and direction of these interactions. The statistical significance was set at an alpha level of 0.05, and any p-value below this threshold was considered to indicate a statistically significant difference between the groups under investigation. Analysis was performed using SPSS 29.0 and R software 4.3.1. | [
1009,
1128
] | [
10,
10
] | [
3,
3
] |
2,977,128 | 19385636 | 32,483 | 2977128 | Using an antibody against a synthetic peptide corresponding to the N-terminal tail of chicken H2A.Z acetylated at residues K4, K7, and K11, it was shown that hyperacetylated H2A.Z is a feature of active genes where it is concentrated at the 5' end in the enhancers of some actively transcribed genes. The acetylation signature of this replacement variant is erased at mitosis. Selection of the peptide for the generation of this antibody was based on information from htz1 acetylation in yeast since the sites of vertebrate H2A.Z acetylation remained undetermined at that time. | [
135
] | [
3
] | [
2
] |
765,830 | 38670095 | 23,307 | 765830 | Next, we investigated whether G6/7R enhances CAR-T cell efficacy against solid tumors. Similar to anti-CD19 CAR-T cells, expression of G6/7R or G6/7R-M452L in T cells engineered with CAR genes encoding different antibody fragments or costimulatory domains (CD28 or 41BB) significantly augmented their proliferative capacity upon antigen stimulation (Figure 5A). A marginal proliferative advantage of G6/7R-M452L over G6/7R was observed in anti-mesothelin 28z and anti-GD2 BBz CAR-T cells but not in anti-GD2 28z CAR-T cells. | [
30,
135,
144,
150,
400,
406,
417
] | [
2,
2,
2,
5,
2,
5,
2
] | [
2,
2,
2,
2,
2,
2,
2
] |
4,454,709 | 27079335 | 40,673 | 4454709 | Throughout the guideline, special issues pertinent to older adults are highlighted, including the following: the observation that 3% to 4% of blacks carry an allele of the serum protein transthyretin (TTR V122I) that appears to increase risk for cardiac amyloid deposition and HF after 65 years of age; the risk of hyperkalemia with standard pharmacological therapy for HF and the underestimation of renal dysfunction in older adults based on serum creatinine; the association of advancing age with increases in natriuretic peptides, thereby limiting their diagnostic utility and their usefulness in guiding therapy in older adults; uncertainty about the value of revascularization in patients with HF and coronary artery disease but without angina; the increased risk of digoxin toxicity in older adults because of impaired renal function and lower lean body mass; and the stronger association of AF to HF with advancing age. The guideline acknowledges that older adults with HF typically have multimorbidity (75% of HF patients >65 years of age have multiple chronic conditions) and that there is therefore a need to consider comorbid conditions, life expectancy, and personal preferences in the application of medical and device therapies. On the basis of data in younger patients, the guideline suggests that such therapies be used in older patients without an age limit but that treatment be individualized based on each patient's unique circumstances and goals of care. | [
205
] | [
5
] | [
2
] |
3,457,108 | 40779492 | 17,041 | 3457108 | Single-agent basket clinical trials of the KRAS G12C inhibitors adagrasib and sotorasib led to approval in NSCLC, but not in other diseases. Daraxonrasib is currently in two Phase 3 clinical trials, one for NSCLC and another for pancreatic ductal adenocarcinoma (PDAC). Bone cancers have not been traditionally well represented in KRAS inhibitor clinical trials because of the low frequency of KRAS mutations and the infrequency of G12C. The recent expansion of the range of druggable KRAS alleles has opened new clinical opportunities to treat rare KRAS-mutant bone cancers. | [
48,
432
] | [
4,
4
] | [
2,
2
] |
4,907,773 | 41288798 | 41,656 | 4907773 | Genetic association of the rs17782313 polymorphism with antipsychotic-induced weight gain | [
27
] | [
10
] | [
3
] |
4,227,316 | 40944809 | 47,555 | 4227316 | The effects observed for p.Pro205Ser, p.Leu206Trp, and p.Arg347Pro on CFTR processing and function align with previous findings on Transmembrane Domain 1 (TMD) 1, where these variants are located. This region has been shown to be essential for CFTR folding, pore formation, and channel conductance. Moreover, these results are in agreement with our recent study, in which we identified that variants in TMD1 tend to be more amenable to rescue by CFTRm when compared with variants in nucleotide-binding domain 1 (NBD1). | [
25,
38,
55
] | [
11,
11,
11
] | [
2,
2,
2
] |
1,397,314 | 9048902 | 132 | 1397314 | 4-Aminobutyrate aminotransferase (4-aminobutyrate: 2-oxoglutarate aminotransferase EC 2.6.1.19) is a key enzyme of the 4-aminobutyric acid shunt. It catalyzes the conversion of 4-aminobutyrate to succinic semialdehyde. In an effort to clarify the structure-function relationships of 4-aminobutyrate aminotransferase, we analyzed 4-aminobutyrate aminotransferase cDNA from pig brain. The inclusion bodies were formed when recombinant 4-aminobutyrate aminotransferase was overexpressed in Escherichia coli. The unfolded overproduced proteins, were purified by hydroxylapatite chromatography in the presence of urea and refolded by a sequential dialysis method. The renatured protein regained its catalytic activity. The lysyl residue at the 330 position of the amino-acid sequence serves as the anchoring site of the cofactor pyridoxal 5'-P. To verify the catalytic site of 4-aminobutyrate aminotransferase, lysine 330 was mutated to arginine by site-specific mutagenesis. Overexpression and purification of the mutated 4-aminobutyrate aminotransferase (K330R) were performed by the same method used the purification of wild-type 4-aminobutyrate aminotransferase. The purified and renatured K330R protein did not show the catalytic activity of wild type 4-aminobutyrate aminotransferase. Furthermore, the mutated protein did not show any absorption band over the spectral range of 320-460 nm characteristic of pyridoxal 5'-P covalently linked to the protein. From the results presented here, it is concluded that lysine 330 is essential for the catalytic function of the aminotransferase. | [
906,
1052,
1189,
1511
] | [
34,
5,
5,
10
] | [
2,
2,
2,
2
] |
1,242,740 | 35632840 | 19,499 | 1242740 | We also produced the unmodified PVX-based vector expressing GFP (GFP/pGR106) as a positive control (Figure 1B,C). The GFP gene was chosen as a reporter because it allows easy study of protein expression, PVX infection, and its spread. First, the internal restriction site ClaI was removed from the GFP sequence by using SOE-PCR and GFP-specific primers carrying the mutation C384A at the ClaI site (Figure 1B, Supplementary Table S1). The amplified GFP was then cloned into the pGR106 vector using the ClaI and SalI sites. The gene of interest (GB part GFP) was flanked by AATG/GCTT "barcodes" using GB specific primers (Supplementary Table S1), amplified by PCR, and cloned into the pJET 1.2/blunt vector. Because the presence of an internal BsaI site in the GFP sequence (Figure 1B) would interfere with direct cloning of the reporter gene into the GB destination vector pDGB3alpha2 using the BsaI restriction enzyme, this internal restriction site was disrupted by introducing the silent mutation C648T using SOE-PCR. The product of SOE-PCR was again cloned into the pJET 1.2/blunt vector and then domesticated into pUPD2b. Finally, the GB parts 35S-PVX 0_17-2, PVX-NOS 18_19, and GFP domesticated in the pUPD2b vector were assembled into the GB destination vector pDGB3alpha2, resulting in the GB-compatible PVX-based vector GFP/pGBX (Figure 1D). A comparison of the insertion sites of the expression vectors is shown in Figure 1E. The GFP reporter was placed downstream of the ClaI site in both expression vectors:GFP/pGR106 and GFP/pGBX. However, in the latter, the ClaI site is interrupted due to the presence of the AATG "barcode". In addition, the NotI and SalI sites were removed. | [
375,
1000
] | [
5,
5
] | [
1,
1
] |
1,725,655 | 26007656 | 14,607 | 1725655 | Endogenous MBD2 proteins bind methylated DNA regions. (A) Experimental scheme; the transformed mesenchymal HMLER cell line is derived from the immortalized epithelial HMEC-hTERT cells by oncogenic transformation using H-RASV12 and SV40 T/t oncogenes. Sequencings were performed on a pool of five independent experiments. (B) Reads visualization at a MBD2 peak present in each cell line; MBD2 reads in black, input reads in gray, MBD2 peaks in black bars. Reads matching the + and - strands are on top and bottom, respectively. (C and F) Read density of MeDPseq, MBD2 ChIPseq and Input at each MBD2 peak. (D and G) Read density of MeDPseq, MBD2 ChIPseq and input at each MeDP peak. (E and H) Read density of MeDPseq, MBD2 ChIPseq and input at each CpG island (CGI), sorted by their size. (C to E) HMLER cell line. (F to H) HMEC-hTERT cell line. | [
788,
814
] | [
6,
6
] | [
2,
2
] |
652,986 | 33622855 | 25,754 | 652986 | Finally, we applied DMAMS to the data of SARS-CoV-2. SARS-CoV-2 appeared at the end of 2019 and caused a worldwide pandemic in 2020. A recent study reported an increase in frequency of a certain mutation, D614G in the S gene encoding spike protein; the mutation potentially increases the fitness of the virus, as shown by clinical and experimental data. Still, the significance of the mutation for public health in the real world is controversial. Using sequence data of the virus published by July 2020 from all over the world, a phylogenetic tree of the virus showed multiple substitution events between D and G on the site and a monophyletic cluster with the genetic signature 614G (Fig. S3E). The site was not under diversifying selection evaluated by SLAC or under convergent evolution toward G detected by DEPS (Table 1). In addition, DMAMS did not show the 614G-specific population growth of monophyletic strains (Table 1). Actually, not only the monophyletic strains with the genetic signature but also strains outside of the cluster without the genetic signature had large-magnitude negative Tajima's D values, -2.79 and -2.80, respectively. The result reflects a rapid growth in population size of the novel virus by a global pandemic in a naive population. There was no significant difference in Tajima's D values between strains with and without the 614G mutation. | [
205,
864,
1362
] | [
5,
4,
4
] | [
2,
2,
2
] |
1,593,595 | 21775680 | 27,448 | 1593595 | HMWF PT-gluten is the high molecular weight (>10kDa) fraction of processed gluten protein fragments, generated by pepsin and trypsin/chymotrypsin digestion and treated with transglutaminase. It has been shown that the presentation of PT-gluten requires internal processing and we also saw that T cell proliferation was dramatically inhibited when APCs were fixed (data not shown). It is known that DM plays an important role in selection of endosomally-generated peptides for presentation. To better understand the effect of DQ2 mutants on this functional interaction with DM, we measured T cell hydridoma activation in response to T2-DM cells fed with PT-gluten. Interestingly, activation of both HH8 and DB4 was significantly compromised when alpha+53G was coexpressed with DM (Fig. 9). DM+ cells with DQ2 WT more efficiently presented the epitope alpha-gliadin 57-73 Q65E than DM-cells (Supp. Fig. 2A&B, left panels). This difference between DM- and DM+ was modest (for HH8) or even reversed (for DB4) for cells containing alpha+53G (Supp. Fig. 2A&B, right panels). Considering the improved sensitivity of alpha+53G to DM effect as demonstrated above, these findings suggest that the presentation of epitope alpha-gliadin 57-73 Q65E is suppressed by DM in endocytic compartments. | [
870,
1231
] | [
4,
4
] | [
2,
2
] |
2,865,216 | 36184667 | 19,380 | 2865216 | The NTD1 is joined to NTD2 by a long loop that runs along the groove of the DNA. The NTD2 domain is functionally similar to the second DNA-binding domain in other transposases. However, it displays limited conservation to the closest homologues of shTnsB (Supplementary Fig. 1), and its structure resembles the paired domain found in Paired box (Pax) genes. The well-conserved R99 in that loop builds polar interactions with the bases of dT31 and dA32, and dA45, while R106 also recognizes the bases of the dT30 and dT46 in different strands. The rest of the associations of the loop with the DNA involve backbone contacts. The NTD2 domain also binds to the DNA in the major groove. However, it displays fewer specific contacts with the bases. Only R158 and K154 associate with dA48-dG49 and dG24, respectively, while the rest of the residues associated with the backbone of the nucleic acid. These interactions are similar in the NTD1 and 2 domains on the LTR(6) and LTR(8) branches of the protein-DNA complex (Supplementary Fig. 7). | [
749
] | [
4
] | [
2
] |
2,701,457 | 41627892 | 107 | 2701457 | BACKGROUND AIMS: Cholangiocarcinoma (CCA) is a rare but aggressive malignancy with poorly understood genetic susceptibility. To date, genome-wide association studies (GWAS) investigating germline variants associated with CCA risk remain limited. We aimed to identify genetic risk loci for CCA and its clinical subtypes through comprehensive GWAS and post-GWAS analyses. APPROACH RESULTS: We conducted a GWAS of 2,366 CCA cases and 11,750 controls of European ancestry. Genome-wide significant loci (P<5x10-8) were identified and further examined through fine-mapping, functional annotation, and HLA imputation. Subgroup analyses were conducted by CCA subtypes and primary sclerosing cholangitis (PSC) status. Cross-trait linkage disequilibrium score regression and Mendelian randomization were employed to investigate the shared genetic architecture and potential causal relationships with a diverse range of traits. We identified one new genome-wide significant variant, rs535777 (OR=1.44), near HLA-DRB1/DQA1 associated with CCA, and two variants associated with extrahepatic CCA: rs116224263 (OR=0.17) in LINC02506 at 4p15.1 and rs6914950 (OR=1.63) near HLA-DRB1/DQB1. Stratified analyses revealed rs2395184 (OR=3.51) near HLA-DRA/DRB5 associated with PSC-related CCA, and rs142674434 (OR=2.98) in THSD7A at 7p21.3 associated with non-PSC-related CCA. HLA imputation uncovered new amino acid residues associated with disease risk. Cross-trait analyses identified shared genetic signals between CCA and anthropometric, lipidemic, lifestyle, and medical traits. Mendelian randomization supported putative causal associations for twelve traits with CCA or its subtypes. CONCLUSIONS: Our large-scale GWAS highlights new genetic variants and HLA-linked mechanisms underlying CCA susceptibility. Integrating multi-step post-GWAS approaches enhances understanding of CCA pathogenesis and may facilitate the development of risk biomarkers for early detection and precision prevention strategies. | [
972,
1083,
1132,
1201,
1276
] | [
8,
11,
9,
9,
11
] | [
3,
3,
3,
3,
3
] |
197,310 | 37181765 | 29,469 | 197310 | In addition to the separated C111-H272 proton transfer and the nucleophilic attack of P1-C by C111-Sgamma, other possible mechanisms of acylation of SARS-CoV-2 PLpro were also explored. First, the case whether the attack of P1-C by C111-Sgamma could be concerted to the C111-H272 proton transfer as the acylation starts from an EN:S complex carrying a neutral form of C111/H272 was examined. In this way, a transient thiohemiketal (THA) state would be formed, which then would undergo P1-C-P1'-N bond breakage assisted by proton transfer from H272H+ to P1'-N, forming an E-I1 intermediate and releasing a P1'-NH2 fragment (Fig. S13a ). The calculated free energy of the THA state is significantly higher than that of EN:S (22.6 kcal mol-1) and the free energy barrier for this stepwise acylation is also large (30.5 kcal mol-1) (Fig. S13b ). The analysis of the reaction path shows that the C111-H272 proton transfer occurs distinctly prior to the attack of P1-C by C111-Sgamma (Fig. S13b and c ). Second, an acylation with a C111-Sgamma attacking the substrate P1-C concerted to the proton transfer from C111-Hgamma to P1'-N was also investigated. The free energy barrier for such a concerted process is also significantly higher than that in the acylation step starting with the ion pair of C111-/H272H+ (20.6 vs. 13.6 kcal mol-1) (Fig. S13e-g vs.Fig. 4). Similar results have been observed in the QM/MM MD simulations of SARS-CoV-2 3CLpro. These results together suggest that a separated C111-H272 proton transfer and nucleophilic attack of P1-C by C111-Sgamma occurs in the PLpro proteolysis. | [
34,
275,
373,
543,
896,
1299,
1496,
1552
] | [
4,
4,
4,
5,
4,
5,
4,
4
] | [
2,
2,
2,
2,
2,
2,
2,
2
] |
3,849,016 | 29138417 | 15,429 | 3849016 | Nonsense mutations detected in the ND5 and ND6 genes. Electrophoregrams and the changes in the amino acid sequence are shown. (A) C12813A mutation in the ND5 gene. (B) G13366A mutation in the ND5 gene. Electrophoregrams of the sequences of the antisense strand are shown. (C) 14504del mutation in the ND6 gene. Electrophoregrams of the sequences of the antisense strand are shown. The mutation is present in the tumour lesion but not in the adjacent mucosal tissue. | [
130,
168,
276
] | [
7,
7,
8
] | [
1,
1,
1
] |
2,848,081 | 41473674 | 26,625 | 2848081 | Diet folate, DNA methylation and genetic polymorphisms of MTHFR C677T in association with the prognosis of esophageal squamous cell carcinoma | [
64
] | [
5
] | [
1
] |
225,402 | 34956081 | 64,431 | 225402 | Prothrombin G20210A Carriers the Genetic Mutation and a History of Venous Thrombosis Contributes to Thrombin Generation Independently of Factor II Plasma Levels | [
12
] | [
7
] | [
1
] |
4,284,144 | 36678038 | 20,020 | 4284144 | To gain more insight into the effect of CNT structure on water molecules' mobility, we computed the self-diffusion coefficient of water molecules inside different CNT sizes at different temperatures. We find a direct connection between water structure and diffusion. In addition, the confinement effect may result in water adopting multiple diffusion modes. Figure 3A depicts the logarithmic plot of the MSD curve versus time for water molecules in the axial direction, z-axis, inside CNTs, at 300 K. To obtain these results, two water models (TIP3P and SPC ) were used for water inside 1.0, 3.0, and 5.0 nm, while only one model (T1P3P) was used for the 0.8 nm CNT. It is observed that MSD behavior in 0.8 nm CNT size is different from those inside larger CNT sizes. At the initial time stage, 0.8 nm CNT water molecules exhibit a single-file behavior consistent with the previous studies. As expected, MSD values increase with increasing the size of CNTs, reaching the maximum values inside 3.0-nm CNT. Figure 3B shows the diffusion modes of water inside CNTs using the two water models. | [
494
] | [
5
] | [
2
] |
3,485,286 | 38923681 | 34,122 | 3485286 | IR, TNF-alpha, and TNF-alpha folding change are associated with AV especially severe grades of acne. The -863 G > A (rs1800630) and -308 G > A (rs1800629) variants polymorphism might have a modulatory effect on the TNF-alpha gene expression and in consequence, serum TNF-alpha levels which have a prominent role in the pathogenesis of AV and has association with IR in acne patients. But further studies should be carried out with more sample size and same and different ethnic groups to confirm these effects. | [
105,
117,
132,
144
] | [
10,
9,
10,
9
] | [
1,
3,
1,
3
] |
28,979 | 39028675 | 21,372 | 28979 | Consistent with the low current levels for S695I in HEK cells, expression of this mutant in Xenopus oocytes with wild-type R1, and using a two-electrode voltage clamp, also revealed reduced maximal GABA current (Fig. 2E; P = 0.0018, two-tailed unpaired t-test). As a consequence, we were unable to construct full concentration curves due to the small-sized currents, although similar reduced efficacy and increased GABA potency for S695I have been reported. | [
43,
432
] | [
5,
5
] | [
2,
2
] |
55,979 | 39031745 | 21,609 | 55979 | rs401681 and rs402710 confer lung cancer susceptibility by regulating TERT expression instead of CLPTM1L in East Asian populations | [
0,
13
] | [
8,
8
] | [
3,
3
] |
1,374,112 | 37898658 | 26,102 | 1374112 | PAPP-A2 and PAPP-A show a similar mode of IGFBP5 recognition yet differ in severity of cleavage reduction for most mutations tested. We hypothesize that PAPP-A2 binding to IGFBP5 is much more dynamic compared to PAPP-A. We directly compared IGFBP5 binding and cleavage by PAPP-A2 and PAPP-A to obtain a better understanding of the differences between the two enzymes. Catalytically inactive PAPP-A2 E500Q shows a 11-fold weaker binding to full-length (FL) IGFBP5 than inactive PAPP-A E483A (Fig. 4a and Supplementary Data 2) and PAPP-A2 cleaved wild type IGFBP5 38-fold less efficiently than PAPP-A (Fig. 4b, Supplementary Fig. 11, and Supplementary Data 2). We next evaluated the contribution of the C-terminal domains of PAPP-A2 to IGFBP5 cleavage. Removal of the C-terminus of the protein starting with the CCP1 domain (PAPP-A21159) resulted in a 2.7- fold reduction in activity (Fig. 4c, Supplementary Fig. 12a, b, and Supplementary Data 2), suggesting that this region could contribute to, but is not essential for IGFBP5 cleavage. This is not surprising as we do not observe density for these regions in the PAPP-A2 cryo-EM structure, the ML-PAPP-A2/IGFBP5 model does not predict their direct interactions with the anchor peptide, and removal of the C-terminal domains of PAPP-A also does not hinder IGFBP5 cleavage. Interestingly, the further deletion of the M2 domain, which we did not observe in the cryo-EM structure, (PAPP-A2927) did not result in an additional reduction in IGFBP5 cleavage (Fig. 4c, Supplementary Fig. 12a, b, and Supplementary Data 2). Key residues from the PAPP-A M2 domain that contribute to IGFBP5 anchor peptide recognition are not conserved in PAPP-A2, suggesting that the M2 domain is not necessary for substrate recognition by PAPP-A2 (Supplementary Fig. 13a-c). Dimerization interfaces are also not well conserved in PAPP-A2, underlying why PAPP-A2 is a monomer (Supplementary Fig. 1, Supplementary Fig. 14a-c). PAPP-A2 shows much lower proteolytic activity for IGFBP5 cleavage compared with PAPP-A monomer variants (PAPP-A1100 -1111* and PAPP-A1100 -1135*) that were described previously, indicating that dimerization is not a key determinant for differences in IGFBP5 cleavage activity between the two enzymes (Fig. 4d, Supplementary Fig. 15a, b, and Supplementary Data 2). Instead, the dynamics of the M2 domain with regard to anchor peptide binding may be important for substrate cleavage for PAPP-A2. | [
399,
484
] | [
5,
5
] | [
2,
2
] |
4,866,309 | 38875362 | 26,801 | 4866309 | HER2 mutations (~3%) are rare compared with amplifications, but they can induce oncogenic effects by constitutively activating HER2 or by promoting the dimerization of HER2 with other constituents of the HER family. Approximately 70% of HER2 mutations happen in the structural domain of the kinase at amino acids 755 and 781 (between exons 19 and 20), and an additional 20% occur at amino acids 309 or 310 (exon 8) in the extracellular domain. The 3 mutations with the highest frequencies in HER2-amplified breast cancer are known as V777L, L755S, and D769Y, all of which are predicted to be driver mutations that appear to be induced (at least in part) by HER2-targeted and endocrine therapies and are prevalent in metastatic tumors. In addition, p95HER2 (a truncated receptor does not possess the extracellular epitope identified by anti-HER antibodies) and Delta16HER2 (a splicing isoform heterodimer encoding a deletion of an extracellular structural domain encoded in exon 16, leading to HER2 homodimerization and constitutive stabilization of HER2 signaling) are also present in patients with HER2-positive breast cancer. Presentation of p95HER2 has been measured in approximately 30% of breast cancers, and among HER2-positive breast cancer patients, those expressing p95HER2 have a poorer prognosis than those expressing full-length HER2. The marked increases in Delta16HER2 in HER2-amplified cancers have been thought to be mechanisms of HER2 tumorigenesis, accounting for 4% to 9% of all HER2 transcripts. According to data displayed on cBioPortal, approximately 2% of breast cancer patients carry a HER3 gene mutation. However, HER2 and HER3 mutations are not frequently co-expressed in HER2 amplification breast cancer cells. | [
534,
541,
552
] | [
5,
5,
5
] | [
2,
2,
2
] |
1,500,501 | 31187503 | 43,149 | 1500501 | Finally, we measured plasma PLP concentrations in all affected individuals. Plasma PLP was greatly reduced in cases carrying p.Arg220Gln and p.Ala228Thr compared to age-matched controls (see Fig 3G, H). | [
125,
141
] | [
11,
11
] | [
2,
2
] |
2,403,965 | 28367058 | 127 | 2403965 | Adenocarcinoma is the most common type of non-small-cell lung cancer (NSCLC). Adenocarcinoma with epidermal growth factor receptor (EGFR) mutations accounts for 8%-30% of all cases of NSCLC depending on the geography and ethnicity. EGFR-mutated NSCLC usually responds to first-line therapy with EGFR tyrosine kinase inhibitors (TKIs). However, there is eventual loss of efficacy to TKIs due to development of resistance. The most frequent cause for resistance is a second EGFR mutation in exon 20 (T790M), which is encountered in up to 62% of patients. Osimertinib is one of the third-generation EGFR TKIs with a high selective potency against T790M mutants. In Phase I trial of osimertinib in advanced lung cancer after progression on EGFR TKIs, the response rate and disease control rate were 61% and 95%, respectively. A subsequent Phase II (AURA2) trial demonstrated a disease control rate of 92%, a response rate of 71%, a median duration of response of 7.8 months, and a median progression-free survival of 8.6 months. Osimertinib was approved by the US Food & Drug Administration in November 2015 for patients whose tumors exhibited T790M mutation and for those with progressive disease on other EGFR TKIs. In this review, we address the role of EGFR TKIs in the management of EGFR mutation lung cancer and the mechanisms of resistance to TKIs with a focus on the role of osimertinib. Data from completed trials of osimertinib, ongoing trials, as well as novel diagnostic methods to detect EGFR T790M mutation are reviewed. | [
498,
644,
1140,
1502
] | [
5,
5,
5,
5
] | [
2,
2,
2,
2
] |
834,663 | 26145817 | 71,191 | 834663 | H18F(aq) (1186 mCi (43.9 GBq) at EOB) in H218O was delivered to a CPCU, collected on a trap/release cartridge, released with K2CO3(aq) (0.9 mg in 0.6 mL H2O), and added to a solution of Kryptofix 222 (5 mg in 1 mL CH3CN) in the CPCU side-arm reaction vessel. The vessel was placed in a 110 C oil bath and the solvent was evaporated with an Ar(g) flow. CH3CN (3.5 mL) was added and evaporated in order to azeotropically dry the Kryptofix 222/K18F. A solution of 35 (5.8 mg) in CH3CN (1 mL) was added to the vessel containing the Kryptofix 222/K18F, the mixture was heated at 110 C for 10 min, and then cooled. EtOEt (~5 mL) was added, the solution was transferred under Ar(g) pressure out of the reaction vessel, through a Waters silica Sep-Pak Classic, and collected in a 15-mL conical tube that had been placed in an adjacent hot cell. The CPCU reaction vessel was rinsed with EtOEt (~5 mL) and this was transferred through the Sep-Pak and into the conical tube. The tube was placed in a warm water bath and the EtOEt was evaporated with an Ar(g) flow until ~2.5 mL remained (705 mCi (26.1 GBq), 82.5% rcy, decay-corrected from EOB, ~52 min). The tube was placed in a 110 C oil bath and the remainder of the EtOEt was evaporated with an Ar(g) flow. | [
0,
442,
543
] | [
4,
4,
4
] | [
2,
2,
2
] |
5,473,904 | 18590794 | 129 | 5473904 | Three cysteine residues, Cys(65), Cys(89), and Cys(186) in lipocalin-type prostaglandin D synthase (L-PGDS), are conserved among all species and the disulfide bond between Cys(89) and Cys(186) is highly conserved among most, but not all, lipocalins. In this study, four rat L-PGDS variants were constructed by site-directed mutagenesis, and the conserved disulfide bond in several variants was removed by substituting cysteine with alanine. The effects of removing this disulfide bond on their biological characteristics were investigated. The NMR experiments indicated that the removal of disulfide did not change their conformations significantly. However, both thermal-induced and urea-induced unfolding experiments showed that the stabilities of enzymes without the disulfide bond decreased significantly. Moreover, the ligand-binding affinities of these variants were assessed by fluorescence experiments. Dissociation constants (K(d)) of 0.668, 0.689, 0.543 and 0.571 microM were obtained for ANS binding to wild-type rat L-PGDS, C(65)A, C(186)A, and C(89,186)A variants, respectively, and 71.2 and 62.3 nM for retinoic acid binding to wild-type rat L-PGDS and the C(186)A variant, respectively. These results suggested that the removal of the disulfide bond slightly increased the affinities for ligand binding by changing the hydrophobic regions. This study may offer valuable information for further studies on other rat lipocalins. | [
418,
1036,
1044,
1171
] | [
21,
6,
7,
7
] | [
2,
1,
1,
1
] |
3,477,350 | 39596168 | 3,101 | 3477350 | We generated an AxD model mouse overexpressing human GFAP carrying the AxD mutation, R239H. Astrocytes in these AxD mice have the following three biochemical, functional, and genetic features: (1) aggregation of Rosenthal fibers (RFs), (2) aberrant extra-large Ca2+ signals (AxCa), and (3) upregulation of genes characteristic of AxD (AxGen). As AxD is a primary astrocyte disease, it is postulated that severe neurological deficits are triggered by astrocyte dysfunction. The astrocyte abnormalities observed in our AxD mice are therefore likely to be involved in the molecular pathogenesis of AxD. | [
85
] | [
5
] | [
2
] |
888,295 | 27129302 | 53,525 | 888295 | HEY1 Leu94Met gene polymorphism dramatically modifies its biological functions | [
5
] | [
8
] | [
2
] |
4,849,337 | 38199849 | 444 | 4849337 | In three axSpA studies, a panel of 14 blood-based ECM biomarkers related to formation of collagen (PRO-C2, PRO-C3, PRO-C6), degradation of collagen by metalloproteinases (C1M, C2M, T2CM, C3M, C4M, C6M, C10C), matrix metalloproteinase (MMP)-degraded prolargin (PROM), MMP-degraded and citrullinated vimentin (VICM), basement membrane turnover (PRO-C4) and neutrophil activity (CPa9-HNE) were assessed to enable patient clustering (endotyping). MASH (n=41) was a cross-sectional study, while Adalimumab in Axial Spondyloarthritis study (ASIM,n=45) and Danish Multicenter Study of Adalimumab in Spondyloarthritis (DANISH, n=49) were randomised, double-blind placebo-controlled trials of adalimumab versus placebo every other week for 6 or 12 weeks, respectively, followed by active treatment. Biomarker data were log-transformed, standardised by mean centering and scaled by the SD prior to principal component analysis and K-means clustering. | [
202
] | [
4
] | [
1
] |
1,523,821 | 25214840 | 28,736 | 1523821 | Association between BRAF V600E mutation and mortality in patients with papillary thyroid cancer | [
25
] | [
5
] | [
2
] |
3,145,747 | 19860828 | 38,310 | 3145747 | A, B. Z sections of MDCK monolayers expressing the Y286A mutant construct showed predominantly apical distribution of Cx43-eYFP (2 independent clones). C, D. Z sections of MDCK monolayers expressing the LSYTRF mutant construct showed signal on both the apical and basolateral membrane domains (2 independent clones). Scale bar, 10 um. | [
51
] | [
5
] | [
2
] |
1,951,367 | 27541298 | 2,437 | 1951367 | A variation on this second approach is to develop a preference-based algorithm with which a full range of cancer-specific health states can be valued. Two such measures, the EORTC-8D and the QLU-C10D, are based on items from the Quality of Life Questionnaire C30 (QLQ-C30). | [
195
] | [
4
] | [
2
] |
4,392,254 | 12121577 | 28,038 | 4392254 | Expression and purification of hAps1, hAps1-39N and hAps2 | [
44
] | [
3
] | [
2
] |
4,999,596 | 33899013 | 55,646 | 4999596 | With the cells to be used for flow cytometry analysis, spin them down at 300 x g for 3 min at room temperature (20 C-25 C). Resuspend pellet in 200-500 mul ice-cold PBS containing 0.1% FBS. | [
115
] | [
6
] | [
1
] |
2,767,341 | 37790362 | 60,146 | 2767341 | (F) Example neurons from a single session. Left, touch responsive neurons. Right, movement-related neurons. For each neuron, response to trials with only one touch type (C2 protractions, C2 retractions, C3 protractions, or C3 retractions) are shown, along with response to movement onset on trials with no touch (whisking onset, right and left licking onset). Top, vS1 example neurons, one per type; bottom, vM1 example neurons. Thick line, mean response; thin lines, individual trial responses. Trial types for which a cell was considered non-responsive are lightened. | [
203,
223
] | [
2,
2
] | [
2,
2
] |
337,649 | 31417337 | 23,506 | 337649 | Expression of the p-alpha-syn, GFAP, and IBA1 in the motor cortex of 5-month-old WT and A53T mice. Representative IF microphotographs of the p-alpha-syn, GFAP, IBA1, and merged image in 5-month WT mice (A-D) and A53T mice (E-H) used for densitometry analysis. Representative IF microphotographs of the DAPI, IBA1, and merged image in 5-month WT mice (I-K) and A53T mice (L-N) used for IBA1-positive cell density analysis. Image J was used to quantify the intensity of p-alpha-syn, GFAP, and IBA1 staining and density of IBA1-positive cells. Increased expression of the p-alpha-Syn (O), GFAP (P), and IBA1 (Q) was observed in A53T mice compared to WT mice. (R) The A53T mice showed increased density of IBA1-positive cells (n = 5/group; *p < 0.05, **p < 0.01). | [
88,
212,
360,
625,
664
] | [
4,
4,
4,
4,
4
] | [
2,
2,
2,
2,
2
] |
1,948,741 | 36499626 | 24,396 | 1948741 | The human ovarian cancer cell line A2780S (93112519) and the cisplatin resistant cell line A2780CP (93112517) were obtained from the European Collection of Authenticated Cell Cultures (ECACC). The human embryonic kidney 293T cell line was obtained from American type culture collection (ATCC) (CRL-3216). All the cell lines were grown at 37 C in a humidified atmosphere of 5% CO2. The cells were cultured in DMEM medium (meilunbio, Dalian, China) supplemented with 10% FBS (yeasen, Shanghai, China). miR-200b/c, miR-429, miR-4499 mimics or the negative control (NC) (RiboBio, Guangzhou, China) were transfected into the cells at a final concentration of 50 nM using the Hieff TransTM liposomal transfection reagent (yeasen, Shanghai, China) according to the manufacturer's instructions. | [
35
] | [
6
] | [
2
] |
1,004,974 | 22590567 | 17,348 | 1004974 | In this study, we have discovered an evolutionarily conserved signaling link between the tyrosine kinase c-Abl and the MST family of kinases that mediates responses to oxidative stress in mammalian cells. Our findings generalize the substrates of c-Abl from MST1 to other family members of the MST proteins. Our major findings are: (1) c-Abl phosphorylates MST2 at the conserved Y81 in vitro and in vivo, (2) the c-Abl-induced phosphorylation of MST2 reduces the interaction between Raf-1 and MST2 and enhances MST2's homodimerization, (3) c-Abl-MST2 signaling plays a critical role in neuronal cell death upon Rotenone treatment. Collectively, we have identified a novel upstream regulator of MST2 underlying the oxidative stress-induced cell death. | [
379
] | [
3
] | [
2
] |
4,187,801 | 37166408 | 27,308 | 4187801 | Based on a study that showed that CDH2 SNPs conferred an increased risk of canine compulsive disorder, Moya et al. searched for CDH2 heterozygous variants in patients with obsessive compulsive disorder and Tourette disorder. Moya et al. found four CDH2 allelic variants, including the p.Val289Ile. This variant was found in two patients and one normal control. The authors concluded that these heterozygous CDH2 variants were not disease-causing by themselves and that further studies were necessary. This is consistent with our findings as neither heterozygous parent of the proband has these disorders. | [
285
] | [
11
] | [
2
] |
1,815,130 | 33714740 | 18,497 | 1815130 | For the identification of crosslinks between CRP and HSA, in solution digestion of protein mixtures was performed on samples that were treated with IAM (final concentration: 50 mM) either without reduction, or with reduction and alkylation using DTT/IAM after digestion. Briefly, protein samples (20 mug) which has been dried down in a Speedvac were redissolved and denatured in urea buffer (8 M urea, 50 mM Tris-HCl, pH 8), and the alkylating reagent IAM (final concentration: 50 mM) was added into the system to block free thiols on HSA. The concentration of urea was then diluted to 1 M with 100 mM ammonium bicarbonate, trypsin was added to achieve a 1:50 (w/w) enzyme/substrate ratio, and the reaction mixtures were incubated at 37 C overnight. After digestion, the samples were either examined directly or subjected to reduction and alkylation to cleave the new disulfide and alkylate the resulting thiols. The latter was achieved by treating the samples with DTT (40 mM in 100 mM ammonium bicarbonate, pH 8.0) for 45 min, followed by incubation with IAM (100 mM in 100 mM ammonium bicarbonate, pH 8.0) for 60 min in the dark. | [
588
] | [
10
] | [
2
] |
4,656,392 | 29247237 | 9,607 | 4656392 | Nucleotidic variation in the CAP-G gene associated with B chromosome presence in E. plorans from Torrox population. The upper panel (white background) shows gDNA counts for 8 nucleotidic positions in 0B and 4B males from Torrox. Note that the 0B reference is usually at lower frequency because of the presence of several gene copies in the B chromosome. The middle panel (grey background) shows RNA counts for these same 8 nucleotidic positions in 0B and 1B females from Torrox. Note that the 0B female has the same nucleotides as the 0B gDNA from Torrox, and that the 1B female has esentially the same nucleotide composition as the B-carrying gDNA libraries, indicating the expression of B chromosome gene copies. The lower panel shows codon (light yellow background) and aminoacidic (yellow background) changes provoked by the 8 substitutions. Note that only nucleotidic changes in positions 643 and 3,010 provoke alterations on the predicted CDS of the B chromosome gene copies (R for C in the 215 residue and E for stop codon in the 1004 residue, respectively), and that the substitution of nucleotide 3,025 is beyond the stop codon. | [
982,
1013
] | [
26,
36
] | [
1,
2
] |
1,558,841 | 27560520 | 23,710 | 1558841 | While none of our genome-wide or suggestive (p < 5 x 10-7) signals included SNPs implicated in either of the previous two European-focused GWA studies, we nevertheless found evidence of association when we tested the top SNPs from these studies against comparable phenotypes from our data. Strongest among these was nasal ala length, a lateral projective measure of the nose extending from alar cartilage to the nasal tip, previously associated with 1p36.32 (rs4648379, PRDM16) or 3p14.3 (rs1982862, CACNA2D3. We found at least nominal associations with both of these regions in our data, with one (rs4648379, PRDM16) showing evidence at p = 1.70 x 10-5. Both prior GWA studies reported an association between SNPs at 2q35 (PAX3) and morphology of the interorbital septum. We tested these SNPs and found an association between rs974448 and intercanthal width (p = 0.002), lending some additional support to the claim that common variants in PAX3 might influence aspects of normal facial morphology. | [
459,
489,
599,
827
] | [
9,
9,
9,
8
] | [
3,
3,
3,
3
] |
2,162,025 | 41326491 | 20,124 | 2162025 | Reduced hTRPV3 exhibited structural similarities to reduced mTRPV3 at 4 C, including the active vanilloid site for the same putative phosphatidylcholine (PC) lipid binding through a pi interaction with W521 and a salt bridge with R567 (Fig. 4A). However, some differences were observed throughout the entire polypeptide chain. For example, when the D519-R698 salt bridge at the VSLD/TRP interface was replaced with the E418-R690 salt bridge at the pre-S1/TRP interface, the H-bond moved from T397-E704 to Y409-E702 together with the formation of the E405-K705 salt bridge. Meanwhile, the Q570-W692 pi interaction was present at the S4-S5 linker/TRP interface. As a result, the total noncovalent interactions and the total grid sizes along the PC-dependent minimal gating pathway from D396 in the pre-S1 domain to K705 in the TRP domain increased from 51 to 52 and from 96 to 98, respectively (Fig. 3A, Table S3). In this case, the systematic thermal instability (Ti) remained at 1.88 (Table 1). | [
231
] | [
4
] | [
2
] |
4,937,606 | 35923246 | 12,927 | 4937606 | Genotype analysis was performed on NC_000007.14:g.139985896C>T of the 3072 samples. Finally, there were 1,991 cases in the MS group and 1,076 cases in the control group completed. The frequency distribution of NC_000007.14:g.139985896C>T genotypes and alleles in control group and MS group was basically consistent with that in HAPMAP-CHB; the frequency distribution of NC_000007.14:g.139985896C>T in both groups did not deviate from the Hardy-Weinberg equilibrium. | [
48,
223,
383
] | [
14,
14,
14
] | [
1,
1,
1
] |
3,637,931 | 16963494 | 42,534 | 3637931 | In vitro and in vivo analyses of a Phe/Tyr switch controlling product specificity of histone lysine methyltransferases | [
35
] | [
7
] | [
2
] |
4,347,307 | 31590428 | 9,772 | 4347307 | Several studies have described the in vitro anti-HIV activities and cytotoxicity of GRFT (Table 2). Mori et al. reported potent, sub-nanomolar antiviral efficacy of both native and recombinant GRFT against laboratory strains and primary isolates of T- and M- tropic HIV-1. In their publication, they observed that GRFT inhibited soluble gp120 from binding to CD4 receptor-expressing cells. Cell-to-cell fusion and transmission of HIV-1 infection were also blocked by GRFT at similar concentrations. In addition, the coadministration of monosaccharides such as glucose, mannose, and N-acetyl glucosamine hindered glycosylation-dependent binding of GRFT to soluble gp120. In parallel with this observation, Emau et al. also demonstrated that GRFT could block the infectivity of CXCR4- and CCR5-tropic HIV viruses at picomolar concentrations. They also confirmed the long-term stability of GRFT in a cervical/vaginal lavage. In order to harness the HIV-inactivating power of GRFT, a new peptide called grifonin-1 was designed based on the three carbohydrate-binding amino acid sequences of GRFT. Its sub-micromolar anti-HIV activity was confirmed using an in vitro TZM-bl cell line and p24 gag antigen release assays. In addition to its ability to suppress HIV-1 transmission in CD4+ T-lymphocytes, GRFT also subverted DC-SIGN (dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin)-mediated HIV capture. Mechanistically, a binding competition between GRFT and gp120 for DC-SIGN was proposed as a potential mode of action for GRFT-mediated inhibition of HIV-1 capture by DC-SIGN. Corresponding to this DC-SIGN-dependent antiviral activity, GRFT also potently inhibited giant cell formation between persistently HIV-infected T cells and noninfected CD4+ target T cells. This led to the suppression of HIV transmission, CD4+ T-cell destruction, and ultimately viral replication through the DC-SIGN mediated pathway. This efficient blockage of the binding of DC-SIGN to immobilized gp120 by GRFT was further confirmed. This observation was in harmony with the GRFT-mediated expulsion of gp120 from the gp120/DC-SIGN complex. Interestingly, this highly potent inhibition of DC-SIGN-mediated capture and transmission by GRFT was markedly impaired when GRFT was mutated in one of its three carbohydrate-binding sites (D30A, D70A, or D112A), further implicating its carbohydrate-binding sites as critical determinants for anti-HIV-1 activity. Regarding its cytotoxicity, two studies demonstrated that the CC50 concentration for GRFT was several hundred nanomolar, thousands of times higher than its reported antiviral concentrations. | [
2334,
2340,
2349
] | [
4,
4,
5
] | [
2,
2,
2
] |
1,089,420 | 33020662 | 29,666 | 1089420 | We next asked whether myo6 phosphorylation at T405 is able to facilitate mitochondrial positioning at presynaptic terminals. While expressing phospho-mimetic mutant myo6-T405E, but not phospho-dead mutant myo6-T405A, facilitated presynaptic mitochondrial recruitment (P < 0.001) (Fig. 5d,e). Enhanced presynaptic capture by expressing myo6-T405E substantially reduced mitochondrial motility along axons (P < 0.001) (Fig. 5f,g). These results reinforce the notion that phosphorylation at myo6-T405 is a key step in this energy-anchoring crosstalk, thus facilitating presynaptic mitochondrial capture. We further characterized the role of PAK signaling in presynaptic mitochondria recruitment. Expressing PAK3 did not affect the percentage of presynaptic terminals co-localized with mitochondria (P > 0.99), consistent with its autoinhibitory conformation. Conversely, expressing kinase constitutively active PAK3-CA significantly increased mitochondrial retention at presynaptic terminals (P < 0.001); which was largely abolished when expressing kinase-dead PAK3-KD (Fig. 5h,i). These data support that PAK signaling is involved in the capture of presynaptic mitochondria. | [
46,
170,
210,
340,
492
] | [
4,
5,
5,
5,
4
] | [
2,
2,
1,
2,
2
] |
348,456 | 30728606 | 7,813 | 348456 | We sequenced two regions: the nuclear ITS1-5.8S-ITS2 region using the primers ITS1F-ITS4 and the RNA polymerase II subunit (RPB2) between primers RPB2-6F-bRPB2-7R for the RPB2 region. PCR reactions were performed in 25 muL per reaction under a program consisting of a hot start at 95 C for 5 (6 in the case of Spanish isolates) min, followed by 35 cycles at 94 C, 54 C and 72 C (45, 30 and 45 s, respectively) and a final 72 C step 10 min. PCR products were checked in 1 % agarose gels, and positive reactions sequenced in both directions. Sequencing primers were the same as employed for PCR amplification. Raw sequence data was manually edited using Chromas 2.5.1 software (Technelysium Pty Ltd., Southport, Queensland, Australia). The identity of obtained consensus sequences was verified through the BLASTn query algorithm in GenBank (http://www.ncbi.nlm.nih.gov) and UNITE (https://unite.ut.ee/) databases. | [
272
] | [
11
] | [
2
] |
1,376,891 | 37268727 | 16,730 | 1376891 | Gene Position III-1 IV-9 Sequencing results MUTATION/HAPLOTYPE TYPE Sequencing results Mutation/haplotype type OPN1MW Exon1 Normal Normal Exon2 Normal (1) c.194T>C p.I65T(2) c.300G>A p.L100L(3) c.331A>G p.I111V(4) c.347A>C p.Y116S (1)Benign(2)Synonymous(3)Benign(4)Benign Exon3 (1) c.465C>G p.V155V(2) c.521C>T p.A174V(3) c.532A>G p.I178V MVVVA (harmful) c.538G>T p.A180S MVAIS (Benign) Exon4 Normal Normal Exon5 Normal c.849A>C p.P283P Synonymous Exon6 Normal Normal OPN1LW Exon1 Normal Normal Exon2 Normal Normal Exon3 (1) c.453A>G p.R151R(2) c.457A>C p.M153L(3) c.465C>G p.V155V(4) c.511_513GTG>ATT p.V171I(5) c.538G>T p.A180S LIAIS (benign) (1) c.453A>G p.R151R(5) c.538G>T p.A180S MVAIS (Benign) Exon4 Normal Normal Exon5 Normal Normal Exon6 Normal Normal | [
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225,
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342,
368,
375,
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447,
559,
566,
579,
586,
599,
606,
617,
634,
647,
654,
683,
690,
703,
710
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6,
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7,
16,
7,
6,
7,
6,
7,
6,
7
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2,
1,
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1,
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1,
2
] |
2,527,711 | 36113581 | 11,196 | 2527711 | To identify the PGA1 locus, a map-based cloning approach was employed, using a F2 population derived from a cross between pga1-1 and the Landsberg erecta (Ler) ecotype. Initial mapping was performed with a DNA pool from 95 pga1-1 individuals using molecular markers distributed on five chromosomes, and the PGA1 locus was located to the long arm of chromosome 1, close to the marker F5A18#1 (Fig. S3). Fine mapping using 285 pga1-1 individuals further placed PGA1 between markers T8K14#1 and F19K16#1 (Fig. 2A). Genomic DNA sequencing of genes in this region identified a G to A missense mutation in the coding region of AT1G79560, converting the 703rd amino acid residue from glycine to arginine (G703R) (Fig. 2A). AT1G79560 encodes AtFtsH12, a member of the chloroplast FtsH protein family. AtFtsH12 protein contains several distinct domains including an N-terminal chloroplast transit peptide, two putative transmembrane domains TM1 and TM2, an ATPase domain, and a conserved HExxH motif for the zinc-dependent proteolytic domain M41 (Figs. 2B, S4 and S5). The G703R mutation was located in the GAD (Glycine-Alanine-Aspartate/Glutamate) motif, which is part of the ATPase domain and is well conserved in FtsH homologs (Figs. 2, B and C and S4). The predicted 3-D structure of the ATPase domain of AtFtsH12 showed that the conserved Gly703 is in an alpha-helix near the ATP-binding pocket, resembling its counterpart Gly484 in yeast Yme1 (Figs. 2C and S4). | [
572,
677,
698,
1064,
1335
] | [
6,
19,
5,
5,
6
] | [
1,
2,
2,
2,
2
] |
78,488 | 39414907 | 29,863 | 78488 | Haplotype analysis of 2 SNPs (rs1801131 and rs1801133) in the participants. | [
30,
44
] | [
9,
9
] | [
3,
3
] |
1,260,576 | 27755544 | 52,621 | 1260576 | Sequences for mev-1 of representative nematode species together with, Homo sapiens, Sus scrofa, and S. cerevisiae were obtained using BlastP and aligned by ClustalW. The key residues involved in quinone binding, are conserved amongst all nematode species examined. The red star indicates the T66I variant that results in resistance to CID 2747322 exposure in the VC3631 strain. Residues important for the left binding pocket of CID 2747322 are indicated with a black star. Image was generated using Geneious version 8.1.7. | [
292
] | [
4
] | [
2
] |
1,921,938 | 27287717 | 34,838 | 1921938 | The Allelic Context of the C797S Mutation Acquired upon Treatment with Third-Generation EGFR Inhibitors Impacts Sensitivity to Subsequent Treatment Strategies | [
27
] | [
5
] | [
2
] |
2,933,725 | 35172173 | 16,717 | 2933725 | The observed 1-RBD-up spike conformation may have evolutionary advantage. For example, the cryptic epitopes, which are only available in the RBD up and are recognized by antibody classes 1 and 4, have a lower frequency of exposure compared with the WT. Together with high mobility of the RBD up and mutations, the Omicron spike can shed off recognition by dominant human antibodies elicited by infection and vaccination. Since many antibodies recognize two RBDs up simultaneously to enhance neutralization through avidity, the reduced number of RBDs up may decrease this effect. In this study, we observed that S2 mutations N764K and N856K may play a role in stabilizing RBDs in the down conformation through additional interactions with SD1 and SD2 domains. L547K and L981F are close to the RBD in the down conformation of adjacent protomers (Figure S4D), which may also contribute by altering S2/RBD interactions. The four mutations are also close to the S2 helix bundle (Figures 2D and S4D), and may contribute to the observed S2 conformational change, but the mechanism remains unclear. | [
624,
634,
759,
769
] | [
5,
5,
5,
5
] | [
2,
2,
2,
2
] |
4,522,619 | 36833190 | 57,684 | 4522619 | Segawa syndrome due to mutation Q89X in the GCH1 gene: A possible founder effect in Cordoba (southern Spain) | [
32
] | [
4
] | [
2
] |
2,868,626 | 28358873 | 10,577 | 2868626 | Patient clinical profiles of the type II pRCC cohort in rs11762213 survival analysis. | [
56
] | [
10
] | [
3
] |
1,316,850 | 39497713 | 47,571 | 1316850 | Acquired BRAF V600E mutation as resistant mechanism after treatment with osimertinib | [
14
] | [
5
] | [
2
] |
3,238,112 | 31591431 | 16,830 | 3238112 | To interpret functions of the SMF-regulated genes in roots and leaves, we performed gene ontology (GO) enrichment analysis. In both SMF-treated roots (N0 and N180), up-regulated DEGs were enriched in the metabolic process, such as the flavonoid biosynthetic pathway (GO: 0009813) (Fig. 5, Supplementary Table S8), suggesting that expression of these genes is associated with SMF intensity but not with orientation. In the SMF-treated leaves, the common down-regulated DEGs were involved in the red (GO: 0010114) or far-red light signaling pathway (GO: 0010017) (Fig. 5, Supplementary Table S8), suggesting a crosstalk between SMF and red/far-red light signaling. Other biological processes were enriched uniquely in a particular treatment. For instance, plant-type cell wall organization (GO: 0009664), nitrate transport (GO: 0015706) and callose deposition in the phloem sieve plate (GO: 0080165) were enriched in the up-regulated N0R transcriptome, while photosynthesis related terms (GO: 0015979, GO: 0009658 and GO: 0010027) in the down-regulated N0R transcriptome (Fig. 5, Supplementary Table S8). Taken together, transcriptomic analysis uncovers biological processes regulated by SMF directions in roots and leaves. | [
158,
1051
] | [
4,
2
] | [
2,
2
] |
2,715,901 | 36841727 | 19,612 | 2715901 | Clinical Characteristic Patients (N = 396) Year of metastatic NSCLC diagnosis <2011 15 (3.79%) 2011 18 (4.55%) 2012 9 (2.27%) 2013 6 (1.52%) 2014 16 (4.04%) 2015 33 (8.33%) 2016 50 (12.63%) 2017 56 (14.14%) 2018 68 (17.17%) 2019 83 (20.96%) 2020 42 (10.61%) Stage at initial NSCLC diagnosis Unknown 6 (1.52%) Stage Ia 29 (7.32%) Stage IIa 13 (3.28%) Stage IIb 23 (5.81%) Stage IIIa 40 (10.10%) Stage IIIb 15 (3.79%) Stage IIIc 2 (0.51%) Stage IV 268 (67.68%) Histology Adenocarcinoma 217 (54.80%) Squamous cell carcinoma 5 (1.26%) Adenosquamous carcinoma 4 (1.01%) Large cell carcinoma 2 (0.51%) Non-small cell carcinoma, NOS 24 (6.06%) Other 4 (1.01%) Not specifically noted 140 (35.35%) PD-L1 grouping <1% 57 (27.01%) 1%-49% 49 (23.22%) >=50% 105 (49.76%) Data not available 185 (46.72%) TMB <10 mutations/megabase 26 (60.47%) >=10 mutations/megabase 17 (39.53%) Data not available 353 (89.14%) CoMutations TP53 152 (38%) STK11 49 (12%) KEAP1 3 (1%) EGFR *n = 1 with L858R, n = 1 with T790M ALK rearrangement 1 (0.3%) Brain metastases at diagnosis Yes 28 (7.1%) No 368 (92.9%) Brain metastases at any time Yes 37 (9.34%) No 359 (90.66%) Adrenal metastases at any time Yes 38 (9.60%) No 358 (90.40%) Bone metastases at any time Yes 76 (19.19%) No 320 (80.81%) Liver metastases at any time Yes 28 (7.07%) No 368 (92.93%) Lung metastases at any time Yes 137 (34.60%) No 259 (65.40%) ECOG score at second line of treatment start 0 14 (14.00%) 1 67 (67.00%) 2 16 (16.00%) > = 3 3 (3.00%) | [
1098,
1116
] | [
5,
5
] | [
2,
2
] |
107,727 | 40693603 | 18,321 | 107727 | Compared with monotherapy, combination of dabrafenib (a BRAF inhibitor) and trametinib (a mitogen-activated protein kinase kinase [MEK] inhibitor) showed favorable efficacy and acceptable safety in several BRAF V600E-mutation tumors. The ROAR study was a single-arm, multicenter basket phase II trial evaluating the efficacy and safety of dabrafenib plus trametinib for previously treated unresectable BTC patients with the BRAF V600E mutation (n = 43, 91% ICC). The investigator-evaluated ORR was 51%, while 47% by independent assessment. Overall, dabrafenib plus trametinib has promising efficacy for CCA patients and has been recommended as second-line regimen for advanced BTC patients with BRAF V600E mutation in the NCCN and CSCO guidelines. | [
211,
429,
700
] | [
5,
5,
5
] | [
2,
2,
2
] |
413,719 | 19572016 | 21,889 | 413719 | The recombinant wild type and mutant viruses (p0) were recovered from the culture media at 3 and 6 days post-electroporation, respectively, and further propagated on Vero cells for 5 passages. Total RNA was extracted from the culture media of cells infected with each passage of the mutant virus and RT-PCR was carried out to amplify the S gene. The RT-PCR products were cloned, 10 bacterial clones were randomly chosen from p0, and the complete nucleotide sequence of the S gene was determined to confirm if the recovered virus maintains the F857-L substitution. As shown in table 1, L857 was found in all 10 clones. However, only five clones had an identical sequence with the original mutant S gene (type FL), and additional mutations at other positions were found in the other five clones (Table 1). Among them, two clones contain a T773-S substitution (FLv1), one contains an I769-V substitution (FLv2), and two contain Q523-L and I769-V substitutions (FLv3) (Table 1). These results demonstrate that the recovered FL mutant virus from p0 contains a mixed population of quasispecies. | [
543,
837,
925
] | [
6,
6,
6
] | [
2,
2,
2
] |
510,781 | 29197260 | 41,394 | 510781 | IFNG +874T/A polymorphism is not associated with American tegumentary leishmaniasis susceptibility but can influence Leishmania induced IFN-gamma production. | [
5
] | [
7
] | [
1
] |
3,733,884 | 23431284 | 31,168 | 3733884 | Peroxisome proliferators-activated receptor gamma2 Pro12Ala variant is associated with body mass index in non-alcoholic fatty liver disease patients | [
51
] | [
8
] | [
2
] |
659,032 | 40425534 | 80,537 | 659032 | WNK1, a novel mammalian serine/threonine protein kinase lacking the catalytic lysine in subdomain II. | [
24
] | [
16
] | [
2
] |
3,255,622 | 33831500 | 12,506 | 3255622 | Cells were grown in 6 well plates and exposed and collected as described above. The concentration of cells in suspension was determined with a Cellometer Auto T4, and total cell counts were noted by multiplying concentration by total suspension volume. For viability assays, an equivalent fraction of each cell suspension was then plated on black 96 well plates, coated in Matrigel. After 24 hours, 2muL of 10% triton X was added to some wells for kill wells, for background subtraction. 20muL of Cell Titer Blue (Promega G8081) was added to each well and the fluorescence signal was read on a Synergy H1 microplate reader (BioTek) at 560/590nm every 15 minutes for two hours. A single time point in the linear phase of the curve was chosen for quantification, to ensure that saturation had not occurred. Background was subtracted and each exposure was normalized to its vehicle control.Statistical Analysis. Data represent 5 independent replicates (CC3, n=3 and CD10, n=2). For D11 cell counts, a one-way ANOVA was performed using GraphPad Prism version 9.0.0 (La Jolla, California USA). For D12 cell viability, a one-way ANOVA with Tukey's multiple comparisons test was conducted. For D21 cell counts, a two-way ANOVA with Dunnet's multiple comparisons test was performed. For D22 cell viability, a two-way ANOVA, to examine interactions between exposure time (E, L, and E+L) and MeHg concentration, with Tukey's multiple comparisons test was conducted. | [
979,
1187
] | [
3,
3
] | [
2,
2
] |
1,505,627 | 19433337 | 36,418 | 1505627 | Tyr504 is located near the heme in both PGHS isoforms (Fig. 1 and). In oPGHS-1 Tyr504 interacts with the proximal heme ligand, His388, via H-bonding with a structured water. Accordingly, a Tyr504 mutation might indirectly perturb the heme structure and impair the binding of peroxide or the reactivity of heme, thus increasing the KM value. In this connection, mutation of a tryptophan radical site ~ 7 A away from the heme propionate of KatG catalase/peroxidase was able to modulate the heme structure via an H-bonding network. Due to low expression yield of the Y504F hPGHS-1, it is difficult to examine directly the effect of mutation on the heme by EPR, as was done with KatG catalase/peroxidase. | [
79,
189,
564
] | [
6,
6,
5
] | [
2,
2,
2
] |
98,223 | 38746411 | 42,450 | 98223 | Herein, we find that as pH is raised from 6.8 to 7.3, the thermostability of Galphai-GDP is greatly enhanced (DeltaTm ~20 C) due to the formation of an electrostatic network within the Ras-like domain. Since thermostability changes for GDP-bound Galphai were significantly larger (~20 ), relative to the GTP-bound form (~8 ), we focused on characterizing pH-dependent structural and dynamic changes associated with the GDP-bound form of Galphai in this study. Using pH-dependent NMR analyses and thermal stability profiling on WT and mutant proteins, we identified three key pH-sensing residues that drive pH-dependent thermostability changes. Two of the residues (E236 and D237) reside in SW-III of Galphai while the third residue (E245) lies in the neighboring alpha3 helix. Mutation of E236 and D237 in SW-III promotes Gbetagamma release in HEK293 cells, supporting the role of these residues in pH-dependent electrostatic interactions that allosterically regulate heterotrimer formation. While both Ras and heterotrimeric G-proteins contain SWI and SWII regions, Ras proteins lack the SW-III region found in Galpha proteins. The presence of this unique SW-III region in heterotrimeric G-proteins may explain the unique pH sensing properties of Galphai and provide a novel role for the SW-III region in pH-dependent Gbetagamma release from the Galphai-Gbetagamma complex. Of note, the pH sensing network identified in this study is distinct from the network predicted by Isom et al. This computationally predicted pH sensing network consists of residues at the Ras/helical domain interface (e.g. K46, D150, D200, D229, R242, K270, and K277). However, our NMR and CD data do not support this interaction network, as observable NMR resonances associated with K270 and K277 do not show pH-dependent perturbations and mutation of K46 and R242 did not alter pH-dependent thermostability changes measured by CD. | [
665,
674,
733,
789,
798,
1622,
1837
] | [
4,
4,
4,
4,
4,
4,
4
] | [
2,
2,
2,
2,
2,
2,
2
] |
3,084,929 | 35294868 | 25,056 | 3084929 | To further examine the functional consequences of overexpression of reference and variant GLRA2 in the nervous system, we performed electroretinogram (ERG) recordings on the fly eye expressing human GLRA2 using two distinct drivers. Pan-neuronal driver (nSyb-GAL4) allows one to express GLRA2 in both pre-synaptic photoreceptors and post-synaptic neurons in the nervous system. Using this driver, we found a significant increase in amplitudes of "OFF" transients with GLRA2T296M (Figures 5E, 5F, S12C, and S12D). This indicates an increase in synaptic transmission, supporting the finding in the notum that p.T296M behaves as a GoF allele. Interestingly, when we limited the expression of GLRA2 to pre-synaptic photoreceptors using Rh1-GAL4, we did not observe any functional difference between GLRA2T296M and the reference allele. However, with this driver, we were able to discern that both GLRA2R252C seen in subject 9 and GLRA2N136S found in an SSC subject behave as LoF alleles based on observing a decrease in amplitude of "OFF" transients, indicating a decrease in synaptic transmission (Figures 5G, 5H, S12E, and S12F). Hence, we have identified a cohort of subjects with deleterious variants in an X-linked gene GLRA2 and have shown that a recurrent missense DNM in females acts as a GoF allele, whereas rare variants found in male subjects behave as LoF alleles. | [
473,
496,
506,
607,
800,
1111,
1121
] | [
5,
4,
4,
7,
5,
4,
4
] | [
2,
2,
2,
2,
2,
2,
2
] |
1,806,492 | 32477355 | 16,112 | 1806492 | Comparison of Q703K-Positive and Q703K-Negative PFAPA Patients: Similar Phenotype in Both Groups | [
14,
33
] | [
5,
5
] | [
2,
2
] |
4,299,357 | 11524459 | 30,025 | 4299357 | Bound beta-scorpion toxins induce only a partial shift of the activation curve of wild-type sodium channels, even after a strong depolarizing prepulse, as indicated by the biphasic activation curves for wild-type channels (Cahalan 1975; Jover et al. 1980; Jaimovich et al. 1982; Meves et al. 1982; Wang and Strichartz 1983; Vijverberg et al. 1984; Jonas et al. 1986; Cestele et al. 1998; Tsushima et al. 1999). The biphasic curves for activation in the presence of the beta-scorpion toxin are proposed to be due to the trapping of the IIS4 segment of a fraction of sodium channels in an outward position by binding the extracellular end of the S4 segment to the previously bound toxin in its receptor site, which includes the IIS3-S4 extracellular loop (Cestele et al. 1998). In the experiments presented here, analysis of mutations that neutralize each of the five positive charges of the IIS4 voltage sensor indicates that beta-toxin action can be strongly enhanced by substitution of the two outermost arginines by glutamine or cysteine. The increase in beta-toxin activity is not caused by a general enhancement of activation, since the neutralization of R850 or R853 favors the resting state of the channels by shifting the voltage dependence of activation toward more positive potentials (Stuhmer et al. 1989; Kontis et al. 1997; present study). These two sets of results imply that neutralization of R850 and R853 reduces the energy barrier for trapping the IIS4 segment in its outward position by binding of beta-scorpion toxin while increasing the electrostatic force required to drive the IIS4 segment outward on depolarization. | [
1159,
1167,
1407,
1416
] | [
4,
4,
4,
4
] | [
2,
2,
2,
2
] |
1,019,256 | 28034695 | 18,743 | 1019256 | The F1 generation of the Abca3E292V mouse model harbored an intronic insertion of the FRT-pgk-gb2- Neo/km-FRT cassette upstream from exon 9 together with E292V point mutation knocked into exon 9 of the mAbca3 locus (Fig. 1A). Litter size was normal with balanced gender distribution and pups appeared healthy with the expected Mendelian patterns of gene transmission of the FRT-flanked pgk-Neo cassette (reversely oriented) mAbca3-E292V (mAbca3E292 V-rNeo) knock in (KI) gene. Mice survived into adulthood without overt signs of respiratory distress. Consistent with a loss of function, analysis of total phospholipid (PL) content of bronchoalveolar lavage (BAL) from these mice revealed allele dependent diminution of total PL levels compared to wild type (WT) control (Fig. 1B). BAL phospholipids were approximately three-quarters (76%) and nearly half (57%) of the WT PL level in heterozygous mAbca3E292V-rNeo (mAbca3E292V-rNeo+/-) and homozygous mAbca3E292V-rNeo (mAbca3E292V-rNeo+/+ mice), respectively. These low levels of surfactant PLs were sustained at all time points examined including 8, 12 (data not shown), and 16 (Fig. 1B) wk old mice. | [
956,
974
] | [
5,
5
] | [
2,
2
] |
4,033,043 | 31086053 | 70,452 | 4033043 | Calmodulin and calbindin D28K in Alzheimer disease | [
25
] | [
4
] | [
2
] |
5,216,448 | 24940886 | 2,110 | 5216448 | Atrial fibrillation (AF) is the most common arrhythmia observed in the clinical setting and is an independent risk factor for stroke. Association studies have reported that individuals who carry certain common single-nucleotide polymorphisms (SNPs) in the genes encoding cardiac ion channels, the renin-angiotensin system, or connexin 40 are predisposed to developing AF. Recently, a genome-wide association study identified a variant named rs4845625, which is located in the intron of the IL6R gene and is associated with AF. | [
441
] | [
9
] | [
3
] |
516,109 | 15824133 | 26,860 | 516109 | pCDNA3.1 plasmids expressing FLAG-beta1 to beta5, and HA-gamma1 to gamma5, and with histidine tags were a gift from S. Gutkind (National Institutes of Health [NIH], Bethesda, MD). pEGFP constructs expressing PLCdelta1, Akt/PKB, and Btk PH domains were donated by D. Alessi (University of Dundee, Scotland, UK). GFP-AKAP-Lbc plasmid was a gift from John D. Scott (Vollum Institute, Portland, OR). PKD plasmids were constructed in our laboratory by Yusuke Maeda (University of Osaka, Japan). HA-gamma2C68S mutant was generated by PCR, replacing the 68th codon, TGC (cysteine) with AGC (serine). PLCbeta2 PH domain and full-length PKCe wild type were amplified by RT-PCR using purified HeLa cells RNA, and cloned in the vector pEGFP-C1 (CLONTECH Laboratories, Inc.). FLAG-PKCeta was a gift from Motoi Ohba (Showa University, Tokyo, Japan). Mutagenesis of both PKCs was done following the manufacturer's protocol for the QuikChange site-directed mutagenesis kit (Stratagene). The final products were PKCeta A160E (PKCeta constitutive active), PKCeta K384A (PKCeta kinase dead), PKCe T566E (PKCe constitutive active), and PKCe K437W (PKCe kinase dead). | [
559,
1003,
1046,
1079,
1122
] | [
32,
5,
5,
5,
5
] | [
2,
2,
2,
2,
2
] |
115,911 | 41325423 | 67,136 | 115911 | Sample quality control analysis provided evidence of reliable data, as evidenced by the Empirical Cumulative Distribution Function, that plots the CV against the percentage of peaks (S11A Fig). PCA analysis showed distinct segregation of negative control and BmNPV infected samples (S11B Fig). | [
183
] | [
4
] | [
2
] |
5,252,140 | 33743732 | 36,935 | 5252140 | Regarding genotype-phenotype correlation, it appears that mutations lying within in or close to TM 5 and 8 contribute to severe manifestations, while mutations closer to the NH2- or COOH-terminals result in milder forms of IFAP. This is not only evident for the p.R429H mutation but also for the p.L433P, p. A454P, p.F475S, p.L476S, p.D477V, p.A478D, and p.G500D mutations that are as well adjacent to the LDG motif and led to clinically severe IFAP phenotypes. Additionally, mutations within the TM 5, p.F229S, p.W226L, p.H227L, p.G253A, and p.I258M are also associated with considerably severe IFAP phenotypes. Interestingly, a mutation was identified at the large luminal loop between TM 6 and 7 (p.C334Y), which the affected male displayed classic clinical features of IFAP along with psoriasiform skin plaques, nail dystrophy, facial dysmorphism, intellectual disability, severe skeletal abnormalities, and chorea-like movement. Though the IFAP phenotypes of this mutation were not severe, it may suggest that a mutation at this site may be particular to severe skeletal anomalies. However, this remains to be clarified. A patient with a p.L24P mutation, the most-proximal mutation close to the NH2-terminal end on TM 1 had mild IFAP phenotypes but also had global developmental delay. In two other patients, one harboring the p.M87I mutation, the second most-proximal mutation on TM 2, and the p.L513P mutation, the most COOH-terminal encountered mutation on TM 8, resulted in milder phenotypes of IFAP (Fig. 4). Nonetheless, it could be contended that no specific phenotype or genotype correlation can be formed from mutation positions. In one study it was reported that a patient carrying the p.R429H mutation displayed mild phenotypes of IFAP, in contrast to what was previously observed, the patient however, did experience neurological abnormalities such as retarded psychomotor development and seizures. Additionally, another patient was not affected by the triad of IFAP but by BRESHECK with atrichia and photophobia. Yet, another patient severely manifested the cardinal triad of IFAP with an additional five features of BRESHECK. Precaution, therefore, must be taken when making predictions of clinical outcome from a specific mutation. | [
262,
296,
305,
315,
324,
333,
342,
355,
503,
512,
521,
530,
543,
700,
1143,
1332,
1400,
1701
] | [
7,
7,
8,
7,
7,
7,
7,
7,
7,
7,
7,
7,
7,
7,
6,
6,
7,
7
] | [
2,
2,
2,
2,
2,
2,
2,
2,
2,
2,
2,
2,
2,
2,
2,
2,
2,
2
] |
4,125,440 | 37986577 | 7,760 | 4125440 | Detected oxidative modifications at Trp317 of D1 in Arabidopsis thaliana. | [
36
] | [
6
] | [
2
] |
2,732,679 | 22386478 | 95 | 2732679 | Fibrinogen plays an important role in the intrinsic and extrinsic pathways of blood coagulation. This study investigated the association between common variants in the fibrinogen gene and the risk of developing sporadic cerebral hemorrhage (CH). We performed genotyping analyses for three single nucleotide polymorphisms (SNP) in the fibrinogen gene in a case-controlled study involving 195 patients with CH and 116 control participants; both groups were of southern Han-Chinese origin. Logistic regression analysis indicated that haplotypes ATA (rs1800790+rs1800787+rs6050), AA (rs1800790+rs6050) and TA (rs1800787+rs6050) could nearly double the risk of sporadic CH (odds ratio [OR]=1.738, 95% confidence interval [CI]: 1.103-2.740, p=0.017; adjusted OR=1.762, 95% CI: 1.042-2.982, p=0.035), although the three SNP were not associated with sporadic CH when analyzed separately. These findings indicate that rs1800790, rs1800787 and rs6050 polymorphisms may contribute to the etiology of sporadic CH in the Chinese population. | [
547,
557,
567,
580,
590,
606,
616,
909,
920,
934
] | [
9,
9,
6,
9,
6,
9,
6,
9,
9,
6
] | [
3,
3,
3,
3,
3,
3,
3,
3,
3,
3
] |
5,117,798 | 36999115 | 8,181 | 5117798 | Although prothrombin gene mutation (G20210A) is an important cause of venous thrombosis, its role in arterial thrombosis remains uncertain. It is inherited in an autosomal dominant pattern, and causes an increased production of prothrombin. It is crucial to identify the presence of genetic mutations in a pediatric patient presenting with stroke to provide prompt treatment, prevent recurrences, and educate on the risk of thrombosis in family members. The signs and symptoms may be vague and non-specific in children; hence, it is difficult to pinpoint the etiology. Presenting symptoms and signs majorly depends on the stroke type and the brain region involved. The localizing signs and symptoms such as hemiparesis or hemifacial weakness, speech or language dysfunctions, vision disturbances, or ataxia occur in children with stroke. A stroke should be considered as a possible diagnosis within the differential for patients who present with new neurological findings. Children who are suspected of having a stroke should undergo urgent neuroimaging. MRI is considered an ideal method to evaluate suspected stroke in pediatric age. The initial evaluation should emphasize supportive measures, such as airway stabilization, administration of oxygen, maintenance of euglycemia, and treatment of seizures if they are present. | [
36
] | [
7
] | [
1
] |
3,530,164 | 41257743 | 12,154 | 3530164 | Case 2: A novel homozygous frameshift variant, c.6107del (p.Asp2036Valfs*3, D2036Vfs*3), was identified in the VPS13B (NM_152564.5) gene (Fig. 2B). Both parents were carriers of this variant in the heterozygous state. According to ACMG guidelines, the variant was classified as likely pathogenic based on the following criteria: it is a frameshift mutation predicted to lead to nonsense-mediated decay (PVS1) and was not found in the gnomAD population database (PM2). | [
47,
58,
76
] | [
9,
14,
10
] | [
1,
2,
2
] |
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