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1.
Future Med Chem ; 2020 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-32397829

RESUMO

Aim: Targeting the protein-protein interactions (PPIs) associated with Mcl-1 has become a promising therapeutic approach for cancer. Herein, we reported the discovery of novel Mcl-1 inhibitors using an integrated computational approach. Results: Among 30 virtual screening hits, five compounds show inhibitory activities against Mcl-1. The most potent inhibitors M02 (K i  = 5.4 µM) and M08 (Ki = 0.53 µM) exhibit good selectivity against Bcl-2 and Bcl-xL. Compound M08 exhibits anti-proliferation activity and induces caspase-3 activation in Jurkat cancer cells. Moreover, 1H-15N HSQC NMR experiments suggested that compound M08 likely binds in the P2 pocket of Mcl-1 and engages R263 in a salt bridge. Conclusion: Our study provides a good starting point for future discovery of more potent Mcl-1 selective inhibitors.

2.
BMC Cancer ; 20(1): 416, 2020 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-32404198

RESUMO

BACKGROUND: KRAS mutations have been characterized as the major predictive biomarkers for resistance to cetuximab treatment. However, studies indicate that not all KRAS mutations are associated with equivalent treatment outcomes. KRAS G13D mutations were observed to account for approximately 16% of all KRAS mutations in advanced colorectal cancer patients, and whether these patients can benefit from cetuximab has not been determined. METHODS: An established KRAS G13D mutant colorectal cancer (CRC) patient-derived xenograft (PDX) model was treated with cetuximab. After repeated use of cetuximab, treatment-resistant PDX models were established. Tissue samples were collected before and during treatment, and multiomics data were subsequently sequenced and processed, including whole-exome, mRNA and miRNA data, to explore potential dynamic changes. RESULTS: Cetuximab treatment initially slowed tumor growth, but resistance developed not long after treatment. WES (whole-exome sequencing) and RNA sequencing found that 145 genes had low P values (< 0.01) when analyzed between the locus genotype and its related gene expression level. Among these genes, SWAP70 was believed to be a probable cause of acquired resistance. JAK2, PRKAA1, FGFR2 and RALBP1, as well as 10 filtered immune-related genes, also exhibited dynamic changes during the treatment. CONCLUSIONS: Cetuximab may be effective in KRAS G13D mutation patients. Dynamic changes in transcription, as determined by WES and RNA sequencing, occurred after repeated drug exposure, and these changes were believed to be the most likely cause of drug resistance.

3.
Ann Thorac Surg ; 2020 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-32407852

RESUMO

BACKGROUND: Evidence about safety and efficacy of transcatheter aortic valve replacement (TAVR) remains limited for patients with aortic regurgitation (AR). METHODS: From the Safety & Efficacy of the J-Valve Ausper System in Patients with Severe Aortic Stenosis and/or Aortic Regurgitation Registry, the clinical outcomes of patients with AR from West China Hospital were analyzed. RESULTS: A total of 134 patients with a mean Society of Thoracic Surgeons risk score of 9.8% underwent TAVR with J-Valve. Thereinto, 5 (3.7%) were converted to surgical aortic valve replacement. The cumulative all-cause mortality was 3.0% at 30 days and 3.7% at 6 months. One (0.7%) major bleeding, 1 (0.7%) major vascular complication, 8 (6.0%) acute kidney diseases, 12 (9.0%) III atrial-ventricular block and 1 (0.7%) paravalvular leakage ≥ moderate occurred. The device success rate was 96.3%. Mean ejection fraction improved from 52.1% to 57.1% (p<0.001) at 30 days and to 58.7% (p<0.001 compared with baseline) at 6 months. Mean estimated pulmonary arterial pressure decreased from 29.3 mmHg to 23.1 mmHg (p<0.001) at 30 days and to 21.5 mmHg (p<0.001 compared with the baseline) at 6 months. On multivariable analysis, New York Heart Association functional class at 6 months [odds ratio=8.87 (1.36-58.06)] was independently associated with all-cause mortality at 6 months. CONCLUSIONS: TAVR with J-Valve proved acceptable early and mid-term clinical outcomes for patients with AR. To the best of our knowledge, this is the largest single-center study that evaluates the safety and efficacy of TAVR in treating AR.

4.
Chem Commun (Camb) ; 2020 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-32409805

RESUMO

We report for the first time the integration of ultra-high-pressure liquid chromatography-tandem mass spectrometry with machine learning for identifying fatty acid metabolite biomarkers of ischemic stroke. In particular, we develop an optimal model to discriminate ischemic stroke patients from healthy persons with 100% sensitivity and 93.18% specificity. This research may facilitate understanding the roles of fatty acid metabolites in stroke occurrence, holding great potential in clinical stroke diagnosis.

5.
Sci Rep ; 10(1): 6151, 2020 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-32273561

RESUMO

The establishment of the Sanjiangyuan National Park (SNP) favours implementation of strictest ecological protection on the Tibetan Plateau, thus firmly ensuring national ecological security. To understand ecological background in the SNP, spatial and temporal variations of ecosystem, and its services during the period 2000-2015 and significance identification were analysed by using the methods of remote sensing, GIS and model simulation. The results showed that: (1) Area with extremely important ecosystem services accounted for approximately 51.4% of the SNP's total area, of which extreme importance water regulation, soil conservation and sand fixation regions contributed 15.3%, 13.7% and 22.4%, respectively. (2) The SNP had formed a spatial pattern of ecosystem services with water regulation as core in the eastern part, soil conservation as core in the central part and sand fixation as core in the western part. (3) For the period 2000-2015, water regulation service generally improved in the SNP. Soil conservation service also improved overall; and sand fixation service exhibited a decreasing trend due to reduction in wind speed and vegetation coverage. (4) Climate warming and humidification, combined with the implementation of ecological protection project in the SNP were the primary reasons for ecosystem services improvement. However, grassland degradation had not yet been fundamentally suppressed, and vegetation coverage was still declining in regional areas. For strict protection and sustainable use of the SNP and its natural resources, overall planning and scientific layout should be paid more attention, and classification and subarea protection should be implemented based on natural ecosystem laws.

6.
Int J Mol Sci ; 21(7)2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-32244800

RESUMO

Fat deposition, which influences pork production, meat quality and growth efficiency, is an economically important trait in pigs. Numerous studies have demonstrated that stearoyl-CoA desaturase (SCD), a key enzyme that catalyzes the conversion of saturated fatty acids into monounsaturated fatty acids, is associated with fatty acid composition in pigs. As SCD was observed to be significantly induced in 3T3-L1 preadipocytes differentiation, we hypothesized that it plays a role in porcine adipocyte differentiation and fat deposition. In this study, we revealed that SCD is highly expressed in adipose tissues from seven-day-old piglets, compared to its expression in tissues from four-month-old adult pigs. Moreover, we found that SCD and lipogenesis-related genes were induced significantly in differentiated porcine adipocytes. Using CRISPR/Cas9 technology, we generated SCD-/- porcine embryonic fibroblasts (PEFs) and found that the loss of SCD led to dramatically decreased transdifferentiation efficiency, as evidenced by the decreased expression of known lipid synthesis-related genes, lower levels of oil red O staining and significantly lower levels of triglyceride content. Our study demonstrates the critical role of SCD expression in porcine adipocyte differentiation and paves the way for identifying it as the promising candidate gene for less fat deposition in pigs.

7.
J Med Chem ; 63(9): 4701-4715, 2020 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-32267687

RESUMO

While proteasome inhibitors such as bortezomib showed satisfactory clinical benefits in the initial treatment of multiple myeloma (MM), drug resistance and relapse are unavoidable. Recent studies suggested inhibition of histone deacetylases (HDACs) restored sensitivity of bortezomib-resistant MM. Hence, we designed dual inhibitors targeting both HDACs and proteasomes to address the resistance of bortezomib. The most potent inhibitors, ZY-2 and ZY-13 showed excellent inhibition against proteasome and good selectivity against HDACs. In particular, ZY-2 not only exhibited good antiproliferative activities on the MM cell lines RPMI-8226, U266, and KM3 (IC50 values of 6.66, 4.31, and 10.1 nM, respectively) but also showed more potent antiproliferative activities against the bortezomib-resistant MM cell line KM3/BTZ compared with bortezomib (IC50 values of 8.98 vs. 226 nM, P < 0.01) and even better than the combination of the HDAC inhibitor MS-275 and bortezomib (1:1) (IC50 values of 8.98 vs. 98.0 nM, P < 0.01).

8.
J Environ Manage ; 265: 110542, 2020 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-32275249

RESUMO

The system performance, sludge property and microbial community shift were evaluated in a nitrifying sludge (NS) bioreactor for simultaneous treating p-Nitrophenol (PNP) and high ammonia wastewater. After long-term acclimation for 80 days, the removal efficiencies of PNP and NH4+-N reached to 99.9% and 99.5%, respectively. Meanwhile, the effluent PNP gradually decreased from 7.9 to 0.1 mg/L by acclimation of sludge. The particle size of NS increased from 115.2 µm to 226.3 µm accompanied by the decreased zeta potential as a self-protection strategy. The presence of PNP exposure altered the effluent soluble microbial products (SMP) fluorescent components and molecular composition. The increase in the relative abundance of Thauera, Nitrospiraceae and Nitrosomonas indicated the nitrification and denitrification capacities of NS increased, which maybe the PNP cometabolic biodegradation effect. Moreover, Ignavibacteria and Aeromonas were responsible as the dominant bacteria for degrading PNP in the nitrifying system.

10.
Small ; 16(14): e2000011, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32174021

RESUMO

Singlet oxygen (1 O2 ) generation has been observed from ultrasmall luminescent gold nanoparticles (AuNPs), but regulation of 1 O2 generation ability from the nanosized noble metals has remained challenging. Herein, the 1 O2 generation ability of ultrasmall AuNPs (d ≈ 1.8 nm) is reported to be highly correlated to the surface factors including the amount of Au(I) species and surface charge. By taking the advantages of facile in situ PEGylation, it is discovered that a high amount of Au(I) species and surface charge results in strong ability in generation of 1 O2 , whereas a relative low amount of Au(I) species and surface charge leads to weak ability in 1 O2 production. A feasible general strategy is then developed to controllably regulate the 1 O2 generation efficiency of the AuNPs through facile ligand exchange with positively-charged or negatively-charged thiolated ligands. The AuNPs as nanophotosensitizer for 1 O2 generation in the cellular level is also demonstrated to be highly controllable through surface ligand exchange with synergistical effects of 1 O2 generation ability and subcellular distribution to lysosome or mitochondria. The strategy in the bidirectional regulation of 1 O2 generation from ultrasmall AuNPs provides guidance for future design of nanosized metal nanomedicine toward specific disease diagnosis and treatment.

11.
Eur J Med Chem ; 191: 112142, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-32088497

RESUMO

The upregulation of the protein myeloid cell leukemia-1 (Mcl-1) is closely associated with various human cancers, which can result in the evasion of apoptosis and a low survival rate. Therefore, developing Mcl-1 inhibitors has become a promising paradigm for cancer therapy. Herein, we designed and synthesized a novel series of tyrosine derivatives, among which compounds 5g, 6l and 6c exhibited very high binding affinity to Mcl-1 with Ki values of 0.18, 0.27 and 0.23 µM, respectively. Interestingly, compound 6l showed not only potent activity against Mcl-1 but also considerable selectivity over Bcl-2 and Bcl-xL, which was rationalized by molecular docking and fragment-centric topographical mapping (FCTM). It is worth noting that compounds 5g, 6l and 6c displayed potent antiproliferative activity against several cancer cell lines and could induce apoptosis of KM3 and HepG2 cells in a dose-dependent manner.

12.
Appl Environ Microbiol ; 86(7)2020 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-32005730

RESUMO

The siderophore synthetic system in Shewanella species is able to synthesize dozens of macrocyclic siderophores in vitro with synthetic precursors. In vivo, however, although three siderophores are produced naturally in Shewanella algae B516, which carries a lysine decarboxylase (AvbA) specific for siderophore synthesis, only one siderophore can be detected from many other Shewanella species. In this study, we examined a siderophore-overproducing mutant of Shewanella oneidensis which lacks an AvbA counterpart, and we found that it can also produce these three siderophores. We identified both SpeC and SpeF as promiscuous decarboxylases for both lysine and ornithine to synthesize the siderophore precursors cadaverine and putrescine, respectively. Intriguingly, putrescine is mainly synthesized from arginine through an arginine decarboxylation pathway in a constitutive manner, not liable to the concentrations of iron and siderophores. Our results provide further evidence that the substrate availability plays a determining role in siderophore production. Furthermore, we provide evidence to suggest that under iron starvation conditions, cells allocate more putrescine for siderophore biosynthesis by downregulating the expression of the enzyme that transforms putrescine into spermidine. Overall, this study provides another example of the great flexibility of bacterial metabolism that is honed by evolution to better fit living environments of these bacteria.IMPORTANCE The simultaneous production of multiple siderophores is considered a general strategy for microorganisms to rapidly adapt to their ever-changing environments. In this study, we show that some Shewanella spp. may downscale their capability for siderophore synthesis to facilitate adaptation. Although S. oneidensis lacks an enzyme specifically synthesizing cadaverine, it can produce it by using promiscuous ornithine decarboxylases. Despite this ability, this bacterium predominately produces the primary siderophore while restraining the production of secondary siderophores by regulating substrate availability. In addition to using the arginine decarboxylase (ADC) pathway for putrescine synthesis, cells optimize the putrescine pool for siderophore production. Our work provides an insight into the coordinated synthesis of multiple siderophores by harnessing promiscuous enzymes in bacteria and underscores the importance of substrate pools for the biosynthesis of natural products.

13.
Nanoscale ; 2020 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-32104820

RESUMO

Polyoxometalates (POMs) have been developed as a class of promising smart material candidates not only due to their multitudinous architectures but also their good redox activities and outstanding electron and proton transport capacities. Recently, abundant studies on POMs composited with metal nanoparticles (NPs), carbon materials (e.g., carbon nanotubes (CNTs), carbon quantum dots (CQDs), graphene), and conducting polymers or highly-porous framework materials (e.g., MOFs, ZIFs) have been performed and POM-based composite materials (PCMs) undoubtedly show enhanced stability and improved electrochemical performances. Therefore, POMs and PCMs are of increasing interest in electrocatalysis, electrochemical detection and energy-related fields (such as fuel cells, redox flow batteries and so on), thus, developing novel PCMs has long been the key research topic in POM chemistry. This review mainly summarizes some representative advances in PCMs with electrochemical applications in the past ten years, expecting to provide some useful guidance for future research.

14.
Pancreatology ; 20(2): 265-277, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31956070

RESUMO

BACKGROUND: Successful clinical evaluation of human tumors relies on proper handling of tissue samples to maximally preserve the cellular and metabolic states in vivo. Pancreatic samples are particularly sensitive to sample mishandling due to the abundance of digestive enzymes. We study how the duration of ischemia, in vivo and ex vivo, both of which are unavoidable lagging periods following surgical dissection, significantly impact the utility of pancreatic samples. METHODS: We systematically characterize a wide range of tissue integrity features, including histological patterns, cellular structures, DNA/RNA quality and activity of major signaling pathways in normal pancreases and pancreatic ductal adenocarcinoma (PDAC) tumor tissues from 41 patients with different ischemia. RESULTS: We reveal that tissues experiencing longer periods of ischemia exhibit significant deterioration and could potentially mislead disease diagnosis and preclinical research. Based on these analyses, we propose an optimal procedure that balances better clinical practice and high tissue sample quality. CONCLUSIONS: Our work provides a guideline for pancreatic sample handling and could have wide implications in clinical diagnosis and translational research.

15.
Clin Cardiol ; 2020 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-31925816

RESUMO

BACKGROUND: Transcatheter aortic valve replacement (TAVR) is a fundamentally new procedure for the treatment of native aortic regurgitation (AR). The number of cases needed to gain proficiency with the procedure is unknown. HYPOTHESIS: This study aimed to evaluate the learning curve for TAVR for native AR. METHODS: This study retrospectively reviewed a prospective database from 134 consecutive native AR patients who underwent the J-valve TAVR system, which performed by a single team interventional cardiologist. The cumulative sum (CUSUM) method was used to analyze the learning curve. Patients were divided into two groups in chronological order, defined by the surgeon's early (group 1: the first 52 cases) and skilled (group 2: the next 82 cases) experience. Demographic data, intraoperative characteristics, and short-term surgical outcomes were compared between the two groups. RESULTS: CUSUM plots revealed decreasing procedure time and fluoroscopy time after patients 52 and 43, respectively. The patient date consistently demonstrated that high-risk scores and major perioperative parameters were comparable between the two groups. The use of contrast dye (group 1, 94.22 ± 30.07 mL; group 2, 70.43 ± 15.02 mL, P<.05), total procedure time (group 1, 84.96 ± 17.76 minutes; group 2, 59.95 ± 12.83 minutes, P<.05), and fluoroscopy time (group 1, 11.52 ± 3.81 minutes; group 2, 6.47 ± 1.53 minutes, P<.05) were significantly reduced in group 2. The overall device success rate in group 1 was 96.2% vs 96.3% in group 2 and remained high (P = 1.0). The overall 30-day mortality was 3.8% in group 2 (group 1, 0 to group 2, 3.8%; P = .16). The complications rate, such as pulmonary hypertension, chronic kidney disease, and coronary artery disease were higher in group 2. CONCLUSIONS: For a surgeon without previous TAVR experience, 52 cases of performance is the minimal requirement to gain the proficiency of TAVR for native AR. The skilled surgeons have been observed with reduced procedural time, fluoroscopy times, radiation exposure dose, and contrast volume usage. However, the overall prognosis was not significantly different between the two groups.

16.
Schizophr Res ; 215: 120-125, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31784339

RESUMO

Patients with schizophrenia (SCZ) consistently show prospective memory (PM) impairments, and the technique of implementation intentions has been shown to improve PM performance in these patients. PM is considered to have prospective and retrospective components. However, it remains unclear which component of PM is impaired in patients with SCZ and which component(s) is facilitated by implementation intentions (II). The present study aimed to examine these two issues. Forty-two patients with SCZ and 42 matched healthy controls were randomly assigned to an II group or a typical instruction group. All participants were administered a color-matching PM task. Results showed that, using a multinomial-modeling approach, patients with SCZ exhibited impairment in the retrospective component of PM. In addition, while II improved the prospective PM component in healthy controls, both prospective and retrospective PM components in patients with SCZ were improved. Together, our results shed light on the mechanism of PM impairment in SCZ patients and the mechanism of II in improving PM performance.

17.
Psych J ; 9(1): 87-95, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31722451

RESUMO

Involuntary mental time travel (MTT) refers to the phenomenon of mentally reliving past experiences or pre-living possible future events in an involuntary form. Few studies have explored involuntary MTT in individuals with schizotypal personality features. The present study aimed to first explore the psychometric properties of the Involuntary Autobiographic Memory Inventory (IAMI) in a Chinese sample (Study 1), and then to explore whether individuals with schizotypal personality features experience involuntary MTT more frequently than individuals without schizotypal features. Moreover, the study explored whether the aberrant frequency of involuntary MTT is correlated with positive schizotypal features (Study 2). The results showed that the IAMI had good structural validity and reliability in a Chinese sample. Individuals with schizotypal traits reported a significantly higher frequency, less positive emotion, and stronger emotional intensity for both involuntary memories and future thoughts compared with individuals without schizotypal features. Further analyses in individuals with schizotypal personality features showed that the frequencies of both involuntary memories and future thoughts were significantly correlated with positive schizotypal traits. These results have potential theoretical and clinical implications for a comprehensive understanding of involuntary MTT among individuals with schizotypal personality features.

18.
Eur J Pharmacol ; 868: 172856, 2020 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-31836533

RESUMO

Saphenous vein grafts (SVG) patency is limited by intimal hyperplasia (IH) caused by endothelial dysfunction. This study aimed to explore the effect of placental growth factor (PlGF) on the endothelial function of SVG. In rat models of external jugular vein-carotid artery graft treated with PlGF or saline hydrogel, PlGF inhibited vein graft IH (day 28: 12.0 ± 1.9 vs. 61.7 ± 13.1 µm, P < 0.001), promoted microvessel proliferation (day 14: 33.3% 3+ vs. 50.0% 2+, P = 0.03), and increased nitric oxide (NO) production (P < 0.05 on days 1/3/5) and NO synthase (NOS) expression by immunohistochemistry. In human umbilical vein endothelial cells (HUVECs) cultured under hypoxia and treated or not with PlGF, PlGF restored the survival (50 ng/ml PlGF, 48 h: 91.7 ± 0.6% vs. 84.9 ± 0.5%, P < 0.01), migration (by Matrigel assay), and tube formation ability (junctions, tubules, and tubule total length; all P < 0.01) of HUVECs after hypoxia. PlGF increased NO production through increased eNOS expression (P < 0.05), without changes in iNOS expression. The mRNA expression of eNOS decreased after the addition of the PI3K inhibitor LY294002 (P < 0.05). PlGF promoted the protein expression of eNOS by up-regulating AKT, and the AKT and eNOS protein levels were decreased after adding LY294002 (all P < 0.05). In conclusion, PlGF is a candidate for the inhibition of IH in SVG after coronary artery bypass graft. The effects of PlGF are mediated by the upregulation of the eNOS mRNA and protein through the PI3K/AKT signaling pathway. PlGF promotes the secretion of NO by endothelial cells and thereby reduces the occurrence and development of IH.

19.
Dev Comp Immunol ; 103: 103495, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31618618

RESUMO

Invertebrates lack an adaptive immune response and thus are reliant on their innate immune response for eliminating invading pathogens. The innate immune responses of silkworms against the pathogen Nosema bombycis include: hemocyte aggregation, melanization, antimicrobial peptides, etc. In our current study, we discovered that a silkworm hemostasis-related protein, hemocytin, is up-regulated after Nosema bombycis infection. This novel finding lead to our hypothesis that hemocytin participates in immune responses against N. bombycis. We investigated this hypothesis by analyzing the adhesive effects of hemocytin to invading N. bombycis, and the hemocytin-mediated hemocyte aggregation and hemolymph melanization. We showed that hemocytin can adhere to the surface of N. bombycis, which facilitates the agglutination of N. bombycis and hemocytes as well as the subsequent melanization. Moreover, when we utilize RNAi technology to decrease in vivo hemocytin expression, we found that the proliferation of N. bombycis within the host significantly increased. These results support our hypothesis that hemocytin exerts pro-inflammatory effects by facilitating pathogen agglutination, along with hemocyte aggregation and melanization, to combat N. bombycis. Our study is the first to determine a function of hemocytin in innate immunity against N. bombycis. Moreover, our findings are of great importance to provide potential targets for developing novel strategy against microsporidia infection.

20.
J Mol Biol ; 432(4): 1035-1047, 2020 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-31863750

RESUMO

Transcription activator-like effectors (TALEs) recognize DNA through repeat-variable diresidues (RVDs), and TALE-DNA interactions are sensitive to DNA modifications. Our previous study deciphered the recognition of 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) by TALEs. Here, we report seven crystal structures of TALE-DNA complexes. The 5mC-specific RVD HA recognizes 5mC through van der Waals interactions and exhibits highly similar loop conformation to natural RVDs. The degenerate RVD RG contacts 5mC and 5hmC via van der Waals interactions as well; however, its loop conformation differs significantly. The loop conformations of universal RVD R* and 5hmC-specific RVD Q* are similar to that of RG, while the interactions of R* with C/5mC/5hmC and Q* with 5hmC are mediated by waters. Together, our findings illustrate the molecular basis for the specific recognition of 5mC and 5hmC by multiple noncanonical TALEs and provide insights into the plasticity of the TALE RVD loops.

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