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1.
Int Urol Nephrol ; 2020 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-31925642

RESUMO

BACKGROUND: Cardiovascular disease (CVD) is the leading cause of mortality among the patients with end-stage renal disease (ESRD). Arterial stiffness is a well-accepted predictor of cardiovascular mortality in general population and ESRD patients. The aim of this study was to compare the change of arterial stiffness in kidney transplant recipients (KTRs) and ESRD patients, and further investigate the impact of kidney transplantation (KT) on arterial stiffness. METHODS: A total of 138 maintenance hemodialysis patients, 198 KTRs and 75 healthy volunteers were enrolled in this study. The carotid-femoral pulse wave velocity (CF-PWV) and carotid-radial PWV (CR-PWV) were determined, and the correlations of PWV with biochemical parameters were analyzed. RESULTS: CF-PWV was highest in the maintenance hemodialysis patients, but similar between KTRs and healthy volunteers. Bivariate correlation analysis among KTRs demonstrated that CF-PWV was positively correlated with high level of peripheral diastolic blood pressure, pulse pressure, mean artery pressure, BUN and HDL, but negatively correlated with albumin. Univariate polytomous logistic regression analysis showed that age, BMI, systolic blood pressure, pulse pressure, length of KT and BUN were associated with the increase of CF-PWV value. CONCLUSIONS: Aortic stiffness could be improved after KT. Meanwhile, age, BMI, systolic blood pressure, pulse pressure, length of KT and BUN were independent predictors of the increase of CF-PWV in KTRs.

2.
J Clin Pharm Ther ; 2020 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-31951037

RESUMO

WHAT IS KNOWN AND OBJECTIVE: To evaluate the effects of statin use on the treatment outcomes (i.e. overall survival and cancer-specific survival) among advanced prostate cancer (PCa) patients treated with androgen deprivation therapy (ADT) or abiraterone/enzalutamide. METHODS: The original studies, examining the effects of statins on the outcomes (i.e. overall survival and cancer-specific survival) among PCa patients treated with ADT or abiraterone/enzalutamide, were identified through a systematic search by two independent reviewers in the PubMed, Cochrane, Embase, American Society of Clinical Oncology and European Society of Medical Oncology databases. Databases were searched using keywords (abiraterone OR enzalutamide OR androgen deprivation therapy) AND statin. In total, nine eligible studies from 111 references were included for final analysis. RESULTS AND DISCUSSION: Statin use significantly lowered the risk of all-cause mortality (100 709 patients, HR = 0.73, 95%CI = 0.64-0.83, P < .00001) and the risk of cancer-specific mortality (100 343 patients, HR = 0.64, 95% CI = 0.53-0.77, P < .00001) in advanced PCa patients treated with ADT. The sensitivity analysis showed that the results were reliable. However, it could not generate reliable evidence in patients with metastatic castration-resistant prostate cancer (mCRPC) treated with abiraterone/enzalutamide, as relevant studies were limited and had inconsistent results. WHAT IS NEW AND CONCLUSION: The review indicated that the use of statins in combination with ADT was associated with better all-cause survival and cancer-specific survival in patients with advanced PCa. Randomized controlled trials should be conducted to establish efficacy of statins among PCa patients.

3.
Genome ; 2020 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-31928416

RESUMO

Chinese indigenous pig and Western commercial pig breeds show different patterns of lipid metabolism, fat deposition, and fatty acid composition, and have become vitally important models of energy metabolism and obesity in humans. To compare the mechanisms underlying lipid metabolism between Yorkshire (lean type) and Anqing six-end-white pigs (obese type), the liver transcriptomes of six castrated boars with a body weight of approximately 100 kg (three Yorkshire and three Anqing) were analyzed by RNA-seq. The total number of reads produced for each liver sample ranged from 47.05 to 62.6 million. Among 362 differentially expressed genes, 142 were up-regulated and 220 were down-regulated in Anqing six-end-white pigs. Based on these data, nine significantly enriched terms were identified by GO enrichment analysis, including lipid metabolic process and carboxylic acid metabolic process. Pathway analysis revealed three significantly enriched KEGG pathways including PPAR signaling pathway, steroid hormone biosynthesis, and retinol metabolism. Based on protein-protein interaction networks, multiple genes responsible for lipid metabolism were identified, such as PCK1, PPARA, and CYP7A1, and these were considered promising candidate genes that could affect porcine liver lipid metabolism and fat deposition. Our results provide abundant transcriptomic information that will be useful for animal breeding and biomedical research.

4.
Curr Opin Struct Biol ; 61: 98-105, 2020 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-31924595

RESUMO

Homologous recombination (HR) is a faithful repair mechanism for double stranded DNA breaks. Two highly homologous master kinases, the tumour suppressors ATM and ATR (Tel1 and Mec1 in yeast), coordinate cell cycle progression with repair during HR. Despite their importance, our molecular understanding of these apical coordinators has been limited, in part due to their large sizes. With the recent development in cryo-electron microscopy, significant advances have been made in structural characterisation of these proteins in the last two years. These structures, combined with new biochemical studies, now provide a more detailed understanding of how a low basal activity is maintained and how activation may occur. In this review, we summarize recent advances in the structural and molecular understanding of these key components in HR, compare the common and distinct features of these kinases and suggest aspects of structural components that are likely to be involved in regulating its activity.

5.
ACS Appl Mater Interfaces ; 12(1): 209-216, 2020 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-31840496

RESUMO

Nanozymes show excellent enzyme activity and robust catalytic properties, but the targeting capability to disease organs is limited because of lack of specificity. Herein, we developed an ultrasmall (∼3 nm) organic nanozyme that can gradually aggregate under a reactive oxygen species (ROS)-rich environment via a spontaneous reaction, namely, ROS-induced aggregation. The size of nanozymes is 75 and 100 times higher than the original size under •OH and H2O2 environments without losing enzyme activity. In vitro experiments confirm that nanozymes prefer to aggregate in mitochondria under ROS-rich conditions. Importantly, the nanozymes show in situ ROS-induced aggregation in the brain, ∼9 times higher uptake than ordinary nanozymes, indicating their potential for treating ROS-related diseases in the central nervous system.

7.
J Environ Manage ; 255: 109916, 2019 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-31785461

RESUMO

The existing literature on environmental efficiency focuses on economic and social factors, and rarely on the role of local leadership. Thus, this study aims to measure the environmental efficiency and analyze the impact of mayors' characteristics on environmental efficiency. By using the metafrontier-stochastic frontier analysis two-step estimate method, the average value of the overall environmental efficiency in China is only 0.523, which is high in the eastern region and low in the central and western regions. Empirical results show that mayors' tenure plays an inverted U-shaped effect on environmental efficiency. Mayors who are highly educated, young, and aware of environmental protection can improve environmental efficiency. Moreover, mayors' experience in official exchange can improve environmental efficiency; mayors with work experience in the central government are effective in terms of environmental governance. The policy implication is that improving the educational level of leaders, appointing young cadres, and strengthening official exchanges can effectively improve environmental efficiency.

8.
Nano Res ; 12: 273-279, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31832124

RESUMO

Theranostic nanoparticles are integrated systems useful for simultaneous diagnosis and imaging guided delivery of therapeutic drugs, with wide ranging potential applications in the clinic. Here we developed a theranostic nanoparticle (~ 24 nm size by dynamic light scattering) p-FE-PTX-FA based on polymeric micelle encapsulating an organic dye (FE) fluorescing in the 1,000-1,700 nm second near-infrared (NIR-II) window and an anti-cancer drug paclitaxel. Folic acid (FA) was conjugated to the nanoparticles to afford specific binding to molecular folate receptors on murine breast cancer 4T1 tumor cells. In vivo, the nanoparticles accumulated in 4T1 tumor through both passive and active targeting effect. Under an 808 nm laser excitation, fluorescence detection above 1,300 nm afforded a large Stokes shift, allowing targeted molecular imaging tumor with high signal to background ratios, reaching a high tumor to normal tissue signal ratio (T/NT) of (20.0 ± 2.3). Further, 4T1 tumors on mice were completed eradicated by paclitaxel released from p-FE-PTA-FA within 20 days of the first injection. Pharmacokinetics and histology studies indicated p-FE-PTX-FA had no obvious toxic side effects to major organs. This represented the first NIR-II theranostic agent developed.

9.
Sci Total Environ ; : 135581, 2019 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-31812392

RESUMO

Plant litter plays an important role in affecting the water quality of wetland ecosystems. However, it is unknown whether litter decomposability and species traits might predict water quality changes during litter submergence. Here, we conducted a greenhouse experiment to examine the effects of four submerged plant species, together with two water sources (sampled from tourism and protected areas), and oxygen injection treatments on the changes of eight water quality parameters during litter submergence. Our results showed that litter submergence significantly affected water quality changes, and the observed effects changed through time and differed between two water sources, between oxygen injection and the control treatments, and among different litter species. Moreover, water electric conductivity (EC), total dissolved solids (TDS), water total nitrogen (TN), ammonium and nitrite nitrogen increased with increasing initial litter total carbon (TC), TN and total phosphorus (TP), but water dissolved oxygen (DO) decreased with increasing litter TC, TN and TP. Moreover, water EC, TDS and TN increased with the final mass losses after 10-week submergence. These results indicated that species traits (including decomposability) might be good predictors for the water quality changes during litter submergence, and such a trait-based approach might be a promising tool to link plant species diversity via plant functional traits to water quality or other wetland ecosystem services.

10.
Aging (Albany NY) ; 112019 Dec 08.
Artigo em Inglês | MEDLINE | ID: mdl-31812952

RESUMO

Local and privileged expression of dendritic proteins allows segregation of distinct functions in a single neuron but may represent one of the underlying mechanisms for early and insidious presentation of sensory neuropathy. Tangible characteristics of early hearing loss (HL) are defined in correlation with nascent hidden hearing loss (HHL) in humans and animal models. Despite the plethora of causes of HL, only two prevailing mechanisms for HHL have been identified, and in both cases, common structural deficits are implicated in inner hair cell synapses, and demyelination of the auditory nerve (AN). We uncovered that Na+-activated K+ (KNa) mRNA and channel proteins are distinctly and locally expressed in dendritic projections of primary ANs and genetic deletion of KNa channels (Kcnt1 and Kcnt2) results in the loss of proper AN synaptic function, characterized as HHL, without structural synaptic alterations. We further demonstrate that the local functional synaptic alterations transition from HHL to increased hearing-threshold, which entails changes in global Ca2+ homeostasis, activation of caspases 3/9, impaired regulation of inositol triphosphate receptor 1 (IP3R1), and apoptosis-mediated neurodegeneration. Thus, the present study demonstrates how local synaptic dysfunction results in an apparent latent pathological phenotype (HHL) and, if undetected, can lead to overt HL. It also highlights, for the first time, that HHL can precede structural synaptic dysfunction and AN demyelination. The stepwise cellular mechanisms from HHL to canonical HL are revealed, providing a platform for intervention to prevent lasting and irreversible age-related hearing loss (ARHL).

11.
Nanoscale ; 2019 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-31815993

RESUMO

Nanoparticle (NP)-based hydrogels that can introduce synergistic advantages to the novel three-dimensional scaffold have garnered much attention recently. However, the application of NP-crosslinked hydrogels still remains challenging due to the complicated synthesis and/or modification of the NPs and the changed properties of the NPs after gelation. Herein, a novel palladium nanosheet (Pd NS)-based hydrogel (Pd Gel) with Pd NSs as crosslinkers was obtained by simply mixing Pd NSs with thiol-terminated four-arm polyethylene glycol (4arm-PEG-thiol). It was found that the formed Pd Gel was injectable, possibly due to the dynamic Pd-S bonds formed between Pd NSs and 4arm-PEG-thiol. In addition, compared with free Pd NSs, the Pd NSs within the hydrogel exhibited a significantly higher stability. We have further demonstrated that the formed hydrogel could encapsulate the commonly used anticancer drug doxorubicin (DOX) to form DOX@Pd Gel for combined chemo-photothermal therapy. Particularly, Pd NSs with a high absorption in the near-infrared (NIR) region could convert the energy of NIR laser into heat with a high efficiency, which is beneficial for photothermal therapy. Moreover, DOX@Pd Gel could maintain a sustainable release of DOX and the NIR laser irradiation could accelerate this drug release process. Then, the explosively released DOX and the hyperthermia generated from Pd NSs under NIR laser irradiation acted in a synergistic way to realize the combined therapeutic effect of the chemo-photothermal treatment. Finally, the in vivo anticancer effect and safety of the combined therapy were also verified by the tumor-bearing mouse model. Taken together, this work constructs a NP-crosslinked, NIR laser-activatable and injectable photothermal hydrogel via dynamic Pd-S bonding, and demonstrates that the hydrogel allows us to release DOX more precisely, eliminate tumor more effectively and inhibit tumor metastasis more persistently, which will advance the development of novel anticancer strategies.

12.
Cancer Lett ; 470: 54-63, 2019 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-31790762

RESUMO

Abnormal lipid metabolism plays crucial roles in the development of cancer. Spindlin 1 (SPIN1) involving the process of spindle organization and chromosomal stability serves as an important player in the carcinogenesis. In this study, we try to identify the new function of SPIN1 in lipid metabolism of liver cancer. Tissue microarray showed that 75% (60/80) of hepatocellular carcinoma (HCC) tissues were positive for SPIN1, which was highly expressed in clinical HCC samples and positively associated with malignancy of HCC. Strikingly, SPIN1 could modulate abnormal lipid metabolism by increasing intracellular triglycerides, cholesterols, and lipid droplets in hepatoma cells, which could remarkably enhance the proliferation of hepatoma cells. Mechanistically, SPIN1 up-regulated FASN in hepatoma cells. SPIN1 co-activated transcriptional factor SREBP1c in the promoter of FASN through interaction with SREBP1c. Moreover, SPIN1 promoted the growth of liver cancer in vitro and in vivo and the levels of intracellular triglycerides, cholesterols and lipid droplets were increased in the tumor tissues from mice. In conclusion, SPIN1 modulates abnormal lipid metabolism and enhances growth of liver cancer through SREBP1c-triggered FASN signaling. Therapeutically, SPIN1 may serve as a novel target for HCC.

13.
Nanoscale ; 2019 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-31793608

RESUMO

Hypoxia is known to be a common feature within many types of solid tumors, which is closely related to the limited efficacy of radiotherapy. Meanwhile, due to the non-discriminatory killing effect of both normal and cancer cells during the radiation process, traditional radiosensitizers could bring severe non-negligible side-effects to the whole body. In this work, stable and atomically precise Mn clusters which possess efficient pH-triggered catalytic selective capacity are developed rationally. Mn clusters could efficiently catalyze oxygen production in an acidic tumor microenvironment, while exhibiting strong reducibility and free radical scavenging ability in neutral circumstances. In vivo experiments show that Mn clusters are able to enhance the radiotherapy effect in the mouse model of 4T1 tumors and protect normal tissues from radiation at the same time. Thus, the present work provides a novel dual-functional strategy to enhance radiotherapy-induced tumor treatment by improving tumor oxygenation and protect normal tissues from radiation simultaneously.

14.
Int J Mol Sci ; 20(23)2019 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-31795510

RESUMO

Cardiovascular diseases (CVDs) are a major cause of health loss in the world. Prevention and treatment of this disease by traditional Chinese medicine is a promising method. Centranthera grandiflora Benth is a high-value medicinal herb in the prevention and treatment of CVDs; its main medicinal components include iridoid glycosides, phenylethanoid glycosides, and azafrin in roots. However, biosynthetic pathways of these components and their regulatory mechanisms are unknown. Furthermore, there are no genomic resources of this herb. In this article, we provide sequence and transcript abundance data for the root, stem, and leaf transcriptome of C. grandiflora Benth obtained by the Illumina Hiseq2000. More than 438 million clean reads were obtained from root, stem, and leaf libraries, which produced 153,198 unigenes. Based on databases annotation, a total of 557, 213, and 161 unigenes were annotated to catalpol, acteoside, and azafrin biosynthetic pathways, respectively. Differentially expressed gene analysis identified 14,875 unigenes differentially enriched between leaf and root with 8,054 upregulated genes and 6,821 downregulated genes. Candidate MYB transcription factors involved in catalpol, acteoside, and azafrin biosynthesis were also predicated. This work is the first transcriptome analysis in C. grandiflora Benth which will aid the deciphering of biosynthesis pathways and regulatory mechanisms of active components.

15.
Br J Radiol ; : 20190669, 2019 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-31799859

RESUMO

OBJECTIVE: This study is part of ongoing efforts aiming to transit from measurement-based to combined patient-specific quality assurance (PSQA) in intensity-modulated proton therapy (IMPT). A Monte Carlo (MC) dose-calculation algorithm is used to improve the independent dose calculation and to reveal the beam modeling deficiency of the analytical pencil beam (PB) algorithm. METHODS: A set of representative clinical IMPT plans with suboptimal PSQA results were reviewed. Verification plans were recalculated using an MC algorithm developed in-house. Agreements of PB and MC calculations with measurements that quantified by the γ passing rate were compared. RESULTS: The percentage of dose planes that met the clinical criteria for PSQA (>90% γ passing rate using 3%/3 mm criteria) increased from 71.40% in the original PB calculation to 95.14% in the MC recalculation. For fields without beam modifiers, nearly 100% of the dose planes exceeded the 95% γ passing rate threshold using the MC algorithm. The model deficiencies of the PB algorithm were found in the proximal and distal regions of the SOBP, where MC recalculation improved the γ passing rate by 11.27% (p < 0.001) and 16.80% (p < 0.001), respectively. CONCLUSIONS: The MC algorithm substantially improved the γ passing rate for IMPT PSQA. Improved modeling of beam modifiers would enable the use of the MC algorithm for independent dose calculation, completely replacing additional depth measurements in IMPT PSQA program. For current users of the PB algorithm, further improving the long-tail modeling or using MC simulation to generate the dose correction factor is necessary. ADVANCES IN KNOWLEDGE: We justified a change in clinical practice to achieve efficient combined PSQA in IMPT by using the MC algorithm that was experimentally validated in almost all the clinical scenarios in our center. Deficiencies in beam modeling of the current PB algorithm were identified and solutions to improve its dose calculation accuracy were provided.

16.
Front Chem ; 7: 784, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31803720

RESUMO

Radiotherapy is the mainstay for abdomen and pelvis cancers treatment. However, high energy ray would inflict gastrointestinal (GI) system and adversely disrupt the treatment. The anti-oxidative agents provide a potential route for protecting body from radiation-induced injuries. Herein, highly catalytic nanocubes with dislocation structure are developed for treatment of intestinal injury. Structural and catalytic properties show that Mo incorporation can enhance antioxidant activity by dislocation structure in the alloy. In vitro studies showed that PtPdMo improved cell survival by scavenging radiation-induced ROS accumulation. Furthermore, after animals were exposed to lethal dose of radiation, the survival was increased by 50% with the PtPdMo i.p. treatment. Radioprotection mechanism revealed that PtPdMo alleviated the oxidative stress in multi-organs especially the small intestine by inhibiting intestinal epithelium apoptosis, reducing DNA strands breaks and enhancing repairing ability. In addition, PtPdMo protected hematopoietic system by improving the number of bone marrow and peripheral blood cells.

17.
Reprod Domest Anim ; 2019 Dec 23.
Artigo em Inglês | MEDLINE | ID: mdl-31869480

RESUMO

Litter size is one of the most important economic traits in pig production. Recent studies identified that Deoxynivalenol (DON), a widespread toxin in fodder, was associated with animal prolificacy. However, the underlying mechanisms have not yet been completely elucidated. Here, we used porcine ovary granulosa cells (pGCs) as a vector to establish DON concentration-time models and performed cell morphology and transcriptome analysis to identify and analyze the effects of DON on reproductive performance in swine. The results showed that DON can induce morphological changes and apoptosis of pGCs, while inhibiting cell proliferation. Moreover, these effects of DON on pGCs were dose dependent. After treatment of pGCs with different concentrations of DON, the percentage of cells in S phase and G2/M phase increased. RNA-seq analyses revealed 5,937 differentially expressed genes, of which 1995 were down-regulated and 3,942 were up-regulated after DON treatment. KEGG enrichment analysis indicated important metabolic pathways such as IL-17 signaling pathway, eukaryotic ribosome synthesis pathway, RNA transport pathway, and RNA degradation. Based on our results, we speculate that the effects of DON are related to the DNA damage process. Our study provides novel insights and a foundation to further understand the effect of DON on swine prolificacy.

18.
Appl Opt ; 58(35): 9524-9531, 2019 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-31873550

RESUMO

In this paper we propose a novel non-contact method of thickness measurement for a transparent plate using a laser auto-focus scanning (LAFS) probe. Through the analysis of the focus error signal (FES) from the actual specimen's upper and lower surface reflectances, a measurement model is introduced to find the best focus position on the corresponding surface of the transparent plate. Thus, the thickness of a specimen can be obtained. Herein, the LAFS probe measurement characteristics by auto-searching the FES method can be analyzed, which can then realize non-contact measurement and focus detection of micro-displacements. Therefore, we have successfully designed a low-cost, high-precision auto-focusing thickness measurement system with linear piezoelectric nano-positioning. To verify the proposed method, some transparent specimens were evaluated, and the thicknesses were rapidly and successfully measured. Experiments confirm the validity of the proposed system, and the results show that the method is effective for the thickness measurement of transparent plates.

19.
Clin Imaging ; 60(1): 123-130, 2019 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-31874336

RESUMO

OBJECTIVES: To evaluate the feasibility of integrating computer-aided diagnosis (CAD) with structured reports of prostate multiparametric MRI (mpMRI). METHODS: This retrospective study enrolled 153 patients who underwent prostate mpMRI for the purpose of targeted biopsy; patients were divided into a group with clinically significant prostate cancer (csPCa, Gleason score ≥ 3 + 4, n = 89) and a group with non-csPCa (n = 64). Ten inexperienced radiologists retrospectively evaluated these cases (single reader per case) twice using structured reports, and they were blinded to the pathologic results. Initially, the readers interpreted mpMRI without CAD. Six weeks later, they evaluated the same cases again with CAD assistance. At each time of image interpretation, lesions detected by the readers were marked on the prostate vector map in structured reports, and a PI-RADS score was given to each lesion. Diagnostic efficacy and reading time were evaluated for the two reading sessions. RESULTS: With the assistance of CAD, the overall diagnostic efficacy was improved, i.e., the AUC increased from 0.83 to 0.89 (p = 0.018). Specifically, per-patient sensitivity (84.3% vs. 93.3%) and per-lesion sensitivity (76.7% vs. 88.8%) were significantly improved (all p < 0.05). Per-patient specificity with CAD (65.6%) was higher than that without CAD (56.3%), but statistical significance was not reached (p = 0.238). The reading time for each case decreased from 10.9 min to 7.8 min (p < 0.001). CONCLUSIONS: It is feasible to integrate CAD with structured reports of prostate mpMRI. This reading paradigm can improve the diagnostic sensitivity of csPCa detection and reduce reading time among inexperienced radiologists.

20.
Structure ; 2019 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-31740029

RESUMO

Yeast Tel1 and its highly conserved human ortholog ataxia-telangiectasia mutated (ATM) are large protein kinases central to the maintenance of genome integrity. Mutations in ATM are found in ataxia-telangiectasia (A-T) patients and ATM is one of the most frequently mutated genes in many cancers. Using cryoelectron microscopy, we present the structure of Tel1 in a nucleotide-bound state. Our structure reveals molecular details of key residues surrounding the nucleotide binding site and provides a structural and molecular basis for its intrinsically low basal activity. We show that the catalytic residues are in a productive conformation for catalysis, but the phosphatidylinositol 3-kinase-related kinase (PIKK) regulatory domain insert restricts peptide substrate access and the N-lobe is in an open conformation, thus explaining the requirement for Tel1 activation. Structural comparisons with other PIKKs suggest a conserved and common allosteric activation mechanism. Our work also provides a structural rationale for many mutations found in A-T and cancer.

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