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1.
Methods Mol Biol ; 2196: 97-116, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-32889716

RESUMO

Recent years have seen great progresses in third-generation sequencing. New commercial platforms from Oxford Nanopore Technologies (ONT) can generate ultra-long reads from single-molecule nucleic acid fragments of kilobases up to megabases, exceeding the limitation of short reads and dependency on template amplification suffered by the previous generation of sequencing technologies. Moreover, it can detect epigenetic modifications directly, as well as providing all-around field usage, being pocket-sized and low cost. It has already been applied to yeast research in many aspects, such as complete de novo genome assemblies, the phylogeny of large-brewing yeasts, gene isoform identification, and base modification detection. These applications have delivered novel insights into yeast genomic and transcriptomic analysis.

2.
J Cell Mol Med ; 2020 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-33047871

RESUMO

Sorafenib has been approved for the treatment of certain cancers in clinic. However, the effects of sorafenib on gastric adenocarcinoma (GAC) were still limited. This study aimed to evaluate both in vitro and in vivo efficacy of sorafenib in combination with pterostilbene (PTE) on the treatment of GAC. Here, the morphological changes and cell viability were recorded in both N87 and MKN45 cells. The cell cycle profile and apoptosis were assessed by flow cytometry. Subcutaneous tumour xenografts were constructed in nude mice, and IHC staining of the dissected tumour tissues was conducted. Our results showed that PTE enhanced sorafenib's inhibitory effects on cell viability. The obvious down-regulation of cyclin D1, Cdk-2, Cdk-4, Cdk-6 and p62 and the up-regulation of LC3II, caspase-9, caspase-3 and PARP cleavages were observed for the combination treatment with PTE and sorafenib than monotherapy. The combination treatment resulted in a higher level of cell cycle arrest at G1 phase and apoptosis than either drug. Besides, drug combination significantly enhanced the inhibition of tumour growth than sorafenib or PET alone in nude mice. The percentage of Ki-67- and PCNA-positive cells was distinctly reduced, and the apoptotic cells was obviously increased when compared with single drug therapy. Altogether, PET obviously enhanced sorafenib's antitumour effects against GAC through inhibiting cell proliferation, inducing autophagy and promoting apoptosis. The combination therapy with PET and sorafenib may serve as a novel therapeutic strategy for treating GAC and deserve further clinical trials.

3.
Sci Rep ; 10(1): 17432, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-33060705

RESUMO

Lung cancer is the leading cause of cancer death worldwide. The Xuanwei-Fuyuan (XF) region of Yunnan, China has a high incidence of lung cancer from coal-related pollution. Effort to raise public awareness screening for lung cancer has been ongoing. We retrospectively analyzed overall survival (OS) of lung cancer patients of a tertiary cancer center in Yunnan to investigate screening and regional residential status as predictive factors. Consecutive cases of newly diagnosed lung cancer were reviewed. The lung cancer cases diagnosed by screening were more likely to be early-staged and treated by surgery than those diagnosed not by screening. In patients diagnosed not by screening, XF residential status was a significant predictor of improved OS. Frailty model detected significant heterogeneity associated with region of residence in unscreened patients. Potential biases associated with screening were examined by Monte Carlo simulations and sensitivity analyses. Focused effort in cancer screening and increased public awareness of pollution-related lung cancer in XF might have led to early diagnosis and improved OS, and increased investment in health care resources in high risk areas may have produced additional unobserved factors that underlay the association of XF residential status with improved OS in patients diagnosed not by screening.

4.
Int J Cancer ; 2020 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-33091956

RESUMO

Evidence links the liver to development of colorectal cancer (CRC). However, it remains unknown how liver function may influence CRC risk in the general population. We conducted a prospective cohort study in the UK Biobank of 375,693 participants who provided blood samples in 2006-2010. Circulating levels of liver function markers [alanine transaminase (ALT), aspartate transaminase (AST), total bilirubin (TBIL), gamma glutamyltransferase (GGT), alkaline phosphatase (ALP), total protein (TP), and albumin (ALB)] were measured. Incident cancer cases were identified through linkage to the national cancer registry up to 2019. Repeated biomarker measurements were available from a subset of 11,320 participants who were re-assessed in 2012-2013. After a median follow-up of 10.0 years, we documented 2,662 cases of CRC. Circulating levels of ALT, AST, TBIL, GGT, TP, and ALB at baseline were inversely associated with CRC risk (P<.01), with multivariable hazard ratio (95% confidence interval) comparing decile 10 versus 1 of 0.62 (0.51-0.75), 0.63 (0.53-0.75), 0.85 (0.72-1.02), 0.74 (0.61-0.89), 0.70 (0.59-0.84), and 0.66 (0.55-0.79), respectively. Strengthened associations were found after recalibration for repeated measurements. The associations appeared stronger for proximal colon cancer than distal colon cancer and rectal cancer, but consistent for early-, mid-, and late-onset CRC. In a large cohort of general population, the UK Biobank, higher circulating levels of ALT, AST, TBIL, GGT, TP, and ALB, largely within the normal range, were associated with a lower risk of CRC. The findings support a link between liver function and CRC, and may spur future research on the gut-microbiota-liver axis. This article is protected by copyright. All rights reserved.

6.
J Am Chem Soc ; 142(42): 18150-18159, 2020 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-32991157

RESUMO

Mimicking nature's ability to orchestrate molecular self-assembly in living cells is important yet challenging. Molecular self-assembly has found wide applications in cellular activity control, drug delivery, biomarker imaging, etc. Nonetheless, examples of suborganelle-confined supramolecular self-assembly are quite rare and research in this area remains challenging. Herein, we have presented a new strategy to program supramolecular self-assembly specifically in mitochondria by leveraging on a unique enzyme SIRT5. SIRT5 is a mitochondria-localized enzyme belonging to a family of NAD+-dependent histone deacetylases. Accumulating studies suggest that SIRT5 is involved in regulating diverse biological processes, such as reactive oxygen defense, fatty acid metabolism, and apoptosis. In this study, we designed a novel class of succinylated peptide precursors that can be transformed into self-assembling building blocks through SIRT5 catalysis, leading to the formation of supramolecular nanofibers in vitro and in living cells. The increased hydrophobicity arising from self-assembly remarkably enhanced the fluorescence of nitrobenzoxadiazole (NBD) in the nanofibers. With this approach, we have enabled activity-based imaging of SIRT5 in living cells for the first time. Moreover, SIRT5-mediated peptide self-assembly was found to depolarize mitochondria membrane potential and promote ROS formation. Coincubation of the peptide with three different chemotherapeutic agents significantly boosted the anticancer activities of these drugs. Our work has thus illustrated a new way of mitochondria-confined peptide self-assembly for SIRT5 imaging and potential anticancer treatment.

7.
Chemistry ; 2020 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-32960463

RESUMO

Effective capture of radioactive iodine is of paramount importance for the safe and long-term storage of fission products in nuclear fuel cycle. Herein, a series of functionalized Th-UiO-66 MOFs was employed as a model to investigate the effects of substituents on iodine adsorption in both solution and vapor states. Sorption studies revealed that the electro-donating amino group exhibits the most positive role on increasing the removal rate of iodine from cyclohexane and the uptake capacity of iodine vapor. Particularly, the disubstituted Th-UiO-66-(NH2)2 can effectively remove 91.9% of iodine (300 mg/L) from cyclohexane and capture 969 mg/g iodine vapor, significantly higher than 59.6% and 334 mg/g of untagged Th-UiO-66, respectively. In addition, the substituent effect on the radiolytic stability of MOFs was for the first time investigated, leading to the unearthing of one of the most radioresistant MOFs Th-UiO-66-NH2 reported up to date.

8.
Acta Ophthalmol ; 2020 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-32996707

RESUMO

PURPOSE: We had found that a multivariate prediction model used for the detection of primary angle-closure suspects (PACS) by combining multiple static and dynamic anterior segment optical coherence tomography (ASOCT) parameters had an area under the receiver operating characteristic curve (AUC) of 0.844. We undertook this study to evaluate this method in screening of PACS with different dominant mechanisms of angle closure (AC). METHODS: The right eyes of subjects aged ≥40 years who participated in the 5-year follow-up of the Handan Eye Study and had undergone gonioscopy and ASOCT examinations under light and dark conditions were included. All ASOCT images were analysed by the Zhongshan Angle Assessment Program. The dominant AC mechanism in each eye was determined to be pupillary block (PB), plateau iris configuration (PIC) or thick peripheral iris roll (TPIR). Backward logistic regression (LR) was used for inclusion of variables in the prediction models. LR, Naïve Bayes' classification (NBC) and neural network (NN) were evaluated and compared using the AUC. RESULTS: Data from 796 subjects (413 PACS and 383 normal eyes) were analysed. The AUCs of LR, NBC and NN in the PB group were 0.920, 0.918 and 0.917. The AUCs of LR, NBC and NN in the PIC group were 0.715, 0.708 and 0.707. The AUCs of LR, NBC and NN in TPIR group were 0.867, 0.833 and 0.886. CONCLUSIONS: Prediction models showed the best performance for detection of PACS with PB mechanism for AC and have potential for screening of PACS.

9.
J Agric Food Chem ; 2020 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-32955873

RESUMO

The German cockroach Blattella germanica (L.) is an important pest in medical, veterinary and public health. Studies on the olfaction mechanism of hemimetabolous insects have rarely been reported, especially in cockroaches. Pheromone-binding proteins (PBPs) play a vital role in insect sex pheromone recognition, which solubilize and carry the hydrophobic pheromonal compounds through the antennal lymph to receptors. In this study, two potential PBPs (BgerOBP26 and 40) were identified based on their biased expression in male antennae using tissue transcriptome data and verified by qPCR approach. We then expressed and purified the two identified OBPs using Escherichia coli expression system and affinity purification. In vitro binding studies showed that the two OBPs display stronger binding affinities to the female volatile sex pheromone blattellaquinone than to its analogs and contact sex pheromone components. Finally, three-dimensional modeling of the two OBPs and dock conformation with sex pheromone molecules showed BgerOBP26 has a larger odorant cavity and more conservative active amino acid residues than those of BgerOBP40. These results illuminated the binding characteristics of potential PBPs of B. germanica, which could lay the ground for improved understanding of many aspects of the chemical ecology of B. germanica. Moreover, this information complements the understanding of the olfactory molecular mechanism in cockroaches and provides potential gene targets for B. germanica control.

10.
J Evid Based Dent Pract ; 20(3): 101468, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32921388

RESUMO

OBJECTIVE: Oral lichen planus (OLP) is a chronic inflammatory immune disease, recognized as an oral potentially malignant disorder by the World Health Organization. There is considerable controversy over the standardized treatment of OLP, with great diversities in the outcome measures in clinical trials. This methodological study aimed to estimate the degree of consensus on outcome measures in randomized controlled trials (RCTs) for OLP treatment. METHODS: PubMed, Embase, and Cochrane databases were searched to identify RCTs published from 2004 to 2018 about OLP treatment. All the outcome measures and measurement methods mentioned in the trials were extracted and analyzed. RESULTS: After identification of 1087 articles, 88 RCTs were included. A total of 193 single-outcome measures and 119 composite outcome measures were classified into 11 different domains, the chief of which consisted of clinical symptom (78 trials; 88.6%) and clinical score (58 trials; 65.9%). Visual analog scale (65 trials; 73.9%) and Thongprasom scoring system (38 trials; 43.2%) were the predominant measurement methods. Oral health-related quality of life (except for clinical symptoms) accounted for 4.8% of all the outcome measures. CONCLUSIONS: There was high heterogeneity in outcome measures of RCTs for OLP treatment, making it difficult to make valid comparisons between different clinical trials. A core outcome set should be developed and adopted in future trials for OLP treatment.


Assuntos
Líquen Plano Bucal , Avaliação de Resultados em Cuidados de Saúde , Ensaios Clínicos Controlados Aleatórios como Assunto , Humanos , Líquen Plano Bucal/tratamento farmacológico , Qualidade de Vida
11.
Acta Pharmacol Sin ; 2020 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-32747718

RESUMO

Aconitine (ACO), a main active ingredient of Aconitum, is well-known for its cardiotoxicity. However, the mechanisms of toxic action of ACO remain unclear. In the current study, we investigated the cardiac effects of ACO and mesaconitine (MACO), a structurally related analog of ACO identified in Aconitum with undocumented cardiotoxicity in guinea pigs. We showed that intravenous administration of ACO or MACO (25 µg/kg) to guinea pigs caused various types of arrhythmias in electrocardiogram (ECG) recording, including ventricular premature beats (VPB), atrioventricular blockade (AVB), ventricular tachycardia (VT), and ventricular fibrillation (VF). MACO displayed more potent arrhythmogenic effect than ACO. We conducted whole-cell patch-clamp recording in isolated guinea pig ventricular myocytes, and observed that treatment with ACO (0.3, 3 µM) or MACO (0.1, 0.3 µM) depolarized the resting membrane potential (RMP) and reduced the action potential amplitude (APA) and durations (APDs) in a concentration-dependent manner. The ACO- and MACO-induced AP remodeling was largely abolished by an INa blocker tetrodotoxin (2 µM) and partly abolished by a specific Na+/K+ pump (NKP) blocker ouabain (0.1 µM). Furthermore, we observed that treatment with ACO or MACO attenuated NKP current (INa/K) and increased peak INa by accelerating the sodium channel activation with the EC50 of 8.36 ± 1.89 and 1.33 ± 0.16 µM, respectively. Incubation of ventricular myocytes with ACO or MACO concentration-dependently increased intracellular Na+ and Ca2+ concentrations. In conclusion, the current study demonstrates strong arrhythmogenic effects of ACO and MACO resulted from increasing the peak INa via accelerating sodium channel activation and inhibiting the INa/K. These results may help to improve our understanding of cardiotoxic mechanisms of ACO and MACO, and identify potential novel therapeutic targets for Aconitum poisoning.

12.
Nat Commun ; 11(1): 3984, 2020 08 07.
Artigo em Inglês | MEDLINE | ID: mdl-32770009

RESUMO

The epsin family of endocytic adapter proteins are widely expressed, and interact with both proteins and lipids to regulate a variety of cell functions. However, the role of epsins in atherosclerosis is poorly understood. Here, we show that deletion of endothelial epsin proteins reduces inflammation and attenuates atherosclerosis using both cell culture and mouse models of this disease. In atherogenic cholesterol-treated murine aortic endothelial cells, epsins interact with the ubiquitinated endoplasmic reticulum protein inositol 1,4,5-trisphosphate receptor type 1 (IP3R1), which triggers proteasomal degradation of this calcium release channel. Epsins potentiate its degradation via this interaction. Genetic reduction of endothelial IP3R1 accelerates atherosclerosis, whereas deletion of endothelial epsins stabilizes IP3R1 and mitigates inflammation. Reduction of IP3R1 in epsin-deficient mice restores atherosclerotic progression. Taken together, epsin-mediated degradation of IP3R1 represents a previously undiscovered biological role for epsin proteins and may provide new therapeutic targets for the treatment of atherosclerosis and other diseases.


Assuntos
Proteínas Adaptadoras de Transporte Vesicular/metabolismo , Aterosclerose/metabolismo , Receptores de Inositol 1,4,5-Trifosfato/metabolismo , Proteólise , Proteínas Adaptadoras de Transporte Vesicular/química , Animais , Aorta/metabolismo , Aorta/patologia , Aterosclerose/patologia , Cálcio/metabolismo , Colesterol/metabolismo , Células Endoteliais/metabolismo , Feminino , Deleção de Genes , Células HEK293 , Homeostase , Humanos , Inflamação/patologia , Masculino , Camundongos Knockout , Ligação Proteica , Domínios Proteicos , Ubiquitinação
13.
Invest Ophthalmol Vis Sci ; 61(10): 15, 2020 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-32766746

RESUMO

Purpose: To examine the risk of open-angle glaucoma (OAG) among patients receiving alpha1-adrenoceptor (α1-AR) antagonists for lower urinary tract symptoms (LUTS). Methods: This was a nationwide, population-based, retrospective cohort study from Asia/Taiwan. One million beneficiaries were randomly sampled from among 27.38 million individuals enrolled in the National Health Insurance program, and subjects with a diagnosis of LUTS from 2001 to 2012 were identified (N = 105,341). After 1:1 propensity score matching by gender, age, comorbid medical diseases, number of all medical visits during the observational period, and index date, 4081 patients were enrolled in the study group, comprised of patients who had taken α1-AR antagonists, and 4081 patients were enrolled in the control group, comprised of patients who had never taken α1-AR antagonists. The incidence and risk of OAG (defined as two ambulatory visits with a ICD-9 diagnosis code 365, excluding ICD-9 diagnosis codes 365.2-365.6, 365.02, 365.03, 365.13, 365.14, and 365.8) were calculated. Results: Patients taking α1-AR antagonists had a higher incidence ratio of 1.86 (95% confidence interval [CI], 1.30-2.65) for developing OAG. After adjusting for age, gender, and comorbidities, the hazard ratio (HR) for OAG for patients taking α1-AR antagonists was 1.66 (95% CI, 1.16-2.39; P = 0.006). Among patients with hypertension, the hazard ratio for OAG associated with taking α1-AR antagonists increased to 1.79 (95% CI, 1.07-2.99; P = 0.003). On the other hand, the association of α1-AR antagonists with OAG was not significant among patients with diabetes mellitus, hyperlipidemia, or older age. Conclusions: The findings of our study suggest an increased risk for OAG among patients taking α1-AR antagonists for LUTS, especially in patients with hypertension.

15.
Genes Dis ; 2020 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-32837984

RESUMO

The pandemic COVID-19, caused by a new coronavirus SARS-CoV-2 infection, has infected over 6 million individuals and caused more than 364,000 death worldwide. Currently, there is no specific drug to treating this disease. Here we summarized the mechanisms of antiviral therapies and the clinic findings from different countries. Antiviral chemotherapies have been conducted by in multiple cohorts in different counties. Although FDA has fast approved remdesivir for treating COVID-19, it only speeds up recovery from COVID-19 with mildly reduced mortality. The chloroquine was suggested a potential drug against SARS-CoV-2 infection due to its in vitro antiviral effects, it is imperative high-quality data from worldwide clinical trials are necessitated for an approved therapy. In terms of hydroxychloroquine (HCQ) therapy, although WHO has stopped all the clinic trials due to its strong side-effects in COVID patients, large scale clinical trials with a long-term outcome follow-up may warrant HCQ and azithromycin combination in combating the virus. Convalescent plasma (CP) therapy suggested its safety use in SARS-CoV-2 infection; but both CP immunotherapy and NK cellular therapy must be manufactured and utilized according to scrupulous ethical and controlled conditions to guarantee a possible role of these products of human origin. Further research should be conducted to define the exact mechanism of SARS-CoV-2 pathogenesis, suitable animal models or ex vivo human lung tissues aid in studying replication, transmission and spread of the novel viruses, thereby facilitating highly effective therapies.

16.
Nat Commun ; 11(1): 3844, 2020 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-32737312

RESUMO

Harnessing renewable electricity to drive the electrochemical reduction of CO2 is being intensely studied for sustainable fuel production and as a means for energy storage. Copper is the only monometallic electrocatalyst capable of converting CO2 to value-added products, e.g., hydrocarbons and oxygenates, but suffers from poor selectivity and mediocre activity. Multiple oxidative treatments have shown improvements in the performance of copper catalysts. However, the fundamental underpinning for such enhancement remains controversial. Here, we combine reactivity, in-situ surface-enhanced Raman spectroscopy, and computational investigations to demonstrate that the presence of surface hydroxyl species by co-electrolysis of CO2 with low concentrations of O2 can dramatically enhance the activity of copper catalyzed CO2 electroreduction. Our results indicate that co-electrolysis of CO2 with an oxidant is a promising strategy to introduce catalytically active species in electrocatalysis.

17.
Transl Vis Sci Technol ; 9(5): 16, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32821488

RESUMO

Purpose: To establish and evaluate algorithms for detection of primary angle closure suspects (PACS), the risk factor for primary angle closure disease by combining multiple static and dynamic anterior segment optical coherence tomography (ASOCT) parameters. Methods: Observational, cross-sectional study. The right eyes of subjects aged ≥40 years who participated in the 5-year follow-up of the Handan Eye Study, and underwent gonioscopy and ASOCT examinations under light and dark conditions were included. All ASOCT images were analyzed by Zhongshan Angle Assessment Program. Backward logistic regression (BLR) was used for inclusion of variables in the prediction models. BLR, naïve Bayes' classification (NBC), and neural network (NN) were evaluated and compared using the area under the receiver operating characteristic curve (AUC). Results: Data from 744 subjects (405 eyes with PACS and 339 normal eyes) were analyzed. Angle recess area at 750 µm, anterior chamber volume, lens vault in light and iris cross-sectional area change/pupil diameter change were included in the prediction models. The AUCs of BLR, NBC, and NN were 0.827 (95% confidence interval [CI], 0.798-0.856), 0.826 (95% CI, 0.797-0.854), and 0.844 (95% CI, 0.817-0.871), respectively. No significant statistical differences were found between the three algorithms (P = 0.622). Conclusions: The three algorithms did not meet the requirements for population-based screening of PACS. One possible reason could be the different angle closure mechanisms in enrolled eyes. Translational Relevance: This study provides a promise for basis for future research directed toward the development of an image-based, noncontact method to screen for angle closure.

18.
Ophthalmic Epidemiol ; : 1-8, 2020 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-32822250

RESUMO

PURPOSE: To investigate willingness to pay for cataract surgery, and its associations, in Northwestern China. METHODS: Four hundred thirty-eight persons aged 50 years and above, diagnosed with cataract indicated for surgery, identified in an outreach screening program were included. Subjects were offered a willingness-to-pay interview for the maximal amount that the subjects would be willing to pay for a cataract surgery. Age, gender, literacy, education level, occupation, and annual household income were recorded. RESULTS: Among 328 (74.9%) subjects who completed the interview, 197 (60.1%) participants were willing to pay something for the cataract surgery (mean, 902.9 ± 856.7 renminbi[RMB], [US$ 145 ± 137]; median, 500RMB, US$ 78). Individuals with presenting visual acuity (PVA) in the worse eye ≤6/60 (OR: 2.1, 95% CI: 1.3-3.2) and a high annual household incomes (OR: 2.0, 95% CI: 0.9-4.6) were likely to be willing to pay for the surgery, as revealed in the regression models. Willingness to pay any amount for cataract surgery was more likely among literate persons (OR: 1.5, 95% CI: 1.0-2.4) and persons with non-agricultural occupation (OR: 1.8, 95% CI: 1.0-3.2). CONCLUSIONS: The amount that subjects were willing to pay is significantly less than the current cost of cataract surgery (5000 RMB, US$320) in the area. Providing low-cost cataract surgery to patients in a financially sustainable manner is important to increase uptake of cataract surgery among rural residents in Northwest China.

19.
Elife ; 92020 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-32755541

RESUMO

Telomeres define the natural ends of eukaryotic chromosomes and are crucial for chromosomal stability. The budding yeast Cdc13, Stn1 and Ten1 proteins form a heterotrimeric complex, and the inactivation of any of its subunits leads to a uniformly lethal phenotype due to telomere deprotection. Although Cdc13, Stn1 and Ten1 seem to belong to an epistasis group, it remains unclear whether they function differently in telomere protection. Here, we employed the single-linear-chromosome yeast SY14, and surprisingly found that the deletion of CDC13 leads to telomere erosion and intrachromosome end-to-end fusion, which depends on Rad52 but not Yku. Interestingly, the emergence frequency of survivors in the SY14 cdc13Δ mutant was ~29 fold higher than that in either the stn1Δ or ten1Δ mutant, demonstrating a predominant role of Cdc13 in inhibiting telomere fusion. Chromosomal fusion readily occurred in the telomerase-null SY14 strain, further verifying the default role of intact telomeres in inhibiting chromosome fusion.

20.
Nat Commun ; 11(1): 3328, 2020 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-32620864

RESUMO

Genes encoding cell-surface proteins control nervous system development and are implicated in neurological disorders. These genes produce alternative mRNA isoforms which remain poorly characterized, impeding understanding of how disease-associated mutations cause pathology. Here we introduce a strategy to define complete portfolios of full-length isoforms encoded by individual genes. Applying this approach to neural cell-surface molecules, we identify thousands of unannotated isoforms expressed in retina and brain. By mass spectrometry we confirm expression of newly-discovered proteins on the cell surface in vivo. Remarkably, we discover that the major isoform of a retinal degeneration gene, CRB1, was previously overlooked. This CRB1 isoform is the only one expressed by photoreceptors, the affected cells in CRB1 disease. Using mouse mutants, we identify a function for this isoform at photoreceptor-glial junctions and demonstrate that loss of this isoform accelerates photoreceptor death. Therefore, our isoform identification strategy enables discovery of new gene functions relevant to disease.


Assuntos
Variação Genética , Proteínas de Membrana/genética , Células Fotorreceptoras de Vertebrados/metabolismo , Isoformas de RNA/genética , Retina/metabolismo , Degeneração Retiniana/genética , Sequência de Aminoácidos , Animais , Sequência de Bases , Perfilação da Expressão Gênica/métodos , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Proteínas de Membrana/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos , Camundongos Knockout , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Isoformas de RNA/metabolismo , Retina/citologia , Retina/crescimento & desenvolvimento , Degeneração Retiniana/metabolismo , Homologia de Sequência de Aminoácidos , Homologia de Sequência do Ácido Nucleico
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