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1.
FASEB J ; 2020 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-32359121

RESUMO

We previously reported that high levels of plasma neurotensin (NT), a gut hormone released from enteroendocrine cells of the small bowel, contribute to obesity and comorbid conditions. Gut microbiota has been implicated in the obesity development. Paneth cells are critical in maintaining gut microbiota composition and homeostasis by releasing antimicrobial proteins including α-defensins. The purpose of our current study was to determine the possible role of NT in gut microbiota composition and α-defensin gene expression associated with obesity. Here we show that the ratio of Firmicutes/Bacteroidetes (F/B ratio) and intestinal proinflammatory cytokines is significantly increased in NT+/+ mice fed with a high-fat diet (HFD) which were improved in NT-deficient mice. HFD disrupted the intestinal Mmp7/α-defensin axis, which was completely prevented in NT-/- mice. In addition, NT treatment inhibited DEFA5 expression and concurrent NF-κB activity, which was blocked by a pan PKC inhibitor (Gö6983) or an inhibitor for atypical PKCs (CRT0066854). More importantly, the shRNA-mediated knockdown of atypical PKCτ reversed NT-attenuated DEFA5 expression and increased NF-κB activity. NT contributes to the HFD-induced disruption of gut microbiota composition and α-defensin expression. PKCτ/λ plays a central role in NT-mediated α-defensin gene expression which might be mediated through the inhibition of NF-κB signaling pathways in Paneth cells.

2.
Artigo em Inglês | MEDLINE | ID: mdl-32424483

RESUMO

PURPOSE: The purpose was to investigate the effects of short acquisition time on the image quality and the lesion detectability of oncological 18F-FDG total-body PET/CT. METHODS: Nineteen oncological patients (6/13 women/men, age 65.6 ± 9.4 years) underwent total-body PET/CT on uEXPLORER scanner using 3D list mode. The administration of 18F-FDG was weight-based (4.4 MBq/kg). The acquisition time was 900 s, and PET data were reconstructed into 900-, 180-, 120-, 60-, 30-, and 18-s duration groups. The subjective PET image quality was scored using a 5-point scale (5, excellent; 1, poor) in 3 perspectives: overall quality, noise, and lesion conspicuity. The objective image quality was evaluated by SUVmax and standard deviation (SD) of the liver, SUVmax of the tumor, and tumor-to-background ratio (TBR). The lesion detectability was the percentage of identifiable lesions in the groups of 180 to 18 s using the group 900 s as reference. RESULTS: Our results showed that sufficient and acceptable subjective image quality could be achieved with 60- and 30-s groups, and good image quality scores were given to 180- and 120-s groups without significant difference. For shortened acquisition time, SD was increased, while SUVmax of tumor and TBR remained unchanged. The lesion detectability was decreased with shorter acquisition time, but the detection performance could be maintained until the 60-s group compared with the 900-s group, although the image quality degraded. CONCLUSION: The total-body PET/CT can significantly shorten the acquisition time with maintained lesion detectability and image quality.

3.
Neurogastroenterol Motil ; : e13891, 2020 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-32449259

RESUMO

BACKGROUND: Little is known about intestinal fungi in IBS patients whose gut bacteria have been investigated a lot. In order to explore causal relationship between IBS and gut mycobiome, and use gut fungi to diagnose or even treat IBS, further characterization of it in IBS is required. METHODS: Fifty-five diarrhea-predominant IBS (D-IBS) patients fulfilling Rome III criteria, and 16 healthy controls (HC) were recruited. Fresh fecal samples were collected and used for 16s rRNA and ITS2 high-throughput sequencing. Diversity and composition of gut bacteria and fungi, as well as bacterial-fungal interactions in D-IBS patients, were characterized. Specific fungal taxa differentiating D-IBS from HC were recognized by LEfSe and RandomForest methods, and their association with clinical symptoms was assessed by Spearman's correlation. RESULTS: Diarrhea-predominant irritable bowel syndrome patients showed abnormal (IBS-dysbiosis) or normal (HC-like IBS) fecal bacterial structure and diversity compared with healthy controls. However, fecal fungal signatures differed absolutely between D-IBS and HC, which indicated a more susceptible alteration of gut fungi than bacteria in D-IBS. Fecal fungi showed significant correlations with IBS symptoms, especially Mycosphaerella, Aspergillus, Sporidiobolus, and Pandora which were identified to potentially differentiate D-IBS from HC. Moreover, compared with HC there were markedly declined bacterial-fungal interactions in D-IBS, in which Candida changed from negative to positive correlations with bacteria, and Eurotium changed from positive correlations to irrelevance, while Debaryomyces gained negative correlations with bacteria. CONCLUSIONS: Gut fungal dysbiosis and altered bacterial-fungal interactions were present in patients with D-IBS, and gut fungi could be used to diagnose D-IBS.

4.
J Phys Chem A ; 124(21): 4235-4240, 2020 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-32364735

RESUMO

In the prodrug research field, information obtained from traditional end point biochemical assays in drug effect studies could provide neither the dynamic processes nor heterogeneous responses of individual cells. In situ imaging microscopy techniques, especially fluorescence lifetime imaging microscopy (FLIM), could fulfill these requirements. In this work, we used FLIM techniques to observe the entry and release of doxorubicin (Dox)-Cu complexes in live KYSE150 cells. The Dox-Cu complex has weaker fluorescence signals but similar lifetime values as compared to the raw Dox, whose fluorescence could be released by the addition of biothiol compound (such as glutathione). The cell viability results indicated that the Dox-Cu compound has a satisfactory killing effect on KYSE150 cells. The FLIM data showed that free doxorubicin was released from Dox-Cu complexes in cytoplasm of KYSE150 cells and then accumulated in the nucleus. After 90 min administration, the fluorescence lifetime signals reached 1.21 and 1.46 ns in the cytoplasm and nucleus, respectively, reflecting the transformation and transportation of Dox-Cu complexes. In conclusion, this work provides a satisfactory example for the research of prodrug monitored by FLIM techniques, expanding the useful applications of FLIM technique in drug development.

5.
Cell Rep ; 31(8): 107682, 2020 May 26.
Artigo em Inglês | MEDLINE | ID: mdl-32460016

RESUMO

Recent breakthroughs in neuroanatomical tracing methods have helped unravel complicated neural connectivity in whole-brain tissue at single-cell resolution. However, in most cases, analysis of brain images remains dependent on highly subjective and sample-specific manual processing, preventing precise comparison across sample animals. In the present study, we introduce AMaSiNe, software for automated mapping of single neurons in the standard mouse brain atlas with annotated regions. AMaSiNe automatically calibrates misaligned and deformed slice samples to locate labeled neuronal positions from multiple brain samples into the standardized 3D Allen Mouse Brain Reference Atlas. We exploit the high fidelity and reliability of AMaSiNe to investigate the topographic structures of feedforward projections from the lateral geniculate nucleus to the primary visual area by reconstructing rabies-virus-injected brain slices in 3D space. Our results demonstrate that distinct organization of neural projections can be precisely mapped using AMaSiNe.

6.
Neuro Oncol ; 2020 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-32386320

RESUMO

BACKGROUND: Twenty-five germline variants are associated with adult diffuse glioma, and some of these variants have been shown to be associated with particular subtypes of glioma. We hypothesized that additional germline variants could be identified if a genome-wide association study (GWAS) was performed by molecular subtype. METHODS: A total of 1320 glioma cases and 1889 controls were used in the discovery set and 799 glioma cases and 808 controls in the validation set. Glioma cases were classified into molecular subtypes based on combinations of IDH mutation, TERT promoter mutation and 1p/19q codeletion. Logistic regression was applied to the discovery and validation sets to test for associations of variants with each of the subtypes. A meta-analysis was subsequently performed using a genome-wide p-value threshold of 5x10-8. RESULTS: Nine variants in or near D2HGDH on chromosome 2 were genome-wide significant in IDH-mutated glioma (most significant was rs5839764, meta p-value = 2.82x10-10). Further stratifying by 1p/19q codeletion status, one variant in D2HGDH was genome-wide significant in IDH-mutated non-codeleted glioma (rs1106639, meta p-value=4.96x10-8). Further stratifying by TERT mutation, one variant near FAM20C on chromosome 7 was genome-wide significant in gliomas that have IDH mutation, TERT mutation and 1p/19q codeletion (rs111976262, meta p-value=9.56x10-9). Thirty-six variants in or near GMEB2 on chromosome 20 near RTEL1 were genome-wide significant in IDH wild-type glioma (most significant was rs4809313, meta p-value=2.60x10-10). CONCLUSIONS: Performing a GWAS by molecular subtype identified two new regions, and a candidate independent region near RTEL1, that were associated with specific glioma molecular subtypes.

7.
Artigo em Inglês | MEDLINE | ID: mdl-32396105

RESUMO

Electronic medical records (EMRs) play an important role in medical data mining and sequential data learning. In this article, we propose to use a sequential neural network with dynamic content-based memories to predict future medications, given EMRs. The local-global memory neural network contains two layers of memories: the local memory and the global memory. Particularly, our method learns the hidden knowledge within EMRs by locally remembering individual patterns of a patient (via local memory) and globally remembering group evidence of disease (via global memory). In addition, we show how our model can be modified to classify the hidden states of EMRs from different patients at each time step into different phases that indicate the progressions of medications in terms of a specific disease, in an unsupervised manner. Experimental results on real EMRs data sets show that, by learning EMRs with external local and global memories, with regard to a given disease, our model improves the prediction performance compared with several alternative methods.

8.
Biomaterials ; 251: 120088, 2020 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-32388167

RESUMO

Hypoxia is one of the hallmarks of solid tumor, which heavily restricts the clinical cancer therapy treatments, especially for the oxygen (O2) -dependent photodynamic therapy (PDT). Herein, an intelligent multi-layer nanostructure was developed for decreasing the O2-consumption and elevating the O2-supply simultaneously. The cell respiration inhibitor -atovaquone (ATO) molecules were reserved in the middle mesoporous silicon layer, and thus were intelligently released at the tumor site after the degradation of gatekeeper of MnO2 layer, which effectively inhibit tumor respiration metabolism to elevate oxygen content. Meanwhile, the degradation of MnO2 layer can generate O2, further boosting oxygen content. Moreover, the inner upconversion nanostructures as the near infrared (NIR) light-transducers enable to activate photosensitizers for deep-tissue PDT. Systematic experiments demonstrate that this suppressing O2-consumption and O2-generation strategy improved oxygen supply to boost the singlet oxygen generation to eradicate cancer cells under NIR light excitation. Better still, superior trimodality imaging capabilities (computed tomography (CT), NIR-II window fluorescence, and tumor microenvironment-responsive T1-weighted magnetic resonance (MR) imaging) of the nanoplatform were evaluated. Our findings offer a promising aproach to conquer the serious hypoxia problem in cancer therapy by turning down the O2 metabolism aveneue and simultaneously generating O2.

9.
Poult Sci ; 99(5): 2444-2451, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32359579

RESUMO

Eimeria necatrix is a high pathogenic pathogen second to Eimeria tenella causing chicken coccidiosis. However, the precise underlying molecular mechanisms of interaction between E. necatrix and chickens are not fully understood. Accumulating evidences suggest that micro-RNAs (miRNAs) play pivotal regulatory roles in various diseases, including parasitic diseases. In the present study, the expression profile of miRNAs in Hy-line variety white chicken small intestines infected with E. necatrix was studied by using deep sequencing. A total of 35 miRNAs (including 16 significantly upregulated and 19 significantly downregulated miRNAs) were significantly differentially expressed (DE) in infected tissues at 108 h post-infection (pi). Real-time polymerase chain of 10 miRNAs (including 5 upregulated and 5 downregulated) randomly selected successfully confirmed the effectiveness of deep sequencing. Target prediction showed that 4,568 mRNAs could be regulated by 21 (including 12 upregulated and 9 downregulated) of 35 differentially expressed miRNAs. Functional analysis indicated that target genes of these differentially expressed miRNAs would be involved in pathways related to infection of E. necatrix, including cell differentiation, adhesion, proliferation, and apoptosis (e.g., MAPK signaling pathway and PPAR signaling pathway). To our best knowledge, this is the first study on the miRNA expression profile of small intestines during E. necatrix infection, and the findings in the present study suggested that these DE miRNAs would play important regulatory role in the interaction between E. necatrix and chicken intestines.

10.
J Dig Dis ; 2020 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-32378783

RESUMO

BACKGROUND: The performance of digestive doctors to diagnose the traditional Chinese medicine (TCM) syndrome of functional dyspepsia (FD) is unknown in China. The aim of the study was to compare the diagnostic agreement of TCM syndromes of FD, including postprandial distress syndrome (PDS) and epigastric pain syndrome (EPS) between the digestive doctors and TCM practitioners. METHODS: Patients with PDS or EPS were enrolled in six tertiary referral centers between January 2016 and December 2017. The TCM syndromes of the patients were first diagnosed by digestive doctors who performed TCM differential diagnosis based on the main symptoms. The TCM practitioners further diagnosed the TCM syndrome types of enrolled patients. The agreement of diagnosis between the digestive doctors and TCM practitioners was calculated. The demographic data and composition of TCM syndrome types were collected and analyzed. RESULTS: 160 patients including 81 PDS and 79 EPS were enrolled in this study. The total diagnosis consistency rate between the digestive doctors and TCM practitioners was 86.3%. The diagnosis consistency rate of PDS and EPS was 87.3% and 85.2%, respectively. The most common TCM syndrome type of PDS was liver-stomach disharmony syndrome (33.3%) and spleen-deficiency and Qi-stagnation syndrome (33.3%), while that for EPS was liver-stomach disharmony syndrome (36.7%). CONCLUSIONS: Digestive doctors had a high diagnostic agreement regarding the TCM syndrome types of FD based on the main symptoms differential diagnosis as compared to the TCM practitioners. This would aid the digestive doctors while selecting the Chinese patent medicine for FD based on syndrome differentiation. This article is protected by copyright. All rights reserved.

11.
Molecules ; 25(7)2020 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-32283819

RESUMO

Tetrandrine, a dibenzyltetrahydroisoquinoline alkaloid isolated from the root of the traditional Chinese medicinal plant Stephania tetrandra S. Moore, a member of the Menispermaceae, showed anti-cancer activity by inhibiting cell proliferation, preventing cell cycle progress and induction of cell death and autophagy. In this study, twelve tetrandrine-l-amino acid derivatives and twelve tetrandrine-14-l-amino acid-urea derivatives were designed and synthesized, using C14-aminotetrandrine as raw material. Then the preliminary in vitro anti-cancer activities of these derivatives against human breast cancer cell line MDA-MB-231, human leukemia cell lines HEL and K562 were evaluated. The in vitro cytotoxicity results showed that these derivatives exhibited potent inhibitory effects on cancer cell growth, and the primary structure-activity relationships were evaluated. Notably, compound 3f exhibited satisfactory anticancer activity against all three cancer cell lines, especially the HEL cell line, with the IC50 value of 0.23 µM. Further research showed that 3f could induce G1/S cycle arrest and apoptosis in a dose- and time- dependent manner on the leukemia cell line HEL. The results suggested that 3f may be used as a potential anti-cancer agent for human leukemia.

12.
Zhongguo Gu Shang ; 33(3): 261-4, 2020 Mar 25.
Artigo em Chinês | MEDLINE | ID: mdl-32233256

RESUMO

OBJECTIVE: To explore clinical effects of platelet rich plasma (PRP) injection in treating atrophic fracture nonunion. METHODS: From March 2015 to March 2017, 15 patients with atrophic fracture nonunion were treated with PRP injection, including 10 males and 5 females, aged from 23 to 56 years old with an average age of (40.0±9.1) years old, the time of fracture nonunion ranged from 6 to 14 months with an average of (8.87±2.45) months. Preparing PRP by extracting 60 to 100 ml peripheral blood. PRP platelet count ranged from 587 to 1 246 with an average of (947.13±158.58) ×10 9 /L. Under the perspective, 13 to 20 ml PRP were injected into the fracture end, and each injection was performed once on the first and the second week of the treatment. Complications such as whether the limb was shortened, angulation, and rotational deformity and radiological examination were observed. RESULTS: All patients were followed up from 6 to 12 months with an average of (6.8± 2.1) months. No shortening, angulation, and rotational deformity occurred. Thirteen patients had fracture healing, the time ranged from 4 to 6 months with an average of (4.8±0.7) months. Two patients had no completely porosis at 12 months during following up, and 1 patient occurred bolt loose. Other patients had no complications. CONCLUSION: The stability of fracture ends of atrophic fracture nonunion after internal fixation is an indication for local PRP injection. PRP treatment for atrophic fractures could completed under local anesthesia, and it has advantages of safe operation and reliable efficacy.


Assuntos
Fraturas não Consolidadas , Adulto , Feminino , Fixação Interna de Fraturas , Consolidação da Fratura , Fraturas não Consolidadas/tratamento farmacológico , Humanos , Masculino , Pessoa de Meia-Idade , Plasma Rico em Plaquetas , Resultado do Tratamento , Adulto Jovem
14.
IEEE Trans Cybern ; 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-32248142

RESUMO

The sliding-mode control (SMC) problem is studied in this article for state-saturated systems over a class of time-varying fading channels. The underlying fading channels, whose channel fading amplitudes (characterized by the expectation and variance) are allowed to be different, are modeled as a finite-state Markov process. A key feature of the problem addressed is to use a hidden Markov mode detector to estimate the actual network mode. The novel model of hidden Markov fading channels (HMFCs) is shown to be more general yet practical than the existing fading channel models. Based on a linear sliding surface, a switching-type SMC law is dedicatedly constructed by just using the estimated network mode. By exploiting the concept of stochastic Lyapunov stability and the approach of hidden Markov models, sufficient conditions are obtained for the resultant SMC systems that ensure both the mean-square stability and the reachability with a sliding region. With the aid of the Hadamard product, a binary genetic algorithm (GA) is developed to solve the proposed SMC design problem subject to some nonconvex constraints induced by the state saturations and the fading channels, where the proposed GA is based on the objective function for optimal reachability. Finally, a numerical example is employed to verify the proposed GA-assisted SMC scheme over the HMFCs.

15.
Parasit Vectors ; 13(1): 167, 2020 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-32245514

RESUMO

BACKGROUND: Eimeria necatrix, the most highly pathogenic coccidian in chicken small intestines, can cause high morbidity and mortality in susceptible birds and devastating economic losses in poultry production, but the underlying molecular mechanisms in interaction between chicken and E. necatrix are not entirely revealed. Accumulating evidence shows that the long-non-coding RNAs (lncRNAs) and circular RNAs (circRNAs) are key regulators in various infectious diseases. However, the expression profiles and roles of these two non-coding RNAs (ncRNAs) during E. necatrix infection are still unclear. METHODS: The expression profiles of mRNAs, lncRNAs and circRNAs in mid-segments of chicken small intestines at 108 h post-infection (pi) with E. necatrix were analyzed by using the RNA-seq technique. RESULTS: After strict filtering of raw data, we putatively identified 49,183 mRNAs, 818 lncRNAs and 4153 circRNAs. The obtained lncRNAs were classified into four types, including 228 (27.87%) intergenic, 67 (8.19%) intronic, 166 (20.29%) anti-sense and 357 (43.64%) sense-overlapping lncRNAs; of these, 571 were found to be novel. Five types were also predicted for putative circRNAs, including 180 exonic, 54 intronic, 113 antisense, 109 intergenic and 3697 sense-overlapping circRNAs. Eimeria necatrix infection significantly altered the expression of 1543 mRNAs (707 upregulated and 836 downregulated), 95 lncRNAs (49 upregulated and 46 downregulated) and 13 circRNAs (9 upregulated and 4 downregulated). Target predictions revealed that 38 aberrantly expressed lncRNAs would cis-regulate 73 mRNAs, and 1453 mRNAs could be trans-regulated by 87 differentially regulated lncRNAs. Additionally, 109 potential sponging miRNAs were also identified for 9 circRNAs. GO and KEGG enrichment analysis of target mRNAs for lncRNAs, and sponging miRNA targets and source genes for circRNAs identified associations of both lncRNAs and circRNAs with host immune defense and pathogenesis during E. necatrix infection. CONCLUSIONS: To the best of our knowledge, the present study provides the first genome-wide analysis of mRNAs, lncRNAs and circRNAs in chicken small intestines infected with E. necatrix. The obtained data will offer novel clues for exploring the interaction mechanisms between chickens and Eimeria spp.

16.
J Ultrasound Med ; 2020 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-32323353

RESUMO

Accurate diagnosis of splenic diseases is important for timely and accurate treatment. The objective of this study was to compare the accuracy of contrast-enhanced ultrasound (CEUS) and conventional ultrasound (US) in detecting splenic lesions. A systematic literature search was undertaken, and 8 studies met the inclusion criteria. The sensitivity and specificity of the consolidated results of CEUS were 0.95 (95% confidence interval [CI], 0.92-0.97) and 0.97 (95% CI, 0.90-0.99), respectively (I2 = 27.4%; area under the curve [AUC] from a summary receiver operating characteristic curve = 0.97). The sensitivity and specificity of the consolidated results of conventional US were 0.70 (95% CI, 0.56-0.80) and 0.96 (95% CI, 0.76-0.99; I2 = 83.4%; AUC = 0.84). In this systematic review and meta-analysis, the sensitivity and specificity of CEUS were higher than those of conventional US in diagnosing splenic lesions. Contrast-enhanced US is a promising method for accurately diagnosing splenic lesions.

17.
J Phys Chem Lett ; : 3672-3680, 2020 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-32298592

RESUMO

Energy transfer upconversion (ETU) can efficiently upconvert near-infrared photons into higher-energy photons. Although a comprehensive understanding of ETU is fundamental to the design of ETU materials, the basic excited-state decay kinetics of ETU remains a complicated problem. Here we unravel the mechanism underlying ETU decay in benchmark ß-NaYF4:Er3+ and ß-NaYF4:Ln3+/Yb3+ (Ln = Er, Ho, Tm) ETU microcrystals by combining rate equation analyses with ETU decay measurements. The results show that all of the excited states of one ETU system decay concordantly, with the ETU decay of the emitting state determined by only its intrinsic decay and the product of the ETU decays of the two intermediate states directly responsible for the emitting-state photon upconversion. This general mechanism may serve as a basic rule for excited-state kinetics in upconversion microparticles and nanoparticles, which could provide detailed insight into ETU processes and guide the design of efficient ETU materials.

18.
Biomed Res Int ; 2020: 9847591, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32190694

RESUMO

Aims: The aims of this study were to characterize nonatrophic and atrophic gastric mucosa under conventional endoscopy and probe-based confocal laser endomicroscopy (pCLE) modes and to define quantitative diagnostic parameters for these lesions under pCLE. Method: In phase I, 64 patients with gastric mucosal lesions diagnosed by gastrointestinal endoscopy were enrolled in the study. Normal mucosa and suspicious lesions were evaluated under normal white light imaging (WLI) and pCLE mode. Descriptive characteristic of gastric mucosal inflammation and atrophy under pCLE were defined according to the histology. In phase II, the criteria for nonatrophic gastritis (NAG) and chronic atrophic gastritis (CAG) under pCLE were used to diagnose the mucosal lesions in 431 patients. Diagnostic accuracy of each endoscopy modes was evaluated by measuring the concordance with histology. Result: A total of 64 patients with 187 positions were enrolled in the first part of this study. According to the histological diagnosis, the vessel diameter was increased in the NAG (11.18 ± 0.1 µm) and CAG (13.21 ± 0.29 µm) and CAG (13.21 ± 0.29 µm) and CAG (13.21 ± 0.29 µm) and CAG (13.21 ± 0.29 µm) and CAG (13.21 ± 0.29 µm) and CAG (13.21 ± 0.29 µm) and CAG (13.21 ± 0.29 . Conclusion: pCLE shows high potential for the diagnosis of gastric inflammation and atrophy based on quantitative criteria and has the ability to be a substitute for histology in the diagnosis of diffuse lesions in the stomach.

19.
Mol Ther ; 28(5): 1339-1358, 2020 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-32209436

RESUMO

The need to distribute therapy evenly systemically throughout the large muscle volume within the body makes Duchenne muscular dystrophy (DMD) therapy a challenge. Cell and exon-skipping therapies are promising but have limited effects, and thus enhancing their therapeutic potency is of paramount importance to increase the accessibility of these therapies to DMD patients. In this study, we demonstrate that co-administered glycine improves phosphorodiamidate morpholino oligomer (PMO) potency in mdx mice with marked functional improvement and an up to 50-fold increase of dystrophin in abdominal muscles compared to PMO in saline. Glycine boosts satellite cell proliferation and muscle regeneration by increasing activation of mammalian target of rapamycin complex 1 (mTORC1) and replenishing the one-carbon unit pool. The expanded regenerating myofiber population then results in increased PMO uptake. Glycine also augments the transplantation efficiency of exogenous satellite cells and primary myoblasts in mdx mice. Our data provide evidence that glycine enhances satellite cell proliferation, cell transplantation, and oligonucleotide efficacy in mdx mice, and thus it has therapeutic utility for cell therapy and drug delivery in muscle-wasting diseases.

20.
Nucleic Acids Res ; 48(8): 4081-4099, 2020 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-32187373

RESUMO

Cytosine methylation is a ubiquitous modification in mammalian DNA generated and maintained by several DNA methyltransferases (DNMTs) with partially overlapping functions and genomic targets. To systematically dissect the factors specifying each DNMT's activity, we engineered combinatorial knock-in of human DNMT genes in Komagataella phaffii, a yeast species lacking endogenous DNA methylation. Time-course expression measurements captured dynamic network-level adaptation of cells to DNMT3B1-induced DNA methylation stress and showed that coordinately modulating the availability of S-adenosyl methionine (SAM), the essential metabolite for DNMT-catalyzed methylation, is an evolutionarily conserved epigenetic stress response, also implicated in several human diseases. Convolutional neural networks trained on genome-wide CpG-methylation data learned distinct sequence preferences of DNMT3 family members. A simulated annealing interpretation method resolved these preferences into individual flanking nucleotides and periodic poly(A) tracts that rotationally position highly methylated cytosines relative to phased nucleosomes. Furthermore, the nucleosome repeat length defined the spatial unit of methylation spreading. Gene methylation patterns were similar to those in mammals, and hypo- and hypermethylation were predictive of increased and decreased transcription relative to control, respectively, in the absence of mammalian readers of DNA methylation. Introducing controlled epigenetic perturbations in yeast thus enabled characterization of fundamental genomic features directing specific DNMT3 proteins.

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