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1.
Br J Surg ; 2021 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-34792107

RESUMO

BACKGROUND: With local recurrence of rectal cancer continuing to decrease, distant recurrence is becoming a major concern, especially for patients with low- and intermediate-risk stage II/III rectal cancer. Therefore, a new treatment strategy is warranted for these patients. This single-arm phase II trial aimed to assess the effect of neoadjuvant chemotherapy (NCT) in low- and intermediate-risk stage II/III rectal cancer and explore candidate radiological and clinical parameters for early prediction of tumour response after two cycles of CAPOX. METHODS: Patients with mid-low stage II/III rectal cancer with low and intermediate risk were examined. The primary outcome was defined as a clinicopathological response by integrating tumour longitudinal length reduction (TLLR) on MRI into pathological tumour regression grade (TRG). After completing NCT, patients with TRG0-2 and TRG3 with a TLLR rate greater than 30 per cent were considered to be responders. Secondary outcomes included pathological complete response (pCR), adverse events and local and distant recurrence. RESULTS: This study enrolled 61 eligible patients. No patient was converted to neoadjuvant chemoradiotherapy owing to tumour progression. The clinicopathological response and pCR rates were 78.7 and 21.3 per cent respectively. After two cycles of CAPOX, TLLR, TRG on MRI, and mucosal lesion regression grade on endoscopy had potential discriminative ability (area under the curve greater than 0.7) for predicting both clinicopathological and pathological response. CONCLUSION: NCT alone achieves good tumour response rates in patients with low- and intermediate-risk stage II/III rectal cancer, and predicting tumour response to NCT is feasible at an early treatment phase. REGISTRATION NUMBER: NCT03666442 (http://www.clinicaltrials.gov).

2.
Anal Chem ; 93(42): 14161-14168, 2021 10 26.
Artigo em Inglês | MEDLINE | ID: mdl-34641671

RESUMO

Blockers of pore-forming toxins (PFTs) limit bacterial virulence by blocking relevant channel proteins. However, screening of desired blockers from a large pool of candidate molecules is not a trivial task. Acknowledging its advantages of low cost, high throughput, and multiplicity, DiffusiOptoPhysiology (DOP), an emerging nanopore technique that visually monitors the states of individual channel proteins without using any electrodes, has shown its potential use in the screening of channel blockers. By taking different α-hemolysin (α-HL) mutants as model PFTs and different cyclodextrins as model blockers, we report direct screening of pore blockers solely by using fluorescence microscopy. Different combinations of pores and blockers were simultaneously evaluated on the same DOP chip and a single-molecule resolution is directly achieved. The entire chip is composed of low-cost and biocompatible materials, which is fully disposable after each use. Though only demonstrated with cyclodextrin derivatives and α-HL mutants, this proof of concept has also suggested its generality to investigate other pore-forming proteins.


Assuntos
Toxinas Bacterianas , Ciclodextrinas , Nanoporos , Eletrodos , Proteínas Hemolisinas
3.
ACS Nano ; 15(10): 16913-16923, 2021 10 26.
Artigo em Inglês | MEDLINE | ID: mdl-34647449

RESUMO

The advent of localization-based super-resolution ultrasound (SRUS) imaging creates a vista for precision vasculature and hemodynamic measurements in brain science, cardiovascular diseases, and cancer. As blinking fluorophores are crucial to super-resolution optical imaging, blinking acoustic contrast agents enabling ultrasound localization microscopy have been highly sought, but only with limited success. Here we report on the discovery and characterization of a type of blinking acoustic nanodroplets (BANDs) ideal for SRUS. BANDs of 200-500 nm diameters comprise a perfluorocarbon-filled core and a shell of DSPC, Pluronic F68, and DSPE-PEG2000. When driven by clinically safe acoustic pulses (MI < 1.9) provided by a diagnostic ultrasound transducer, BANDs underwent reversible vaporization and reliquefaction, manifesting as "blinks", at rates of up to 5 kHz. By sparse activation of perfluorohexane-filled BANDs-C6 at high concentrations, only 100 frames of ultrasound imaging were sufficient to reconstruct super-resolution images of a no-flow tube through either cumulative localization or temporal radiality autocorrelation. Furthermore, the use of high-density BANDs-C6-4 (1 × 108/mL) with a 1:9 admixture of perfluorohexane and perfluorobutane supported the fast SRUS imaging of muscle vasculature in live animals, at 64 µm resolution requiring only 100 frames per layer. We anticipate that the BANDs developed here will greatly boost the application of SRUS in both basic science and clinical settings.


Assuntos
Piscadela , Meios de Contraste , Acústica , Animais , Imagem Óptica , Ultrassonografia
4.
Nat Commun ; 12(1): 5811, 2021 10 04.
Artigo em Inglês | MEDLINE | ID: mdl-34608151

RESUMO

Chemical reactions of single molecules, caused by rapid formation or breaking of chemical bonds, are difficult to observe even with state-of-the-art instruments. A biological nanopore can be engineered into a single molecule reactor, capable of detecting the binding of a monatomic ion or the transient appearance of chemical intermediates. Pore engineering of this type is however technically challenging, which has significantly restricted further development of this technique. We propose a versatile strategy, "programmable nano-reactors for stochastic sensing" (PNRSS), by which a variety of single molecule reactions of hydrogen peroxide, metal ions, ethylene glycol, glycerol, lactic acid, vitamins, catecholamines or nucleoside analogues can be observed directly. PNRSS presents a refined sensing resolution which can be further enhanced by an artificial intelligence algorithm. Remdesivir, a nucleoside analogue and an investigational anti-viral drug used to treat COVID-19, can be distinguished from its active triphosphate form by PNRSS, suggesting applications in pharmacokinetics or drug screening.


Assuntos
Técnicas Biossensoriais/instrumentação , Nanoporos , Inteligência Artificial , Processos Estocásticos
5.
Theor Appl Genet ; 2021 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-34665265

RESUMO

KEY MESSAGE: YrFDC12 and PbcFDC, co-segregated in chromosome 4BL, and significantly interacted with Yr30/Pbc1 to enhance stripe rust resistance and to promote pseudo-black chaff development. Cultivars with durable resistance are the most popular means to control wheat stripe rust. Durable resistance can be achieved by stacking multiple adult plant resistance (APR) genes that individually have relatively small effect. Chinese wheat cultivars Ruihua 520 (RH520) and Fengdecun 12 (FDC12) confer partial APR to stripe rust across environments. One hundred and seventy recombinant inbred lines from the cross RH520 × FDC12 were used to determine the genetic basis of resistance and identify genomic regions associated with stripe rust resistance. Genotyping was carried out using 55 K SNP array, and eight quantitative trait loci (QTL) were detected on chromosome arms 2AL, 2DS, 3BS, 4BL, 5BL (2), and 7BL (2) by inclusive composite interval mapping. Only QYr.nwafu-3BS from RH520 and QYr.nwafu-4BL.2 (named YrFDC12 for convenience) from FDC12 were consistent across the four testing environments. QYr.nwafu-3BS is likely the pleiotropic resistance gene Sr2/Yr30. YrFDC12 was mapped in a 2.1-cM interval corresponding to 12 Mb and flanked by SNP markers AX-111121224 and AX-89518393. Lines harboring both Yr30 and YrFDC12 displayed higher resistance than the parents and expressed pseudo-black chaff (PBC) controlled by loci Pbc1 and PbcFDC12, which co-segregated with Yr30 and YrFDC12, respectively. Both marker-based and pedigree-based kinship analyses revealed that YrFDC12 was inherited from founder parent Zhou 8425B. Fifty-four other wheat cultivars shared the YrFDC12 haplotype. These results suggest an effective pyramiding strategy to acquire highly effective, durable stripe rust resistance in breeding.

6.
Nanoscale ; 13(35): 15021-15030, 2021 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-34533142

RESUMO

Anaplastic thyroid carcinoma (ATC), as one of the most aggressive human malignancies, cannot be cured by 131iodine (131I) internal radiotherapy (RT) because the tumor cells cannot effectively take up 131I and are resistant to radiotherapy. In this study, a facile and simple method was proposed to synthesize mesoporous polydopamine nanoparticles (MPDA) and tailor their morphologies by component-adjusting Pluronic micelle-guided polymerization. Then, MPDA were used not only as nanocarriers to radiolabel 131I, but also as photothermal conversion agents for photothermal therapy (PTT) to promote RT. The iodine-labeling capacity and photothermal conversion efficiency of MPDA can be enhanced by optimizing their morphologies. It was found that MPDA NPs with a cerebroid pore channel structure (CPDA) showed the highest iodine-carrying capacity and a higher photothermal conversion efficiency as a result of their maximum specific surface area and unique morphology. In subsequent experiments in vitro and in vivo, our ATC animal models showed impressive therapeutic responses to CPDA-131I NPs because of the synergistic effect of PTT and RT. Additionally, CPDA-125I NPs can be utilized to obtain high-quality SPETC/CT images of tumors, which can guide clinical therapy for ATC. Considering their great biosafety, these radioiodine-labeled CPDA NPs may serve as a promising tool in combined therapy and diagnosis in ATC.


Assuntos
Nanopartículas , Carcinoma Anaplásico da Tireoide , Neoplasias da Glândula Tireoide , Animais , Humanos , Indóis , Radioisótopos do Iodo/uso terapêutico , Fototerapia , Polímeros , Carcinoma Anaplásico da Tireoide/diagnóstico por imagem , Carcinoma Anaplásico da Tireoide/terapia , Neoplasias da Glândula Tireoide/diagnóstico por imagem , Neoplasias da Glândula Tireoide/terapia
7.
Front Oncol ; 11: 723362, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34568051

RESUMO

Background: There is no effective prognostic signature that could predict the prognosis of nasopharyngeal carcinoma (NPC). Methods: We constructed a prognostic signature based on five microRNAs using random forest and Least Absolute Shrinkage And Selection Operator (LASSO) algorithm on the GSE32960 cohort (N = 213). We verified its prognostic value using three independent external validation cohorts (GSE36682, N = 62; GSE70970, N = 246; and TCGA-HNSC, N = 523). Through principal component analysis, receiver operating characteristic curve analysis, and C-index calculation, we confirmed the predictive accuracy of this prognostic signature. Results: We calculated the risk score based on the LASSO algorithm and divided the patients into high- and low-risk groups according to the calculated optimal cutoff value. The patients in the high-risk group tended to have a worse prognosis outcome and chemotherapy response. The time-dependent receiver operating characteristic curve showed that the 1-year overall survival rate of the five-microRNA signature had an area under the curve of more than 0.83. A functional annotation analysis of the five-microRNA signature showed that the patients in the high-risk group were usually accompanied by activation of DNA repair and MYC-target pathways, while the patients in the low-risk group had higher immune-related pathway signals. Conclusions: We constructed a five-microRNA prognostic signature, which could accurately predict the prognosis of nasopharyngeal carcinoma, and constructed a nomogram that could conveniently predict the overall survival of patients.

8.
Angew Chem Int Ed Engl ; 60(44): 23863-23870, 2021 10 25.
Artigo em Inglês | MEDLINE | ID: mdl-34449124

RESUMO

Recent developments concerning large protein nanopores suggest a new approach to structure profiling of native folded proteins. In this work, the large vestibule of Mycobacterium smegmatis porin A (MspA) and calmodulin (CaM), a Ca2+ -binding protein, were used in the direct observation of the protein structure. Three conformers, including the Ca2+ -free, Ca2+ -bound, and target peptide-bound states of CaM, were unambiguously distinguished. A disease related mutant, CaM D129G was also discriminated by MspA, revealing how a single amino acid replacement can interfere with the Ca2+ -binding capacity of the whole protein. The binding capacity and aggregation effect of CaM induced by different ions (Mg2+ /Sr2+ /Ba2+ /Ca2+ /Pb2+ /Tb3+ ) were also investigated and the stability of MspA in extreme conditions was evaluated. This work demonstrates the most systematic single-molecule investigation of different allosteric conformers of CaM, acknowledging the high sensing resolution offered by the MspA nanopore trap.

9.
Chem Sci ; 12(27): 9339-9346, 2021 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-34349904

RESUMO

Acknowledging its unique conical lumen structure, Mycobacterium smegmatis porin A (MspA) was the first type of nanopore that has successfully sequenced DNA. Recent developments of nanopore single molecule chemistry have also suggested MspA to be an optimum single molecule reactor. However, further investigations with this approach require heavy mutagenesis which is labor intensive and requires high end instruments for purifications. We here demonstrate an efficient and economic protocol which performs rapid and multiplex preparation of a variety of MspA mutants. The prepared MspA mutants were demonstrated in operations such as nanopore insertion, sequencing, optical single channel recording (oSCR), nanopore single molecule chemistry and nanopore rectification. The performance is no different from that of pores however prepared by other means. The time of all human operations and the cost for a single batch of preparation have been minimized to 40 min and 0.4$, respectively. This method is extremely useful in the screening of new MspA mutants, which has an urgent requirement in further investigations of new MspA nanoreactors. Its low cost and simplicity also enable efficient preparations of MspA nanopores for both industrial manufacturing and academic research.

10.
Bone Res ; 9(1): 37, 2021 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-34400611

RESUMO

A comprehensive understanding of the cellular heterogeneity and molecular mechanisms underlying the development, homeostasis, and disease of human intervertebral disks (IVDs) remains challenging. Here, the transcriptomic landscape of 108 108 IVD cells was mapped using single-cell RNA sequencing of three main compartments from young and adult healthy IVDs, including the nucleus pulposus (NP), annulus fibrosus, and cartilage endplate (CEP). The chondrocyte subclusters were classified based on their potential regulatory, homeostatic, and effector functions in extracellular matrix (ECM) homeostasis. Notably, in the NP, a PROCR+ resident progenitor population showed enriched colony-forming unit-fibroblast (CFU-F) activity and trilineage differentiation capacity. Finally, intercellular crosstalk based on signaling network analysis uncovered that the PDGF and TGF-ß cascades are important cues in the NP microenvironment. In conclusion, a single-cell transcriptomic atlas that resolves spatially regulated cellular heterogeneity together with the critical signaling that underlies homeostasis will help to establish new therapeutic strategies for IVD degeneration in the clinic.

11.
Front Pharmacol ; 12: 724416, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34305622

RESUMO

[This corrects the article DOI: 10.3389/fphar.2020.599577.].

12.
ACS Sens ; 6(8): 3082-3092, 2021 08 27.
Artigo em Inglês | MEDLINE | ID: mdl-34319692

RESUMO

Cisplatin, which selectively binds to N7 atoms of purines to inhibit normal replication and transcription, is a widely applied chemotherapeutic drug in the treatment of cancer. Though direct identification of cisplatin lesions on DNA is of great significance, existing sequencing methods have issues such as complications of preamplification or enrichment-induced false-positive reports. Direct identification of cisplatin lesions by nanopore sequencing (NPS) is in principle feasible. However, relevant investigations have never been reported. By constructing model sequences (83 nucleotides in length) containing a sole cisplatin lesion, identification of corresponding lesions by NPS is achieved with <10 ng of input sequencing library. Moreover, characteristic high-frequency noises caused by cisplatin lesions are consistently observed during NPS, clearly identifiable in corresponding high-pass filtered traces. This feature is, however, never observed in any other combinations of natural DNA bases and could be taken as a reference to identify cisplatin lesions on DNA. Further investigations demonstrate that cisplatin stalls the replication of phi29 DNA polymerase, which appears as a ∼5 pA level fluctuation in the single-molecule resolution. These results have confirmed the feasibility of NPS to identify cisplatin lesions at the genomic level and may provide new insights into understanding the molecular mechanism of platinum-based drugs.


Assuntos
Sequenciamento por Nanoporos , Nanoporos , Cisplatino , DNA/genética , DNA Polimerase Dirigida por DNA
13.
Nano Lett ; 21(15): 6703-6710, 2021 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-34319744

RESUMO

Diverse functions of proteins, including synthesis, catalysis, and signaling, result from their highly variable amino acid sequences. The technology allowing for direct analysis of protein sequences, however, is still unsatisfactory. Recent developments of nanopore sequencing of DNA or RNA have motivated attempts to realize nanopore sequencing of peptides in a similar manner. The core challenge has been to achieve a controlled ratcheting motion of the target peptide, which is currently restricted to a limited choice of compatible enzymes. By constructing peptide-oligonucleotide conjugates (POCs) and measurements with nanopore-induced phase-shift sequencing (NIPSS), direct observation of the ratcheting motion of peptides has been successfully achieved. The generated events show a clear sequence dependence on the peptide that is being tested. The method is compatible with peptides with either a conjugated N- or C-terminus. The demonstrated results suggest a proof of concept of nanopore sequencing of peptide and can be useful for peptide fingerprinting.


Assuntos
Nanoporos , Mycobacterium smegmatis , Nanotecnologia , Peptídeos , Porinas/genética
14.
Nat Commun ; 12(1): 4391, 2021 07 19.
Artigo em Inglês | MEDLINE | ID: mdl-34282140

RESUMO

Acquired heterotopic ossification (HO) is the extraskeletal bone formation after trauma. Various mesenchymal progenitors are reported to participate in ectopic bone formation. Here we induce acquired HO in mice by Achilles tenotomy and observe that conditional knockout (cKO) of fibroblast growth factor receptor 3 (FGFR3) in Col2+ cells promote acquired HO development. Lineage tracing studies reveal that Col2+ cells adopt fate of lymphatic endothelial cells (LECs) instead of chondrocytes or osteoblasts during HO development. FGFR3 cKO in Prox1+ LECs causes even more aggravated HO formation. We further demonstrate that FGFR3 deficiency in LECs leads to decreased local lymphatic formation in a BMPR1a-pSmad1/5-dependent manner, which exacerbates inflammatory levels in the repaired tendon. Local administration of FGF9 in Matrigel inhibits heterotopic bone formation, which is dependent on FGFR3 expression in LECs. Here we uncover Col2+ lineage cells as an origin of lymphatic endothelium, which regulates local inflammatory microenvironment after trauma and thus influences HO development via FGFR3-BMPR1a pathway. Activation of FGFR3 in LECs may be a therapeutic strategy to inhibit acquired HO formation via increasing local lymphangiogenesis.


Assuntos
Receptores de Proteínas Morfogenéticas Ósseas Tipo I/genética , Receptores de Proteínas Morfogenéticas Ósseas Tipo I/metabolismo , Vasos Linfáticos/metabolismo , Ossificação Heterotópica/metabolismo , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/genética , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/metabolismo , Tendão do Calcâneo , Animais , Modelos Animais de Doenças , Células Endoteliais/metabolismo , Endotélio Linfático/metabolismo , Técnicas de Silenciamento de Genes , Linfangiogênese , Masculino , Células-Tronco Mesenquimais , Camundongos , Tenotomia
15.
ANZ J Surg ; 91(10): 2199-2200, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34124826

RESUMO

Intestinal resection surgery for multiple intestinal vascular malformations in the blue rubber bleb nevus syndrome is traumatic and time-consuming. This study and Video S1 introduce a novel vascular malformation suture method to manage this problem without bowel resection.


Assuntos
Neoplasias Gastrointestinais , Nevo Azul , Neoplasias Cutâneas , Malformações Vasculares , Neoplasias Gastrointestinais/complicações , Neoplasias Gastrointestinais/cirurgia , Humanos , Nevo Azul/cirurgia , Neoplasias Cutâneas/cirurgia , Suturas , Malformações Vasculares/diagnóstico , Malformações Vasculares/diagnóstico por imagem
16.
J Clin Anesth ; 74: 110410, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34175638

RESUMO

STUDY OBJECTIVE: To determine whether ultrasound-guided serratus anterior plane block (SAPB) is associated with decreased prevalence of chronic postsurgical pain (CPSP) after modified radical mastectomy. DESIGN: Randomized, double-blind, placebo-controlled study. SETTING: University hospital. PATIENTS: We enrolled 198 patients aged 18-65 years with American Society of Anesthesiologists physical status I to II, undergoing unilateral modified radical mastectomy. INTERVENTIONS: Patients were randomly allocated to receive SAPB with 30 ml of 0.5% ropivacaine (SAPB group) or 0.9% normal saline (Control group). MEASUREMENTS: The primary outcome was the prevalence of CPSP three months after surgery. Secondary outcomes were area under the curve of the numeric rating scale pain scores over 24 h, postoperative 24-h morphine consumption, quality of recovery, length of post-anesthesia care unit stay, postoperative nausea and vomiting, dizziness, SAPB-related adverse events, the prevalence of CPSP at six months, and pain-related function at three and six months. MAIN RESULTS: Preoperative SAPB with 0.5% ropivacaine reduced the prevalence of CPSP at three postoperative months from 46/89 (51.7%) to 22/90 (25.6%), relative risk (95% confidence interval): 0.47 (0.31-0.72), P < 0.001. The prevalence of CPSP was reduced at six months from 37/89 (41.6%) to 17/90 (18.9%), relative risk (95% confidence interval): 0.72 (0.58-0.88), P = 0.001. Moreover, SAPB decreased the area under the curve of the numeric rating scale pain scores over 24 h, shortened the length of post-anesthesia care unit stay, reduced postoperative 24-h morphine consumption and the occurrence of postoperative nausea and vomiting, and improved quality of recovery and patient satisfaction, with P < 0.05 for all. No SAPB-related complications occurred. CONCLUSIONS: Preoperative SAPB with ropivacaine improved acute postoperative analgesia and quality of recovery and decreased the prevalence of CPSP at three and six months after modified radical mastectomy.

17.
ACS Sens ; 6(6): 2449-2456, 2021 06 25.
Artigo em Inglês | MEDLINE | ID: mdl-34107684

RESUMO

Protein nanopores can be engineered as nanoreactors to investigate single-molecule chemical reactions. Recent studies have demonstrated that Mycobacterium smegmatis porin A (MspA) nanopore is a superior engineering template acknowledging its geometrical advantages. However, reported engineering of MspA to form a nanoreactor has focused only on site 91 and mapping of other engineering sites have never been performed before. By taking tetrachloraurate(III) ([AuCl4]-) as a model reactant, potential engineering sites within the pore constriction of MspA have been thoroughly investigated. It is discovered that the produced event amplitude is inversely correlated to the cross-sectional diameter of the pore constriction size at the engineering site, providing evidence that site 91 is actually already the optimum place to introduce the chemical reactivity. Other unavailable engineering sites, which either significantly interfere with the pore assembly or produce reactive sites facing to the pore's exterior instead of to the pore lumen, were also spotted and discussed. All results demonstrated above have provided a complete map of engineering sites within the constriction area of MspA and may be beneficial as a reference in future engineering of corresponding nanoreactors.


Assuntos
Nanoporos , Porinas , Estudos Transversais , Mycobacterium smegmatis , Nanotecnologia
18.
Eur J Obstet Gynecol Reprod Biol ; 262: 216-220, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34062308

RESUMO

OBJECTIVE: To study the feasibility of a randomized controlled trial (RCT) comparing intrauterine insemination (IUI) with and without letrozole in couples with unexplained or mild male factor infertility STUDY DESIGN: We performed a randomized pilot study including 100 couples with unexplained or mild male factor infertility in the Reproductive Medicine Centre of Peking University Third Hospital in China. The couples scheduled for IUI were randomized to IUI with or without ovarian stimulation (letrozole) for up to 3 cycles within a time horizon of 4 months. Women in the letrozole group received 5 mg oral letrozole daily starting from cycle day 3-5 for 5 days. Women in the natural cycle IUI group did not receive any ovarian stimulation before IUI. The primary outcome is ongoing pregnancy leading to live birth. The study was registered under trial number NCT03455426 RESULTS: Between March 2018 and January 2019, 158 couples were eligible to participate after initial screening and 100 (63.3 %) couples agreed to participate. Of the 100 recruited couples, 50 were randomly allocated to IUI with letrozole and 50 to natural cycle IUI. Live birth occurred in 12 women (24.0 %) in the letrozole group and 10 women (20.0 %) in the natural cycle group (RR 1.20 (95 % CI 0.57-2.52)). Clinical pregnancy rates were 28 % and 26 % in the letrozole group and natural cycle group respectively (RR 1.08 (95 % CI 0.56-2.05). There were no multiple pregnancies in both groups. Patients were willing to be randomized and useful information was gained to plan a definitive trial. CONCLUSIONS: We showed that an RCT comparing IUI with letrozole versus natural cycle IUI in couples with unexplained or mild male factor infertility is feasible and acceptable.


Assuntos
Infertilidade Masculina , Infertilidade , China , Feminino , Humanos , Inseminação , Inseminação Artificial , Letrozol , Masculino , Indução da Ovulação , Projetos Piloto , Gravidez , Taxa de Gravidez
19.
Nat Commun ; 12(1): 3368, 2021 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-34099723

RESUMO

Folding of RNA can produce elaborate tertiary structures, corresponding to their diverse roles in the regulation of biological activities. Direct observation of RNA structures at high resolution in their native form however remains a challenge. The large vestibule and the narrow constriction of a Mycobacterium smegmatis porin A (MspA) suggests a sensing mode called nanopore trapping/translocation, which clearly distinguishes between microRNA, small interfering RNA (siRNA), transfer RNA (tRNA) and 5 S ribosomal RNA (rRNA). To further profit from the acquired event characteristics, a custom machine learning algorithm is developed. Events from measurements with a mixture of RNA analytes can be automatically classified, reporting a general accuracy of ~93.4%. tRNAs, which possess a unique tertiary structure, report a highly distinguishable sensing feature, different from all other RNA types tested in this study. With this strategy, tRNAs from different sources are measured and a high structural conservation across different species is observed in single molecule.


Assuntos
Mycobacterium smegmatis/metabolismo , Nanoporos , Porinas/metabolismo , RNA/metabolismo , Aprendizado de Máquina , MicroRNAs/química , MicroRNAs/genética , MicroRNAs/metabolismo , Simulação de Dinâmica Molecular , Peso Molecular , Mycobacterium smegmatis/genética , Conformação de Ácido Nucleico , Porinas/química , Porinas/genética , RNA/química , RNA/genética , Dobramento de RNA , Transporte de RNA , RNA Ribossômico 5S/química , RNA Ribossômico 5S/genética , RNA Ribossômico 5S/metabolismo , RNA Interferente Pequeno/química , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , RNA de Transferência/química , RNA de Transferência/genética , RNA de Transferência/metabolismo
20.
Elife ; 102021 05 25.
Artigo em Inglês | MEDLINE | ID: mdl-34032212

RESUMO

Disparate redox activities that take place beyond the bounds of the prokaryotic cell cytosol must connect to membrane or cytosolic electron pools. Proteins post-translationally flavinylated by the enzyme ApbE mediate electron transfer in several characterized extracytosolic redox systems but the breadth of functions of this modification remains unknown. Here, we present a comprehensive bioinformatic analysis of 31,910 prokaryotic genomes that provides evidence of extracytosolic ApbEs within ~50% of bacteria and the involvement of flavinylation in numerous uncharacterized biochemical processes. By mining flavinylation-associated gene clusters, we identify five protein classes responsible for transmembrane electron transfer and two domains of unknown function (DUF2271 and DUF3570) that are flavinylated by ApbE. We observe flavinylation/iron transporter gene colocalization patterns that implicate functions in iron reduction and assimilation. We find associations with characterized and uncharacterized respiratory oxidoreductases that highlight roles of flavinylation in respiratory electron transport chains. Finally, we identify interspecies gene cluster variability consistent with flavinylation/cytochrome functional redundancies and discover a class of 'multi-flavinylated proteins' that may resemble multi-heme cytochromes in facilitating longer distance electron transfer. These findings provide mechanistic insight into an important facet of bacterial physiology and establish flavinylation as a functionally diverse mediator of extracytosolic electron transfer.


Assuntos
Bactérias/metabolismo , Citosol/metabolismo , Dinitrocresóis/metabolismo , Processamento de Proteína Pós-Traducional , Oxirredução
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