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1.
J Cell Mol Med ; 2021 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-33951279

RESUMO

MicroRNAs have emerged as essential regulators in the biological process of liver regeneration by modulating the post-transcriptional expression of the target genes. In the present study, we found miR-20a expression is decreased remarkably in three rodent liver regeneration models using miRNA PCR array and Venn diagram analysis. Inhibition of miR-20a expression enhanced hepatocytes proliferation in vivo and in vitro. In contrast, overexpression of miR-20a reduces hepatocytes proliferation and subsequently impaired liver regeneration in the mouse PHx model. Moreover, we have identified TCF4 as a target gene of miR-20a using the PCR Array and luciferase assay. Next, mice with TCF4 deficiency were used to establish the PHx model and subjected to the examination of liver regeneration capacity. We found TCF4-deficient mice exhibited impaired liver regeneration compared with control. Given that TCF4 acts as a transcription factor, we sort to elucidate the downstream genes involved in liver regeneration. Promoter analysis and Chip assay confirmed that TCF4 enhances CDC2 and CDC6 expression through binding to the promoter region and leads to the proliferation and cell cycle progression in hepatocytes. In conclusion, this study provides evidence that the miR20a-TCF4-CDC2/6 axis plays an essential role during liver regeneration.

2.
Phys Ther Sport ; 50: 89-96, 2021 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-33940556

RESUMO

OBJECTIVE: To review past literature regarding exercise-induced hypoalgesia and pain reduction following blood flow restriction interventions, and to discuss potential mechanisms as well as future considerations towards the efficacy of blood flow restriction in pain reduction following exercise. METHODS: To be eligible for inclusion, studies had to include acute exercise, or long-term training interventions, with blood flow restriction, along with including pre and post intervention pain measurements. RESULTS: A total of 13 studies met the inclusion criteria. Among these 13 studies, 3 studies examined exercise-induced hypoalgesia after an acute bout of resistance exercise with blood flow restriction, and 10 studies investigated pain reduction following long-term blood flow restriction training. CONCLUSIONS: Existing literature suggests that low load resistance exercise with blood flow restriction may serve as an effective pain management method for those who are unable or unwilling to train with high loads. Several potential mechanisms have been suggested, however, the roles of these mechanisms are still unclear and require further clarification. Future research should consider implementing different methods of blood flow restriction application, and research study design to clarify the utility and efficacy of blood flow restriction as a pain management tool, by itself or in combination with exercise.

3.
Medicine (Baltimore) ; 100(18): e25880, 2021 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-33951002

RESUMO

ABSTRACT: Whether breast-conserving therapy (BCT) should be chosen as a local treatment for young women with early-stage breast cancer is controversial. This study compared the survival benefits of BCT or mastectomy in young women under 40 with early-stage breast cancer and further explored age-stratified outcomes. This study investigated whether there is a survival benefit when young women undergo BCT compared with mastectomy.The characteristics and prognosis of white women under 40 with stage I-II breast cancer from 1988 to 2016 were analyzed using the Surveillance, Epidemiology, and End Results (SEER) database. These women were either treated with BCT or mastectomy. The log-rank test of the Kaplan-Meier survival curve and Cox proportional risk regression model were used to analyze the data and survival. The analysis was stratified by age (18-35 and 36-40 years).A total of 23,810 breast cancer patients were included, of whom 44.9% received BCT and 55.1% underwent mastectomy, with a median follow-up of 116 months. Patients undergoing mastectomy had a higher tumor burden and younger age. By the end of the 20th century, the proportion of BCT had grown from nearly 35% to approximately 60%, and then gradually fell to 35% into the 21st century. Compared with the mastectomy group, the BCT group had improved breast cancer-specific survival (BCSS) (hazard ratio [HR] 0.917; 95% CI, 0.846-0.995, P = .037) and overall survival (OS) (HR 0.925; 95% CI, 0.859-0.997, P = .041). In stratified analysis according to the different ages, the survival benefit of BCT was more pronounced in the slightly older (36-40 years) group while there was no significant survival difference in the younger group (18-35 years).In young women with early-stage breast cancer, BCT showed survival benefits that were at least no worse than mastectomy, and these benefits were even better in the 36 to 40 years age group. Young age may not be a contraindication for BCT.

4.
J Chem Inf Model ; 2021 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-33913713

RESUMO

We present a systematic approach for the identification of statistically relevant conformational macrostates of organic molecules from molecular dynamics trajectories. The approach applies to molecules characterized by an arbitrary number of torsional degrees of freedom and enables the transferability of the macrostates definition across different environments. We formulate a dissimilarity measure between molecular configurations that incorporates information on the characteristic energetic cost associated with transitions along all relevant torsional degrees of freedom. Such metric is employed to perform unsupervised clustering of molecular configurations based on the Fast Search and Find of Density Peaks algorithm. We apply this method to investigate the equilibrium conformational ensemble of Sildenafil, a conformationally complex pharmaceutical compound, in different environments including the crystal bulk, the gas phase, and three different solvents (acetonitrile, 1-butanol, and toluene). We demonstrate that while Sildenafil can adopt more than 100 metastable conformational configurations, only 12 are significantly populated across all of the environments investigated. Despite the complexity of the conformational space, we find that the most abundant conformers in solution are the closest to the conformers found in the most common Sildenafil crystal phase.

5.
Cells ; 10(4)2021 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-33801626

RESUMO

Muscle tissue is often removed during hamstring tendon graft preparation for anterior cruciate ligament (ACL) reconstruction. The purpose of the study was to test whether preservation of muscle remnants on a tendon graft is beneficial to the graft healing process following ACL reconstruction. Co-culturing of tendon-derived cells (TDCs) and muscle-derived cells (MDCs) was performed at various ratios, and their potential for cell viability and multilineage differentiation was compared to a single TDC cell group. Ligamentous and chondrogenic differentiation was most enhanced when a small population of MDCs was co-cultured with TDCs (6:2 co-culture group). Cell viability and osteogenic differentiation were proportionally enhanced with increasing MDC population size. MDCs co-cultured with TDCs possess both the ability to enhance cell viability and differentiate into other cell lineages.

6.
Virulence ; 12(1): 1199-1208, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-33870852

RESUMO

Background: COVID-19 has rapidly become a major health emergency worldwide. The characteristic, outcome, and risk factor of COVID-19 in patients with decompensated cirrhosis remain unclear.Methods: Medical records were collected from 23 Chinese hospitals. Patients with decompensated cirrhosis and age- and sex-matched non-liver disease patients were enrolled with 1:4 ratio using stratified sampling.Results: There were more comorbidities with higher Chalson Complication Index (p < 0.001), higher proportion of patients having gastrointestinal bleeding, jaundice, ascites, and diarrhea among those patients (p < 0.05) and in decompensated cirrhosis patients. Mortality (p < 0.05) and the proportion of severe ill (p < 0.001) were significantly high among those patients. Patients in severe ill subgroup had higher mortality (p < 0.001), MELD, and CRUB65 score but lower lymphocytes count. Besides, this subgroup had larger proportion of patients with abnormal (PT), activated partial thromboplatin time (APTT), D-Dimer, alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBL) and Creatinine (Cr) (p < 0.05). Multivariate logistic regression for severity shown that MELD and CRUB65 score reached significance. Higher Child-Pugh and CRUB65 scores were found among non-survival cases and multivariate logistic regression further inferred risk factors for adverse outcome. Receiver Operating Characteristic (ROC) curves also provided remarkable demonstrations for the predictive ability of Child-Pugh and CRUB65 scores.Conclusions: COVID-19 patients with cirrhosis had larger proportion of more severely disease and higher mortality. MELD and CRUB65 score at hospital admission may predict COVID-19 severity while Child-Pugh and CRUB65 score were highly associated with non-survival among those patients.


Assuntos
/mortalidade , Cirrose Hepática/complicações , Índice de Gravidade de Doença , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco
7.
Org Biomol Chem ; 2021 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-33908557

RESUMO

A series of unnatural tripeptides, each consisting of two aromatic γ-amino acid residues and an ϖ-amino acid residue, are designed to probe their folding into hairpin conformations. The ϖ-amino acid residues, with aliphatic or aromatic spacers of different sizes, serve as the loop of the hairpins. Studies based on one-dimensional (1D) 1H NMR performed at different concentrations, solvent polarity, and temperature, along with 2D-NMR studies, demonstrated that the doubly H-bonded aromatic γ-amino acid residues play important roles in driving these tripeptides into the hairpin conformation. The loop based on 5-aminovaleric acid, which offers a four-carbon (CH2)4 spacer, enhanced the stability of the corresponding hairpin, while loops having a shorter, a longer and a more rigid spacer disfavored the formation of the hairpins. Results from computational studies are in good agreement with the experimental observations. Furthermore, the crystal structure of peptide 1b revealed the expected hairpin conformation in the solid state. This turn motif, which contains H-bonded aromatic γ-amino acid residues as the core unit and an ϖ-amino acid residue serving as the loop, provides a new platform that can be used to obtain a variety of turn conformations by incorporating diverse amino acids into the loops.

8.
Transpl Int ; 2021 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-33811394

RESUMO

Severe pulmonary hypertension (PHT) is a contraindication to liver transplantation (LT); however, the prognostic implication of mild to moderate PHT in living-donor LT (LDLT) is unknown. The study cohort retrospectively included 1307 patients with liver cirrhosis who underwent LDLT. PHT was defined as a mean pulmonary artery pressure (PAP) of ≥25 mmHg, measured intraoperatively just before surgery. The primary endpoint was graft failure within 1 year after LDLT, including retransplantation or death from any cause. The secondary endpoints were in-hospital adverse events. In the overall cohort, the median Model for End-stage Liver Disease-Sodium (MELD-Na) score was 19, and 100 patients (7.7%) showed PHT. During 1-year follow-up, graft failure occurred in 94 patients (7.2%). Patients with PHT had lower 1-year graft survival (86% vs. 93.4%, P = 0.005) and survival rates (87% vs. 93.6%, P = 0.011). Mean PAP was associated with a high risk of in-hospital adverse events and 1-year graft failure. Adding the mean PAP to the clinical risk model improved the risk prediction. In conclusion, mild to moderate PHT was associated with higher risks of 1-year graft failure and in-hospital events, including mortality after LDLT in patients with liver cirrhosis. Intraoperative mean PAP can help predict the early clinical outcomes after LDLT.

9.
Dent Mater ; 2021 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-33867171

RESUMO

OBJECTIVE: Clasps of removable partial dentures (RPDs) often suffer from fatigue stress that leads to plastic deformation, loss of retention, and RPD failure. Recently, computer-based technologies were proposed to optimize clasp geometry design. The objective of this study was to create an analytic model of I-bar clasps for computer-aided design (CAD)-RPD. METHODS: The analytical model based on mechanical laws was established to simulate I-bar clasp retention, and optimize its design. The model considered the lengths of the vertical (L1) and horizontal (L2) arms of the I-bar as well as the radius (r) of its half-round cross-section. The analytical model was validated with mechanical experiments evaluating the retention of cobalt-chromium (Co-Cr) clasps in vitro and compared with finite element analysis (FEA). RESULTS: The analytical model was in good agreement with the mechanical experiments and FEA, and showed that I-bar clasp design could provide optimal mechanical performance as long as the length of arms (L1 and L2) do not exceed 6 mm. Clasps with L1 > 8 mm and L2 > 9 mm presented stress values exceeding the fatigue limit of Co-Cr. The proposed solution was to increase the radius of I-bar to conserve the initial mechanical performance of Co-Cr. SIGNIFICANCE: Co-Cr I-bar clasps perform best on teeth with reduced mesiodistal dimensions (canine and premolar), and their designs could be optimized to prevent stress from reaching the yield strength and the fatigue failure limit.

10.
Medicine (Baltimore) ; 100(14): e25467, 2021 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-33832159

RESUMO

RATIONALE: Coronavirus disease 2019 (COVID-19) is a disease caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which commonly presents with symptoms including fever, cough, and dyspnea. More recently, however, some patients have tested positive for COVID-19 after developing gastrointestinal (GI) symptoms either solely or in conjunction with respiratory symptoms. This may be due to SARS-CoV-2 infection of the GI tract. In patients with chronic GI illnesses, COVID-19 may initially present as a flare of their underlying GI conditions as viruses have historically been implicated in exacerbations of GI disorders, including gastroparesis. PATIENT CONCERNS: We report a case of a 37-year-old female with a history of diabetic gastroparesis who presented to the Emergency Department (ED) with nausea and vomiting similar to her gastroparesis flares. DIAGNOSES: Her symptoms in the ED failed to improve with fluids and anti-emetic medications. After developing a fever, she was tested and found to be positive for COVID-19. INTERVENTIONS: She was started on antibiotic, steroid, and antiviral medications. OUTCOMES: Her symptoms improved, her fever defervesced on day 4 of hospitalization, and she was discharged on day 5 of hospitalization. The patient reported symptom improvement at a follow-up outpatient gastroenterology visit 2 months after hospitalization. LESSONS: To the best of our knowledge, at the present time, this is the first report of a patient with COVID-19 presenting with signs and symptoms of a gastroparesis flare. This case illustrates that COVID-19 may present in an exacerbation of symptoms of an underlying disorder, such as a severe gastroparesis flare, in a patient with underlying gastroparesis. Initial presentation of these patients manifesting as a flare of their chronic GI disease, more severe than usual, should prompt an index of suspicion for COVID-19.


Assuntos
/complicações , Complicações do Diabetes/complicações , Complicações do Diabetes/fisiopatologia , Gastroparesia/fisiopatologia , Adulto , Feminino , Humanos
11.
BMC Cancer ; 21(1): 426, 2021 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-33865364

RESUMO

BACKGROUND: In the era of immunotherapy, it is still unclear which is the best first-line therapy for patients with oncogenic driver negative advanced non-squamous non-small cell lung cancer (NS-NSCLC) who cannot tolerate immunotherapy, or subsequent therapy for patients with oncogenic driver positive NS-NSCLC whose disease progressed on prior targeted therapy. To assess the optimal choice of first-line and maintenance treatment regimens, we performed a meta-analysis of prospective randomized controlled clinical trials (RCTs) of patients with NS-NSCLC on bevacizumab combined with chemotherapy. METHODS: All eligible RCTs comparing pemetrexed-platinum with or without bevacizumab (PP ± B) and paclitaxel-carboplatin with bevacizumab (PC + B) as a first-line therapy, or comparing bevacizumab plus pemetrexed (Pem + B) and bevacizumab alone (B) as a maintenance treatment for advanced NS-NSCLC, were included after systematically searching web databases and meeting abstracts. The main research endpoints were comparisons of overall survival (OS) and progression-free survival (PFS). The other endpoints were objective response rate (ORR), 1-year PFS rate (PFSR1y) and major grade 3/4 treatment-related adverse events. RESULTS: Data of 3139 patients from six RCTs were incorporated into analyses. Three RCTs were included in an analysis that compared PP ± B and PC + B as a first-line therapy for advanced NS-NSCLC. Patients treated with first-line PP ± B showed similar OS and ORR, but significantly improved PFS (hazard ratio [HR], 0.88) and PFSR1y (risk ratio [RR], 0.83), as compared to patients treated with PC + B (all P < 0.05). PP ± B resulted in higher rates of grade 3/4 anemia and thrombocytopenia, but lower rates of neutropenia, febrile neutropenia, and sensory neuropathy than PC + B (all P < 0.001). The other three RCTs were included in an analysis that compared Pem + B and B as a maintenance treatment. Compared with B, Pem + B maintenance treatment resulted in significant improvements in OS (HR, 0.88), PFS (HR, 0.64), and PFSR1y (RR, 0.70), but higher rates of anemia, thrombocytopenia, and neutropenia (all P < 0.001). CONCLUSION: Although the first-line PP + B regimen had longer PFS and PFSR1y than the PC + B regimen, no OS difference was observed. Addition of pemetrexed to bevacizumab as maintenance therapy significantly improved OS compared with bevacizumab maintenance alone, but led to more toxicity.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bevacizumab/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Feminino , Humanos , Quimioterapia de Indução , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/mortalidade , Quimioterapia de Manutenção , Masculino , Metástase Neoplásica , Estadiamento de Neoplasias , Paclitaxel/administração & dosagem , Pemetrexede/administração & dosagem , Viés de Publicação , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento
12.
FASEB J ; 35(5): e21371, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33811694

RESUMO

Studies demonstrate a role for neurotensin (NT) in obesity and related comorbidities. Bile acid (BA) homeostasis alterations are associated with obesity. We determined the effect of NT on BA metabolism in obese and non-obese conditions. Plasma and fecal BA profiles were analyzed by LC-MS/MS in male and female NT+/+ and NT-/- mice fed low-fat (LFD) or high-fat diet (HFD) for 6 weeks (early stage of obesity) or greater than 20 weeks (late stage of obesity). The nuclear farnesoid X receptor (FXR) and BA transporter mRNA expression were assessed in ileum, mouse enteroids, and human cell lines. HFD decreased plasma primary and secondary BAs in NT+/+ mice; HFD-induced decrease of plasma BAs was improved in NT-deficient mice. In NT+/+ mice, HFD inhibited ileal FXR and BA transporter expression; HFD-decreased expression of FXR and BA transporters was prevented in NT-/- mice. Compared with LFD-fed NT+/+ mice, LFD-fed NT-/- mice had relatively lower levels of ileal FXR and BA transporter expression. Moreover, NT stimulates the expression of FXR and BA transporters in Caco-2 cells; however, stimulated expression of BA transporters was attenuated in NT-/- enteroids. Therefore, we demonstrate that HFD disrupts the BA metabolism and ileal FXR and BA transporter axis which are improved in the absence of NT, suggesting that NT contributes to HFD-induced disruption of BA metabolism and plays an inhibitory role in the regulation of ileal FXR and BA transporter signaling under obese conditions. Conversely, NT positively regulates the expression of ileal FXR and BA transporters under non-obese conditions. Therefore, NT plays a dual role in obese and non-obese conditions, suggesting possible therapeutic strategies for obesity control.

13.
Mater Sci Eng C Mater Biol Appl ; 123: 112010, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33812629

RESUMO

A truly bioinspired approach to design optimization should follow the energetically favorable natural paradigm of "minimum inventory with maximum diversity". This study was inspired by constructive regression of trabecular bone - a natural process of network connectivity optimization occurring early in skeletal development. During trabecular network optimization, the original excessively connected network undergoes incremental pruning of redundant elements, resulting in a functional and adaptable structure operating at lowest metabolic cost. We have recapitulated this biological network topology optimization algorithm by first designing in silico an excessively connected network in which elements are dimension-independent linear connections among nodes. Based on bioinspired regression principles, least-loaded connections were iteratively pruned upon simulated loading. Evolved networks were produced along this optimization trajectory when pre-set convergence criteria were met. These biomimetic networks were compared to each other, and to the reference network derived from mature trabecular bone. Our results replicated the natural network optimization algorithm in uniaxial compressive loading. However, following triaxial loading, the optimization algorithm resulted in lattice networks that were more stretch-dominated than the reference network, and more capable of uniform load distribution. As assessed by 3D printing and mechanical testing, our heuristic network optimization procedure opens new possibilities for parametric design.

14.
ACS Nano ; 2021 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-33900074

RESUMO

Proteins, a type of natural biopolymer that possess many prominent merits, have been widely utilized to engineer nanomedicine for fighting against cancer. Motivated by their ever-increasing attention in the scientific community, this review aims to provide a comprehensive showcase on the current landscape of protein-based nanomedicine for cancer therapy. On the basis of role differences of proteins in nanomedicine, protein-based nanomedicine engineered with protein therapeutics, protein carriers, enzymes, and composite proteins is introduced. The cancer therapeutic benefits of the protein-based nanomedicine are also discussed, including small-molecular therapeutics-mediated therapy, macromolecular therapeutics-mediated therapy, radiation-mediated therapy, reactive oxygen species-mediated therapy, and thermal effect-mediated therapy. Lastly, future developments and potential challenges of protein-based nanomedicine are elucidated toward clinical translation. It is believed that protein-based nanomedicine will play a vital role in the battle against cancer. We hope that this review will inspire extensive research interests from diverse disciplines to further push the developments of protein-based nanomedicine in the biomedical frontier, contributing to ever-greater medical advances.

15.
Molecules ; 26(7)2021 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-33916390

RESUMO

In the present study, a simple and environmentally friendly extraction method based on natural deep eutectic solvents (NADESs) was established to extract four bioactive steroidal saponins from Dioscoreae Nipponicae Rhizoma (DNR). A total of twenty-one types of choline chloride, betaine, and L-proline based NADESs were tailored, and the NADES composed of 1:1 molar ratio of choline chloride and malonic acid showed the best extraction efficiency for the four steroidal saponins compared with other NADESs. Then, the extraction parameters for extraction of steroidal saponins by selected tailor-made NADES were optimized using response surface methodology and the optimal extraction conditions are extraction time, 23.5 min; liquid-solid ratio, 57.5 mL/g; and water content, 54%. The microstructure of the DNR powder before and after ultrasonic extraction by conventional solvents (water and methanol) and the selected NADES were observed using field emission scanning electron microscope. In addition, the four steroidal saponins were recovered from NADESs by D101 macroporous resin with a satisfactory recovery yield between 67.27% and 79.90%. The present research demonstrates that NADESs are a suitable green media for the extraction of the bioactive steroidal saponins from DNR, and have a great potential as possible alternatives to organic solvents for efficiently extracting bioactive compounds from natural products.

16.
Biomolecules ; 11(4)2021 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-33920120

RESUMO

As a traditional medicine with potential antioxidant effects, Tenodera angustipennis egg cases (Mantidis ootheca) are a potential source of new bioactive substances. Herein, three new N-acetyldopamine derivatives, namely, (+)-tenoderin A (1a), (-)-tenoderin A (1b), and tenoderin B (2), along with thirteen known compounds (3-15), were isolated from a 70% EtOH extract of T. angustipennis egg cases. Compound 1 was isolated as a racemic mixture, and two enantiomers (1a and 1b) were successfully separated by chiral-phase preparative HPLC. The chemical structures of the new compounds were established by NMR spectroscopy and high-resolution electrospray ionization mass spectrometry, and the absolute configurations of enantiomers 1a and 1b were determined by electronic circular dichroism spectroscopy. All the new compounds exhibited antioxidant activities with IC50 values of 19.45-81.98 µM, as evaluated using free-radical scavenging assays, with the highest activity observed for compound 2. In addition, compounds 1a, 1b, and 2 exhibited inhibitory activities on intracellular reactive oxygen species generation.

17.
Genes (Basel) ; 12(4)2021 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-33920780

RESUMO

Understanding the recognition of specific epitopes by cytotoxic T cells is a central problem in immunology. Although predicting binding between peptides and the class I Major Histocompatibility Complex (MHC) has had success, predicting interactions between T cell receptors (TCRs) and MHC class I-peptide complexes (pMHC) remains elusive. This paper utilizes a convolutional neural network model employing deep metric learning and multimodal learning to perform two critical tasks in TCR-epitope binding prediction: identifying the TCRs that bind a given epitope from a TCR repertoire, and identifying the binding epitope of a given TCR from a list of candidate epitopes. Our model can perform both tasks simultaneously and reveals that inconsistent preprocessing of TCR sequences can confound binding prediction. Applying a neural network interpretation method identifies key amino acid sequence patterns and positions within the TCR, important for binding specificity. Contrary to common assumption, known crystal structures of TCR-pMHC complexes show that the predicted salient amino acid positions are not necessarily the closest to the epitopes, implying that physical proximity may not be a good proxy for importance in determining TCR-epitope specificity. Our work thus provides an insight into the learned predictive features of TCR-epitope binding specificity and advances the associated classification tasks.

18.
Artigo em Inglês | MEDLINE | ID: mdl-33834597

RESUMO

Azolium cumulenolates are a special type of intermediates in N-heterocyclic carbene catalysis. They contain elongated linear structures with three contiguous C=C bonds and sterically unhindered α-carbon. These structure features make it difficult to develop enantioselective reactions for these intermediates. Here we disclose the first carbene-catalyzed highly enantioselective addition reactions of azolium cumulenolates. The reaction starts with alkynals as the precursors for azolium cumulenolate intermediates that undergo enantioselective addition to activated ketones. From the same set of substrates, both allene and spirooxindole products can be obtained with high yields and excellent enantioselectivities. The allene moieties in our optically enriched products carry rich reactivities and can be transformed to diverse molecules. The spirooxindole scaffolds in our products are important structural motifs in natural products and medicines.

19.
Front Cell Infect Microbiol ; 11: 579386, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33834002

RESUMO

Gut microbiota alterations occur in end-stage renal disease (ESRD) patients with or without dialysis. However, it remains unclear whether changes in gut microbiota of dialysis ESRD patients result from dialysis or ESRD, or both. Similarly, there is a dearth of information on the relationship between gut microbiota and ESRD prognoses. We collected fecal samples and tracked clinical outcomes from 73 ESRD patients, including 33 pre-dialysis ESRD patients, 19 peritoneal dialysis (PD) patients, and 21 hemodialysis (HD) patients. 16S rRNA sequencing and bioinformatics tools were used to analyze the gut microbiota of ESRD patients and healthy controls. Gut microbiota diversity was different before and after dialysis. Bacteroidetes were significantly deceased in HD patients. Twelve bacterial genera exhibited statistically significant differences, due to dialysis (all P < 0.05, FDR corrected). HD reversed abnormal changes in Oscillospira and SMB53 in pre-dialysis patients. Functional predictions of microbial communities showed that PD and HD altered signal transduction and metabolic pathways in ESRD patients. Furthermore, Bacteroides and Phascolarctobacterium were associated with cardiovascular mortality. Dorea, Clostridium, and SMB53 were related to peritonitis in PD patients. This study not only demonstrated differences in gut microbiota between pre-dialysis and dialysis ESRD patients, but also firstly proposed gut bacteria may exert an impact on patient prognosis.

20.
Chemistry ; 2021 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-33792092

RESUMO

Transition-metal phosphates have been widely applied as promising candidates for electrochemical energy storage and conversion fields. In this study, we report a simple method to prepare a N, F-co doped mesoporous cobalt phosphate with rich-oxygen vacancies via in-situ pyrolysis of a Co-phosphate precursor with NH 4 + cations and F - anions. Due to this heteroatom doping, it could achieve current density of 10 mA/cm 2 at lower overpotential of 276 mV and smaller Tafel slope of 57.11 mV dec -1 on glassy carbon, besides, it has excellent stability and durability current density with 92% of initial current density for 35 hrs. Furthermore, the optimal material applied in supercapacitor displays specific capacitance of 206.3 F g -1 at 1 A·g -1 and maintains cycling stability with 80% after 3000 cycles. The excellent electrochemical properties should be attributed to N, F-co doping into this Co-based phosphate effectively modulates its electronic structure; in addition, its amorphous structure provides more active sites; moreover, its mesoporous structure should be beneficial to the mass transfer and electrolyte diffusion.

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