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1.
J Chem Phys ; 153(3): 034107, 2020 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-32716189

RESUMO

We present NECI, a state-of-the-art implementation of the Full Configuration Interaction Quantum Monte Carlo (FCIQMC) algorithm, a method based on a stochastic application of the Hamiltonian matrix on a sparse sampling of the wave function. The program utilizes a very powerful parallelization and scales efficiently to more than 24 000 central processing unit cores. In this paper, we describe the core functionalities of NECI and its recent developments. This includes the capabilities to calculate ground and excited state energies, properties via the one- and two-body reduced density matrices, as well as spectral and Green's functions for ab initio and model systems. A number of enhancements of the bare FCIQMC algorithm are available within NECI, allowing us to use a partially deterministic formulation of the algorithm, working in a spin-adapted basis or supporting transcorrelated Hamiltonians. NECI supports the FCIDUMP file format for integrals, supplying a convenient interface to numerous quantum chemistry programs, and it is licensed under GPL-3.0.

2.
J Immunol ; 203(1): 31-38, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-31092638

RESUMO

Alternaria is a major outdoor allergen. Immunotherapy with Alternaria extracts has been documented to be effective in the sensitized patients. However, Alternaria extracts are notoriously difficult to standardize. Our aim is to screen the B cell mimotopes of Alternaria and to evaluate the therapeutic effects of B cell mimotope peptides on a BALB/c mouse model of Alternaria allergy. After a human sera pool from Alternaria monosensitized patients was established, B cell mimotopes were screened by a phage-displayed random heptamer peptide library that was identified via mixed Alternaria-specific IgE in the sera pool. B cell mimotopes with phage as a carrier were used to perform immunotherapy in an Alternaria allergy mouse model. Serological Ab levels, lung histology, and cytokine profiles were compared in the mimotope immunotherapy group, natural extract immunotherapy group, irrelevant phage control group, Alternaria-sensitized model group, and saline-blank group. Two mimotopes (MISTSRK and QKRNTIT) presented high binding ability with the sera of the Alternaria-allergic patients and mice and, therefore, were selected for immunotherapy in the mouse model. Compared with irrelevant phage control, model, and natural extract immunotherapy group, mimotope immunotherapy group significantly reduced serum IgE levels, inflammatory cells infiltration in the lung tissue, and IL-4 levels in bronchoalveolar lavage fluid, whereas serum IgG1 and IFN-γ levels in bronchoalveolar lavage fluid were increased. Our results indicate that B cell mimotopes of Alternaria alleviates allergic response in a mouse model and have potential as novel therapeutic agents for IgE-mediated Alternaria-allergic diseases.


Assuntos
Alérgenos/metabolismo , Antígenos de Fungos/metabolismo , Dessensibilização Imunológica/métodos , Hipersensibilidade/terapia , Pulmão/patologia , Alérgenos/genética , Alérgenos/imunologia , Alternaria/imunologia , Animais , Antígenos de Fungos/genética , Antígenos de Fungos/imunologia , Técnicas de Visualização da Superfície Celular , Modelos Animais de Doenças , Epitopos de Linfócito B/genética , Humanos , Hipersensibilidade/imunologia , Imunoglobulina E/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Mimetismo Molecular
3.
Am J Transl Res ; 11(4): 2393-2402, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31105845

RESUMO

Type 1 diabetes mellitus (T1DM) is still one of the major threats on global public health. This autoimmune condition is mainly caused by the imbalance of auto-reactive inflammatory effector T cells (Teffs) and protective regulatory T cells (Tregs). Therefore, inhibiting the development of Teffs and/or promoting Tregs provides a therapeutic strategy for preventing the development of T1DM. Pathways of energy metabolism have been shown to play a pivotal role in dictating the activation, differentiation and immune function of T cells. Studies have shown that inhibition of glycolysis suppresses the development of Th1 and Th17 cells, but promotes Treg production. AMP-activated protein kinase (AMPK) is a master sensor and regulator of cellular energy metabolism in mammals, which has also been demonstrated to interfere with T cell differentiation and effector function through inhibiting mammalian target of rapamycin (mTOR) and subsequent inhibition of glycolysis, and enhancement of lipid oxidation. In this study, we found that AMPK activator metformin suppresses T cell proliferation and inhibits the differentiation of Th1 and Th17 cells while promoting the development of Tregs in vitro in a dose-dependent manner. Treatment of NOD mice with metformin significantly mitigated autoimmune insulitis and substantially decreased the number of pro-inflammatory IFN-γ+ as well as IL17+ CD4 T cells in the spleens of NOD mice. However, a significantly increased percentage of regulatory IL-10+ and Foxp3+ CD4 T cells were seen. We provided a novel potential therapeutic method--by regulating T cell metabolism through targeting AMPK, to reduce the severity of autoimmune insulitis.

4.
J Allergy Clin Immunol Pract ; 7(1): 272-278, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-29886146

RESUMO

BACKGROUND: Allergic Rhinitis Control Test (ARCT) has been validated in the allergic rhinitis (AR) step-up pharmacotherapy management approach. OBJECTIVE: The aim of our study was to evaluate the potential of ARCT in AR step-down pharmacotherapy. METHODS: In an open-labeled randomized controlled study, patients with AR controlled with intranasal corticosteroid (INS) plus antihistamine (step 4) were included and randomized into an ARCT or a control group. In the ARCT group, the patients were followed up every 15 days; if the ARCT score was ≥20 (controlled AR), the patient would step down to step 3 (INS), step 2 (daily antihistamine), step 1 (antihistamine as needed), and step 0 (no medication) consecutively; if the ARCT score was strictly <20, the treatment would not be adjusted. In the control group, patients would be treated with step 4 medications during the whole study. Rhinitis Quality-of-Life Questionnaire (RQLQ), Morisky Questionnaire, and Brief Illness Perception Questionnaire (B-IPQ) were completed at baseline and the end of the study. Medication use and side effects were recorded. RESULTS: A total of 255 patients with AR were enrolled into the study; 27 patients dropped out. The control rates at day 45 were 77.8% in the ARCT group and 85.8% in the control group (P > .05). The ARCT group had less mean medication use than the control group (INS 1.27 vs 2.22 bottle, antihistamines 35.9 vs 61.4 tablets) (P < .05). RQLQ, Morisky, and B-IPQ score were significantly improved in both groups after treatment (P < .05). CONCLUSIONS: Stepping down AR medications in controlled patients led to similar clinical outcomes at reduced cost compared with those who maintained their current treatment level. ARCT is an optimal tool for evaluating the step-down eligibility.


Assuntos
Corticosteroides/uso terapêutico , Antagonistas dos Receptores Histamínicos/uso terapêutico , Rinite Alérgica/diagnóstico , Inquéritos e Questionários , Administração Intranasal , Adolescente , Adulto , Tomada de Decisão Clínica , Tratamento Farmacológico , Quimioterapia Combinada , Feminino , Seguimentos , Humanos , Masculino , Seleção de Pacientes , Guias de Prática Clínica como Assunto , Qualidade de Vida , Rinite Alérgica/terapia , Adulto Jovem
5.
Transplantation ; 103(3): 502-511, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30211824

RESUMO

BACKGROUND: Advances in immunosuppressive therapy have significantly improved short-term but not long-term survival of cardiac transplant recipients; this is largely due to severe cardiac allograft vasculopathy (CAV). Glucagon-like peptide-1 receptor (GLP-1R)-based therapy exerts physiological effects on the cardiovascular system in addition to its traditional role in controlling glucose. We have investigated the effects of liraglutide, a GLP-1R agonist, on the development of CAV in a murine heart transplant model. METHODS: Heterotopic murine cardiac transplantation was performed with a major histocompatibility complex class II-mismatched model. Recipient mice were subcutaneously administered vehicle (0.9% saline solution) or liraglutide (300 µg·kg every 12 hours) from the day of transplantation. Allografts were harvested at 2 or 8 weeks and histologically analyzed. Inflammatory infiltrates were measured by immunohistochemistry, and immunofluorescence and western blotting analyzes were used to evaluate GLP-1R expression and markers of endothelial-to-mesenchymal transition (EndMT) in cardiac allografts and human coronary artery endothelial cells challenged with transforming growth factor-beta 1. RESULTS: Glucagon-like peptide-1 receptor was predominantly localized to vascular endothelial cells and was upregulated in cardiac allografts after liraglutide treatment. Liraglutide ameliorated CAV and cardiac fibrosis with reduced inflammatory cell infiltration and downregulated expression of adhesion molecules. Liraglutide inhibited EndMT in allografts and attenuated EndMT by inhibiting Smad3 activation in transforming growth factor-beta 1-treated human coronary artery endothelial cells. CONCLUSIONS: Administration of liraglutide from the time of transplantation upregulated GLP-1R in the transplanted heart and reduced cardiac fibrosis, inflammation, and CAV development. Therefore, liraglutide may be a novel therapy for CAV.


Assuntos
Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/cirurgia , Transplante de Coração , Liraglutida/farmacologia , Doenças Vasculares/tratamento farmacológico , Animais , Vasos Coronários/patologia , Modelos Animais de Doenças , Células Endoteliais/citologia , Fibrose , Glucose/metabolismo , Antígenos de Histocompatibilidade Classe II/metabolismo , Humanos , Hipoglicemiantes/farmacologia , Imuno-Histoquímica , Imunossupressão , Imunossupressores/uso terapêutico , Inflamação , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteína Smad3/metabolismo
6.
Biochem Biophys Res Commun ; 506(3): 619-625, 2018 11 30.
Artigo em Inglês | MEDLINE | ID: mdl-30454697

RESUMO

We previously demonstrated the protective effect of MSCs in an adaptive transfer mouse model. However, their therapeutic potential in an allogeneic immunocompetent setting mimicking clinical context of islet transplantation remained unknown. The aim of this study was to determine whether MSCs therapy, either by itself, or combined with Rapamycin could benefit the allograft survival of fully MHC-mismatched mouse islet transplant. Combination therapy of MSCs and low-dose Rapamycin significantly prolonged the survival of islet allografts, whereas treatment of MSCs, or Rapamycin alone, had no impact. Interestingly, this protective effect was associated with an induced expansion of regulatory T cells in islet grafts and draining lymph nodes, a skewed T-cell differentiation toward immunotolerance, and a profound suppression of alloreactivity against donor antigen. Our study suggests that a combination therapy of MSCs and low-dose Rapamycin can prolong the survival and preserve the function of islet allograft in the MHC-mismatched mouse model of islet transplantation.


Assuntos
Aloenxertos/imunologia , Sobrevivência de Enxerto/imunologia , Transplante das Ilhotas Pancreáticas , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/citologia , Sirolimo/farmacologia , Linfócitos T Reguladores/imunologia , Aloenxertos/efeitos dos fármacos , Animais , Diferenciação Celular/efeitos dos fármacos , Terapia Combinada , Relação Dose-Resposta a Droga , Sobrevivência de Enxerto/efeitos dos fármacos , Inflamação/patologia , Rim/efeitos dos fármacos , Rim/patologia , Linfonodos/efeitos dos fármacos , Linfonodos/patologia , Células-Tronco Mesenquimais/efeitos dos fármacos , Mesentério/efeitos dos fármacos , Mesentério/patologia , Camundongos Endogâmicos C57BL , Baço/efeitos dos fármacos , Baço/patologia , Linfócitos T Reguladores/efeitos dos fármacos
7.
Pharmacol Res ; 131: 102-111, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29530599

RESUMO

Renal fibrosis is recognized as the common route of all chronic kidney disease (CKD) progressing to end-stage renal disease (ESRD). Additionally, accumulating evidence suggests that epithelial-mesenchymal transition (EMT) plays a significant role in the process of renal fibrogenesis. Liraglutide is a long-acting glucagon-like peptide-1 (GLP-1) analog that has been widely used to treat type 2 diabetes. Recent studies have demonstrated that the GLP-1 analogs could also exert protective effects in cardiac fibrosis models. However, the effects of liraglutide on the progression of CKD remain largely unknown. In the present study, we investigated the effects of liraglutide on the progression to renal fibrosis induced by unilateral ureteral obstruction (UUO) and EMT of rat renal tubular epithelial cells (NRK-52E) induced with recombinant transforming growth factor-beta 1 (TGF-ß1). The results indicated that UUO increased collagen deposition and the mRNA expression of fibronectin (FN) and collagen type I alpha 1 (Col1α1) in the obstructed kidney tissues. The effects were blunted in liraglutide-treated UUO mice compared with control mice. The upregulation of Snail1 and alpha smooth muscle actin (α-SMA), and downregulation of E-cadherin revealed that EMT occurred in the UUO kidneys, and these effects were ameliorated following liraglutide treatment. Additionally, liraglutide treatment decreased the expression of TGF-ß1 and its receptor (TGF-ß1R) and inhibited the activation of its downstream signaling molecules (pSmad3 and pERK1/2). The in vitro results showed that the EMT and extracellular matrix (ECM) secretion of NRK-52E cells were induced by TGF-ß1. In addition, the Smad3 and ERK1/2 signaling pathways were highly activated in cells cultured with TGF-ß1. All these effects were attenuated by liraglutide treatment. However, the protective effects of liraglutide were abolished by co-incubation of the GLP-1 receptor (GLP-1R) antagonist exendin-3 (9-39). These results suggest that liraglutide attenuates the EMT and ECM secretion of NRK-52E cells induced by TGF-ß1 and EMT and renal fibrosis induced by UUO. The potential mechanism involves liraglutide binding to and activating GLP-1R, which prevents EMT by inhibiting the activation of TGF-ß1/Smad3 and ERK1/2 signaling pathways, thereby decreasing the ECM secretion and deposition. Therefore, liraglutide is a promising therapeutic agent that may halt the progression of renal fibrosis.


Assuntos
Hipoglicemiantes/uso terapêutico , Rim/efeitos dos fármacos , Rim/patologia , Liraglutida/uso terapêutico , Obstrução Ureteral/tratamento farmacológico , Animais , Linhagem Celular , Colágeno/análise , Colágeno/metabolismo , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Fibrose , Peptídeo 1 Semelhante ao Glucagon/análogos & derivados , Peptídeo 1 Semelhante ao Glucagon/uso terapêutico , Rim/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Ratos , Transdução de Sinais/efeitos dos fármacos , Obstrução Ureteral/complicações , Obstrução Ureteral/metabolismo , Obstrução Ureteral/patologia
8.
J Chem Phys ; 147(18): 184111, 2017 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-29141437

RESUMO

A new large-scale parallel multiconfigurational self-consistent field (MCSCF) implementation in the open-source NWChem computational chemistry code is presented. The generalized active space approach is used to partition large configuration interaction (CI) vectors and generate a sufficient number of batches that can be distributed to the available cores. Massively parallel CI calculations with large active spaces can be performed. The new parallel MCSCF implementation is tested for the chromium trimer and for an active space of 20 electrons in 20 orbitals, which can now routinely be performed. Unprecedented CI calculations with an active space of 22 electrons in 22 orbitals for the pentacene systems were performed and a single CI iteration calculation with an active space of 24 electrons in 24 orbitals for the chromium tetramer was possible. The chromium tetramer corresponds to a CI expansion of one trillion Slater determinants (914 058 513 424) and is the largest conventional CI calculation attempted up to date.

9.
Transplantation ; 101(7): 1600-1608, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28640790

RESUMO

BACKGROUND: MicroRNA-155 (miR-155) is known to be involved in autoimmune diseases, inflammation, and transplantation. However, its role in a warm hepatic ischemia-reperfusion (IR) model has not been fully elucidated. METHODS: Partial hepatic IR was performed in wild-type and miR-155-deficient mice treated with or without GdCl3, and then the serum transaminase concentration and histology were analyzed. Kupffer cells (KCs) were isolated from the liver after IR, and immunohistochemistry was used to evaluate activation and polarization. In addition, the mRNA concentrations of various inflammatory cytokines were measured. Macrophages were obtained from the abdominal cavity and challenged with or without lipopolysaccharide to determine the influence of miR-155 deficiency on macrophage polarization in vitro. Furthermore, we used in vitro coculture assays to determine the effect of miR-155 deficiency on hepatocyte apoptosis induced directly by KCs. RESULTS: miR-155 deficiency ameliorated liver IR injury, and inhibition of KCs by GdCl3 abolished this protective effect. miR-155 deficiency decreased CD80, CD86, and major histocompatibility complex class II expression in KCs after IR and tipped the M1/M2 balance toward an anti-inflammatory profile, where proinflammatory cytokine secretion was suppressed and IL-10 was enhanced. In addition, hepatocyte apoptosis was reduced in coculture with miR-155-deficient KCs in vitro. CONCLUSIONS: miR-155 deficiency plays an effective role in attenuating liver IR injury likely by regulating the activation and inflammatory response, as well as modifying the polarization of KCs.


Assuntos
Macrófagos do Fígado/metabolismo , Hepatopatias/prevenção & controle , Fígado/metabolismo , Ativação de Macrófagos , MicroRNAs/metabolismo , Traumatismo por Reperfusão/prevenção & controle , Alanina Transaminase/sangue , Animais , Apoptose , Aspartato Aminotransferases/sangue , Biomarcadores/sangue , Plasticidade Celular , Células Cultivadas , Técnicas de Cocultura , Citocinas/metabolismo , Modelos Animais de Doenças , Predisposição Genética para Doença , Hepatócitos/metabolismo , Hepatócitos/patologia , Macrófagos do Fígado/patologia , Fígado/patologia , Hepatopatias/genética , Hepatopatias/metabolismo , Hepatopatias/patologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , MicroRNAs/genética , Fenótipo , Traumatismo por Reperfusão/genética , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia
10.
Phys Chem Chem Phys ; 19(3): 2417-2424, 2017 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-28058426

RESUMO

In this work, five new palladium(ii) complexes have been designed as the model catalysts for methane to methyl trifluoroacetate conversion. All these compounds are analogues of the well-established (bis-NHC)PdBr2 complex (NHC, N-heterocyclic carbenes), derived by complexing the palladium(ii) metal ion with the derivatives of bis-2-borabicyclo[1.1.0]but-1(3)-ene (bis-2BB) ligands using the sp2 carbons. Our density functional theory calculation results suggest that the (bis-2BB)PdBr2 catalysts outperform the popular (bis-NHC)PdBr2 complex in the desired catalytic process, and further reveal that the charge-shift bonding in the bis-2BB ligands contributes to the improved catalytic performance. These findings may spark new ideas for experimental design of more efficient organometallic catalysts for C-H bond activation and functionalization.

11.
J Heart Lung Transplant ; 36(2): 175-184, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27296836

RESUMO

BACKGROUND: MicroRNAs (miRNAs) are integral for maintaining immune homeostasis and self-tolerance. The influence of miRNAs on T-cell differentiation and plasticity are critical in the development of chronic rejection of transplanted hearts. In this study, we sought to determine whether the knockout of miR-155 affects the development of cardiac allograft vasculopathy (CAV) in a murine model. METHODS: miRNA microarray and quantitative polymerase chain reaction (qPCR) analyses were performed for allograft neointimal lesion samples in chronic rejection. A model of heterotopic murine heart transplantation (bm12 to miR-155+/+ or miR-155-/- mice) was then used to analyze allograft survival, histology, mRNA expression and T-cell sub-populations in spleens. The accelerated experiments were performed by intraperitoneal injection of either recombinant interleukin-17A or phosphate-buffered saline (PBS) after heart transplantation. For the competitive transfer experiments, CD4+ splenocytes from wild-type (WT) or miR-155-/- mice were mixed and injected into Rag1-/- mice, and cardiac transplantation was performed after 24 hours. The differentiation of T-helper subsets (Th1/Th17/iTreg) was investigated in vitro. RESULTS: miR-155-/- mice showed resistance to cardiac rejection along with weakened T-cell-mediated inflammation, especially for Th17 cells. Recombinant IL-17A could restore this relieved injury. The competitive experiments implied that miR-155 plays a vital role in the stability of the Th17 phenotype. In vitro, we also demonstrated that miR-155-/- mice exhibit a defect in Th17 differentiation. CONCLUSIONS: miR-155 regulates Th1/Th17-related inflammation in chronic cardiac rejection and may be a potential therapeutic target to attenuate cardiac allograft rejection. Despite advancements in immunosuppressive therapy, the immunologic mechanisms responsible for allograft rejection remain an important issue for both clinicians and researchers. Allograft rejection is a T-cell-dependent phenomenon and is critically dependent on inflammation mediated by CD4+ Th subsets, including Th1, Th2, Th17, Th9 and regulatory T (Treg) cells.


Assuntos
Diferenciação Celular/genética , Regulação da Expressão Gênica , Rejeição de Enxerto/genética , Transplante de Coração/efeitos adversos , MicroRNAs/genética , Aloenxertos , Animais , Western Blotting , Doença Crônica , Modelos Animais de Doenças , Citometria de Fluxo , Rejeição de Enxerto/imunologia , Transplante de Coração/métodos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Distribuição Aleatória , Reação em Cadeia da Polimerase em Tempo Real/métodos , Células Th1/imunologia , Células Th17/imunologia , Imunologia de Transplantes/genética , Regulação para Cima
12.
Am J Transl Res ; 8(8): 3603-13, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27648151

RESUMO

Acute allograft rejection is a serious and life-threatening complication of organ transplantation. Th17 cells induced inflammation has been described to play an important role in allograft rejection. Since there is a plenty of evidence indicating that transcriptional factor BATF regulates the differentiation of Th17 and follicular T helper cells both in vitro and in vivo, we investigated whether is BATF involved in acute rejection and allograft survival by injecting lentivirus containing BATF shRNA through tail vein before the cardiac transplantation operation. We found that the allograft survival time of the mice treated with BATF shRNA was significantly prolonged compared with that of negative shRNA treated group and the control group. Further pathological analysis revealed that the BATF shRNA treatment group had significantly lower rejection degree than the negative shRNA group, while there was no significant difference between the negative shRNA group and the control group. Furthermore, flow cytometry analysis and quantitative polymerase chain reaction and enzyme-linked immuno sorbent assay were used to determine the proportion of T helper cells, the expression of specific transcription factor and the inflammatory cytokines respectively. Data showed that BATF regulated Th17 and Treg responses during allograft rejection. And BATF inhibition led to reduction of the expression level of Rorγ-t and enhancement of the Foxp-3. In addition, cytokines IL-17A and IL-4 were found decreased. This may indicate BATF as a novel therapy target for treatment of acute allograft rejection.

13.
J Chem Theory Comput ; 12(7): 3208-13, 2016 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-27276688

RESUMO

A multireference second-order perturbation theory approach based on the generalized active space self-consistent-field (GASSCF) wave function is presented. Compared with the complete active space (CAS) and restricted active space (RAS) wave functions, GAS wave functions are more flexible and can employ larger active spaces and/or different truncations of the configuration interaction expansion. With GASSCF, one can explore chemical systems that are not affordable with either CASSCF or RASSCF. Perturbation theory to second order on top of GAS wave functions (GASPT2) has been implemented to recover the remaining electron correlation. The method has been benchmarked by computing the chromium dimer ground-state potential energy curve. These calculations show that GASPT2 gives results similar to CASPT2 even with a configuration interaction expansion much smaller than the corresponding CAS expansion.

14.
PLoS One ; 11(3): e0152087, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26990974

RESUMO

BACKGROUND: Islet transplantation may potentially cure type 1 diabetes mellitus (T1DM). However, immune rejection, especially that induced by the alloreactive T-cell response, remains a restraining factor for the long-term survival of grafted islets. Programmed death ligand-1 (PD-L1) is a negative costimulatory molecule. PD-L1 deficiency within the donor heart accelerates allograft rejection. Here, we investigate whether PD-L1 deficiency in donor islets reduces allograft survival time. METHODS: Glucose Stimulation Assays were performed to evaluate whether PD-L1 deficiency has detrimental effects on islet function. Islets isolated from PDL1-deficient mice or wild- type (WT) mice (C57BL/6j) were implanted beneath the renal capsule of streptozotocin (STZ)-induced diabetic BALB/c mice. Blood glucose levels and graft survival time after transplantation were monitored. Moreover, we analyzed the residual islets, infiltrating immune cells and alloreactive cells from the recipients. RESULTS: PD-L1 deficiency within islets does not affect islet function. However, islet PD-L1 deficiency increased allograft rejection and was associated with enhanced inflammatory cell infiltration and recipient T-cell alloreactivity. CONCLUSIONS: This is the first report to demonstrate that PD-L1 deficiency accelerated islet allograft rejection and regulated recipient alloimmune responses.


Assuntos
Antígeno B7-H1/deficiência , Rejeição de Enxerto , Transplante das Ilhotas Pancreáticas , Animais , Antígeno B7-H1/metabolismo , Ilhotas Pancreáticas/metabolismo , Ilhotas Pancreáticas/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Transplante Homólogo/métodos
15.
J Comput Chem ; 37(5): 506-41, 2016 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-26561362

RESUMO

In this report, we summarize and describe the recent unique updates and additions to the Molcas quantum chemistry program suite as contained in release version 8. These updates include natural and spin orbitals for studies of magnetic properties, local and linear scaling methods for the Douglas-Kroll-Hess transformation, the generalized active space concept in MCSCF methods, a combination of multiconfigurational wave functions with density functional theory in the MC-PDFT method, additional methods for computation of magnetic properties, methods for diabatization, analytical gradients of state average complete active space SCF in association with density fitting, methods for constrained fragment optimization, large-scale parallel multireference configuration interaction including analytic gradients via the interface to the Columbus package, and approximations of the CASPT2 method to be used for computations of large systems. In addition, the report includes the description of a computational machinery for nonlinear optical spectroscopy through an interface to the QM/MM package Cobramm. Further, a module to run molecular dynamics simulations is added, two surface hopping algorithms are included to enable nonadiabatic calculations, and the DQ method for diabatization is added. Finally, we report on the subject of improvements with respects to alternative file options and parallelization.


Assuntos
Algoritmos , Elétrons , Compostos Macrocíclicos/química , Timidina/química , Simulação de Dinâmica Molecular , Teoria Quântica , Software , Termodinâmica
16.
ACS Omega ; 1(4): 620-625, 2016 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-31457151

RESUMO

We have theoretically investigated the stability, chemical bonding, and coordination ability of the 2-Me-2-borabicyclo[1.1.0]but-1(3)-ene (2-Me-2BB) molecule using density functional theory and ab initio molecular dynamics (AIMD) simulations. Calculated results indicated that 2-Me-2BB is both thermodynamically and kinetically stable. The C=C bonds in 2-Me-2BB contain a π bond and a charge shift (CS) bond, different from those in 1-Me-borirene and cyclopropylene. Moreover, 2-Me-2BB can be a σ donor, leading to the formation of TM(2-Me-2BB)L n complexes containing planar tetracoordinate carbon (ptC) with transition metals (TM = Sc-Cu), in which the lone electron pair of 2-Me-2BB results from its ionic resonance form. The lengths and Wiberg bond indices of the TM-ptC bond in TM(2-Me-2BB)L n (TM = Sc-Cu) reveal that 2-Me-2BB can be a ligand similar to N-heterocyclic carbene. Therefore, 2-Me-2BB and its derivatives are promising molecules to obtain complexes with ptC. The natural charges on TM atoms in TM(2-Me-2BB)L n (TM = Sc-Cu) complexes range from -0.97 to 1.54e, indicating that such complexes with ptC might have potential applications in catalytic chemistry.

18.
J Chem Theory Comput ; 11(7): 3010-21, 2015 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-26575738

RESUMO

The applicability and accuracy of the generalized active space self-consistent field, (GASSCF), and (SplitGAS) methods are presented. The GASSCF method enables the exploration of larger active spaces than with the conventional complete active space SCF, (CASSCF), by fragmentation of a large space into subspaces and by controlling the interspace excitations. In the SplitGAS method, the GAS configuration interaction, CI, expansion is further partitioned in two parts: the principal, which includes the most important configuration state functions, and an extended, containing less relevant but not negligible ones. An effective Hamiltonian is then generated, with the extended part acting as a perturbation to the principal space. Excitation energies of ozone, furan, pyrrole, nickel dioxide, and copper tetrachloride dianion are reported. Various partitioning schemes of the GASSCF and SplitGAS CI expansions are considered and compared with the complete active space followed by second-order perturbation theory, (CASPT2), and multireference CI method, (MRCI), or available experimental data. General guidelines for the optimum applicability of these methods are discussed together with their current limitations.

19.
J Chem Phys ; 141(11): 114104, 2014 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-25240342

RESUMO

In this work, we present a method, called the DQ scheme (where D and Q stand for dipole and quadrupole, respectively), for transforming a set of adiabatic electronic states to diabatic states by using the dipole and quadrupole moments to determine the transformation coefficients. It is more broadly applicable than methods based only on the dipole moment; for example, it is not restricted to electron transfer reactions, and it works with any electronic structure method and for molecules with and without symmetry, and it is convenient in not requiring orbital transformations. We illustrate this method by prototype applications to two cases, LiH and phenol, for which we compare the results to those obtained by the fourfold-way diabatization scheme.

20.
J Chem Theory Comput ; 10(9): 3669-80, 2014 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-26588512

RESUMO

We present a new theoretical framework, called Multiconfiguration Pair-Density Functional Theory (MC-PDFT), which combines multiconfigurational wave functions with a generalization of density functional theory (DFT). A multiconfigurational self-consistent-field (MCSCF) wave function with correct spin and space symmetry is used to compute the total electronic density, its gradient, the on-top pair density, and the kinetic and Coulomb contributions to the total electronic energy. We then use a functional of the total density, its gradient, and the on-top pair density to calculate the remaining part of the energy, which we call the on-top-density-functional energy in contrast to the exchange-correlation energy of Kohn-Sham DFT. Because the on-top pair density is an element of the two-particle density matrix, this goes beyond the Hohenberg-Kohn theorem that refers only to the one-particle density. To illustrate the theory, we obtain first approximations to the required new type of density functionals by translating conventional density functionals of the spin densities using a simple prescription, and we perform post-SCF density functional calculations using the total density, density gradient, and on-top pair density from the MCSCF calculations. Double counting of dynamic correlation or exchange does not occur because the MCSCF energy is not used. The theory is illustrated by applications to the bond energies and potential energy curves of H2, N2, F2, CaO, Cr2, and NiCl and the electronic excitation energies of Be, C, N, N(+), O, O(+), Sc(+), Mn, Co, Mo, Ru, N2, HCHO, C4H6, c-C5H6, and pyrazine. The method presented has a computational cost and scaling similar to MCSCF, but a quantitative accuracy, even with the present first approximations to the new types of density functionals, that is comparable to much more expensive multireference perturbation theory methods.

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