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1.
J Chem Inf Model ; 64(3): 905-917, 2024 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-38282538

RESUMO

Inositol-requiring enzyme 1 (IRE1) is a transmembrane sensor that is part of a trio of sensors responsible for controlling the unfolded protein response within the endoplasmic reticulum (ER). Upon the accumulation of unfolded or misfolded proteins in the ER, IRE1 becomes activated and initiates the cleavage of a 26-nucleotide intron from human X-box-containing protein 1 (XBP1). The cleavage is mediated by the RtcB ligase enzyme, which splices together two exons, resulting in the formation of the spliced isoform XBP1s. The XBP1s isoform activates the transcription of genes involved in ER-associated degradation to maintain cellular homeostasis. The catalytic activity of RtcB is controlled by the phosphorylation and dephosphorylation of three tyrosine residues (Y306, Y316, and Y475), which are regulated by the ABL1 tyrosine kinase and PTP1B phosphatase, respectively. This study focuses on investigating the mechanism by which the PTP1B phosphatase activates the RtcB ligase using a range of advanced in silico methods. Protein-protein docking identified key interacting residues between RtcB and PTP1B. Notably, the phosphorylated Tyr306 formed hydrogen bonds and salt bridge interactions with the "gatekeeper" residues Arg47 and Lys120 of the inactive PTP1B. Classical molecular dynamics simulation emphasized the crucial role of Asp181 in the activation of PTP1B, driving the conformational change from an open to a closed state of the WPD-loop. Furthermore, QM/MM-MD simulations provided insights into the free energy landscape of the dephosphorylation reaction mechanism of RtcB, which is mediated by the PTP1B phosphatase.


Assuntos
Ligases , Monoéster Fosfórico Hidrolases , Humanos , Ligases/metabolismo , Monoéster Fosfórico Hidrolases/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Fosforilação , Isoformas de Proteínas/metabolismo , Proteína Tirosina Fosfatase não Receptora Tipo 1/metabolismo
2.
Orbit ; 37(3): 208-211, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29053048

RESUMO

Neurofibromatosis type 1 (NF1) is an inherited disorder often associated with optic nerve gliomas, low-grade brain tumors, and readily visible signs. Though these features are frequently emphasized, the psychosocial and emotional morbidities are often overlooked. We present a patient with depressive disorder resulting in suicide in a patient with NF1.


Assuntos
Astrocitoma/patologia , Transtorno Depressivo/patologia , Neoplasias Hipotalâmicas/patologia , Neurofibromatose 1/patologia , Neoplasias do Nervo Óptico/patologia , Suicídio , Adolescente , Astrocitoma/diagnóstico por imagem , Transtorno Depressivo/diagnóstico , Feminino , Humanos , Neoplasias Hipotalâmicas/diagnóstico por imagem , Imageamento por Ressonância Magnética , Neurofibromatose 1/diagnóstico por imagem , Neoplasias do Nervo Óptico/diagnóstico por imagem
3.
J Forensic Sci ; 63(2): 619-621, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28597933

RESUMO

A 64-year-old woman was found dead at home after undergoing a screening colonoscopy. At autopsy, 1.9 L of blood was discovered within her abdominal cavity. The only major abnormality was nontraumatic avulsion of the splenic capsule. This was the only identifiable abnormality capable of causing the severe hemoperitoneum and demise of the patient. Although rare, splenic capsule avulsion is a recognized complication of colonoscopy. Many have theorized that it results from excessive traction on the splenocolic ligament resulting in a tear of the splenic capsule. Most patients present within the first 24 hours after the procedure with nonspecific symptoms, and many patients may not seek medical attention. The paucity of the literature in the area of splenic capsular avulsion after colonoscopy reinforces the importance of reporting known cases, and by doing so raise awareness of this rare but devastating complication of an otherwise beneficial screening procedure.


Assuntos
Colonoscopia/efeitos adversos , Hemoperitônio/patologia , Baço/lesões , Feminino , Hemoperitônio/etiologia , Humanos , Doença Iatrogênica , Pessoa de Meia-Idade , Baço/patologia
4.
AJP Rep ; 5(2): e150-2, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26495174

RESUMO

Background Eosinophilic endomyocarditis (EEM) is a rare diagnosis that is extremely uncommon in newborns. This case report aimed to present a case of neonatal mortality from acute cardiac failure due to EEM. Case Our report presents a term male neonate with minor complications in the immediate postnatal course, who was discharged at 48 hours of life, but who developed unexpected respiratory distress, followed by cardiac arrest and death at 3 days of life. One day after discharge, the infant developed respiratory distress and cool skin, and then developed cardiac arrest at the pediatrician's office, undergoing resuscitation with intravenous fluid, cardiopulmonary resuscitation, epinephrine, atropine, and failed intubation. Autopsy revealed EEM, an inflammatory infiltrative process involving the endomyocardium. Pathology Pathogenesis involves three stages: (1) myocarditis with an acute eosinophilic inflammatory infiltrate followed by (2) myocyte necrosis and eventually (3) fibrosis in the final stage of the disease. Discussion The cause of death was acute cardiac failure due to intense eosinophilic infiltration and degranulation with early subendocardial myocyte necrosis but before development of extensive myocyte necrosis. This case appears to be the youngest patient reported with EEM.

5.
Environ Manage ; 56(5): 1252-71, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26163198

RESUMO

The processes of landscape change are complex, exhibiting spatial variability as well as linear, cyclical, and reversible characteristics. To better understand the various processes that cause transformation, a data aggregation, validation, and attribution approach was developed and applied to an analysis of the Southeastern Coastal Plains (SECP). The approach integrates information from available national land-use, natural disturbance, and land-cover data to efficiently assess spatially-specific changes and causes. Between 2001 and 2006, the processes of change affected 7.8% of the SECP but varied across small-scale ecoregions. Processes were placed into a simple conceptual framework to explicitly identify the type and direction of change based on three general characteristics: replacement, recurrence, and recovery. Replacement processes, whereby a land use or cover is supplanted by a new land use, including urbanization and agricultural expansion, accounted for approximately 15% of the extent of change. Recurrent processes that contribute to cyclical changes in land cover, including forest harvest/replanting and fire, accounted for 83%. Most forest cover changes were recurrent, while the extents of recurrent silviculture and forest replacement processes such as urbanization far exceeded forest recovery processes. The total extent of landscape recovery, from prior land use to natural or semi-natural vegetation cover, accounted for less than 3% of change. In a region of complex change, increases in transitory grassland and shrubland covers were caused by large-scale intensive plantation silviculture and small-scale activities including mining reclamation. Explicit identification of the process types and dynamics presented here may improve the understanding of land-cover change and landscape trajectory.


Assuntos
Conservação dos Recursos Naturais , Agricultura Florestal/métodos , Agricultura/métodos , Agricultura/tendências , Florestas , Pradaria , Sudeste dos Estados Unidos , Árvores , Urbanização/tendências
6.
JAMA Ophthalmol ; 131(11): 1468-70, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24077385

RESUMO

IMPORTANCE: To establish that the intracranial and ophthalmologic findings present in victims of abusive head trauma can also be seen in shaken adults. OBSERVATIONS: We report 2 cases of shaken adults with intracranial and ophthalmologic findings that resulted from repetitive acceleration-deceleration injury. These findings included intracranial hemorrhages, hemorrhages involving the optic nerve sheath, intraretinal and subretinal hemorrhages, and macular folds. CONCLUSIONS AND RELEVANCE: The intracranial and ophthalmologic findings that are characteristic of abusive head trauma--subdural hemorrhages, optic nerve sheath hemorrhages, and retinal hemorrhages--are generally thought to be limited to young children and infants. Adults may also be victims of shaking abuse, and an ophthalmic examination may be beneficial when shaking is suspected.


Assuntos
Hematoma Subdural/etiologia , Traumatismos do Nervo Óptico/etiologia , Hemorragia Retiniana/etiologia , Hemorragia Subaracnoídea Traumática/etiologia , Intoxicação Alcoólica/etiologia , Hematoma Subdural/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Traumatismos do Nervo Óptico/patologia , Hemorragia Retiniana/patologia , Hemorragia Subaracnoídea Traumática/patologia , Inconsciência/etiologia
9.
Bioorg Med Chem Lett ; 17(13): 3575-80, 2007 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-17482464

RESUMO

Novel 2,4-diaminopyrimidine-based small molecule renin inhibitors are disclosed. Through high throughput screening, parallel synthesis, X-ray crystallography, and structure based drug design, we have developed the first non-chiral, non-peptidic, small molecular template to possess moderate potency against renin. The designed compounds consist of a novel 6-ethyl-5-(1,2,3,4-tetrahydroquinolin-7-yl)pyrimidine-2,4-diamine ring system that exhibit moderate potency (IC(50): 91-650 nM) against renin while remaining 'Rule-of-five' compliant.


Assuntos
Química Farmacêutica/métodos , Pirimidinas/química , Renina/antagonistas & inibidores , Animais , Cristalografia por Raios X , Desenho de Fármacos , Concentração Inibidora 50 , Modelos Químicos , Modelos Moleculares , Conformação Molecular , Pirimidinas/síntese química , Pirimidinas/farmacologia , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade
10.
Bioorg Med Chem Lett ; 17(8): 2150-5, 2007 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-17303420

RESUMO

Several novel series of nitrile-containing fluoroquinolones with weakly basic amines are reported which have reduced potential for hERG (human ether-a-go-go gene) channel inhibition as measured by the dofetilide assay. The new fluoroquinolones are potent against both Gram-positive and fastidious Gram-negative strains, including Methicillin resistant Staphylococcus aureus and fluoroquinolone-resistant Streptococcus pneumoniae. Several analogs also showed low potential for human genotoxicity as measured by the clonogenicity test. Compounds 22 and 37 (designated PF-00951966 and PF-02298732, respectively), which had good in vitro activity and in vitro safety profiles, also showed good pharmacokinetic properties in rats.


Assuntos
Antibacterianos/síntese química , Fluoroquinolonas/síntese química , Nitrilas/farmacologia , Animais , Antibacterianos/farmacologia , Farmacorresistência Bacteriana/efeitos dos fármacos , Fluoroquinolonas/farmacologia , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Humanos , Estrutura Molecular , Testes de Mutagenicidade , Nitrilas/química , Ratos , Relação Estrutura-Atividade
11.
Bioorg Med Chem Lett ; 17(5): 1312-20, 2007 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-17196390

RESUMO

A series of 3-aminoquinazolinediones was synthesized and evaluated for its antibacterial and DNA gyrase activity. The SAR around the quinazolinedione core was explored and the optimal substitutions were combined to give two compounds, 2r and 2s, with exceptional enzyme potency (IC50 = 0.2 microM) and activity against gram-positive organisms (MIC's = 0.015-0.06 microg/mL).


Assuntos
Antibacterianos/síntese química , Quinazolinonas/síntese química , Quinazolinonas/farmacologia , Inibidores da Topoisomerase II , Aminas/química , Aminas/farmacologia , Antibacterianos/química , DNA Girase , Bactérias Gram-Positivas/efeitos dos fármacos , Concentração Inibidora 50 , Quinazolinonas/química , Relação Estrutura-Atividade
12.
Antimicrob Agents Chemother ; 51(4): 1191-201, 2007 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-17261623

RESUMO

PD 0305970 and PD 0326448 are new bacterial gyrase and topoisomerase inhibitors (quinazoline-2,4-diones) that possess outstanding in vitro and in vivo activities against a wide spectrum of bacterial species including quinolone- and multidrug-resistant gram-positive and fastidious organism groups. The respective MICs (microg/ml) for PD 0305970 capable of inhibiting>or=90% of bacterial strains tested ranged from 0.125 to 0.5 versus staphylococci, 0.03 to 0.06 versus streptococci, 0.25 to 2 versus enterococci, and 0.25 to 0.5 versus Moraxella catarrhalis, Haemophilus influenzae, Listeria monocytogenes, Legionella pneumophila, and Neisseria spp. PD 0326448 MIC90s were generally twofold higher versus these same organism groups. Comparative quinolone MIC90 values were 4- to 512-fold higher than those of PD 0305970. In testing for frequency of resistance, PD 0305970 and levofloxacin showed low levels of development of spontaneous resistant mutants versus both Staphylococcus aureus and Streptococcus pneumoniae. Unlike quinolones, which target primarily gyrA and parC, analysis of resistant mutants in S. pneumoniae indicates that the likely targets of PD 0305970 are gyrB and parE. PD 0305970 demonstrated rapid bactericidal activity by in vitro time-kill testing versus streptococci. This bactericidal activity carried over to in vivo testing, where PD 0305970 and PD 0326448 displayed outstanding Streptococcus pyogenes 50% protective doses (PD50s) (oral dosing) of 0.7 and 3.6 mg/kg, respectively (ciprofloxacin and levofloxacin PD50s were>100 and 17.7 mg/kg, respectively). PD 0305970 was also potent in a pneumococcal pneumonia mouse infection model (PD50=3.2 mg/kg) and was 22-fold more potent than levofloxacin.


Assuntos
Resistência a Múltiplos Medicamentos , Bactérias Gram-Positivas/efeitos dos fármacos , Inibidores da Topoisomerase II , Antibacterianos/farmacologia , Farmacorresistência Bacteriana , Bactérias Gram-Positivas/enzimologia , Infecções por Bactérias Gram-Positivas/tratamento farmacológico , Testes de Sensibilidade Microbiana , Pirrolidinas/farmacologia , Quinazolinonas/farmacologia
13.
J Med Chem ; 49(22): 6435-8, 2006 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-17064062

RESUMO

The 3-aminoquinzolinediones represent a new series of antibacterial agents structurally related to the fluoroquinolones. They are inhibitors of bacterial gyrase and topoisomerase IV and demonstrate clinically useful antibacterial activity against fastidious Gram-negative and Gram-positive organisms, including multidrug- and fluoroquinolone-resistant organisms. These agents also demonstrate in vivo efficacy in murine systemic infection models.


Assuntos
Antibacterianos/síntese química , Antibacterianos/farmacologia , Bactérias/efeitos dos fármacos , Quinazolinonas/síntese química , DNA Topoisomerase IV/antagonistas & inibidores , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Resistência a Meticilina , Testes de Sensibilidade Microbiana , Relação Estrutura-Atividade , Inibidores da Topoisomerase II
14.
Bioorg Med Chem Lett ; 16(9): 2500-4, 2006 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-16480874

RESUMO

A systematic investigation of the S3 sub-pocket activity requirements was conducted. It was observed that linear and sterically small side chain substituents are preferred in the S3 sub-pocket for optimal renin inhibition. Polar groups in the S3-sub-pocket were not well tolerated and caused a reduction in renin inhibitory activity. Further, compounds with clog P's < or = 3 demonstrated a dramatic reduction in CYP3A4 inhibitory activity.


Assuntos
Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Piperazinas/química , Piperazinas/farmacologia , Renina/antagonistas & inibidores , Cristalografia por Raios X , Citocromo P-450 CYP3A , Sistema Enzimático do Citocromo P-450/efeitos dos fármacos , Inibidores Enzimáticos/síntese química , Humanos , Modelos Moleculares , Estrutura Molecular , Piperazinas/síntese química , Estereoisomerismo , Relação Estrutura-Atividade
15.
Bioorg Med Chem Lett ; 14(17): 4405-9, 2004 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-15357962

RESUMO

A series of 3-hydroxyquinazoline-2,4-diones was synthesized and evaluated for antibacterial activity. This series represents a novel addition to the DNA gyrase inhibitor class of antibacterials. Appropriate substitutions onto the core template yielded compounds with excellent potency against E. coli gyrase and significant in vitro Gram-negative and Gram-positive antibacterial activity.


Assuntos
Antibacterianos/síntese química , Quinazolinas/síntese química , Hidroxiquinolinas/síntese química , Testes de Sensibilidade Microbiana/estatística & dados numéricos , Relação Estrutura-Atividade
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