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1.
Bioorg Med Chem Lett ; 102: 129680, 2024 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-38428537

RESUMEN

Dihydroquinolizinones (DHQs) that inhibit cellular polyadenylating polymerases 5 and 7 (PAPD5 & 7), such as RG7834, have been shown to inhibit both hepatitis A (HAV) and hepatitis B virus (HBV) in vitro and in vivo. In this report, we describe RG7834-based proteolysis-targeting chimeras (PROTACs), such as compound 12b, (6S)-9-((1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-21-oxo-3,6,9,12,15,18-hexaoxa-22-azapentacosan-25-yl)oxy)-6-isopropyl-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic acid. The PROTAC DHQs described here inhibited an HAV reporter virus in vitro with an IC50 of 277 nM. Although the PROTAC DHQs were also inhibitory to HBV, their activities were substantially less potent against HBV in vitro, being in the 10 to 20 µM range, based on the reduction of HBsAg and HBV mRNA levels. Importantly, unlike RG7834, the incubation of cells in vitro with PROTAC DHQ 12b resulted in the degradation of PAPD5, as expected for a PROTAC compound, but curiously not PAPD7. PAPD5 polypeptide degradation was prevented when a proteasome inhibitor, epoxomicin, was used, indicating that proteasome mediated proteolysis was associated with the observed activities of 12b. Taken together, these data show that 12b is the first example of a PROTAC that suppresses both HAV and HBV that is based on a small molecule warhead. The possibility that it has mechanisms that differ from its parent compound, RG7834, and has clinical value, is discussed.


Asunto(s)
Virus de la Hepatitis A , Virus de la Hepatitis B , Proteolisis , Complejo de la Endopetidasa Proteasomal
2.
J Vasc Surg ; 75(1): 238-247.e1, 2022 01.
Artículo en Inglés | MEDLINE | ID: mdl-34303803

RESUMEN

OBJECTIVE: Preliminary outcomes for percutaneous endovascular autogenous access (endoAVF) have shown promising results; however, comparisons with surgical cohorts in dialysis populations are lacking. This study compares autogenous arteriovenous access created with the EverlinQ endoAVF system with accesses created by conventional surgical technique with respect to functional and patency related outcomes. METHODS: This is a multicenter, retrospective review of autogenous arteriovenous accesses entered into a prospective database. Patients receiving radiocephalic, brachiocephalic, or endoAVF arteriovenous accesses between 2014 and 2019 were included. Autogenous access maturation, primary patency, secondary patency, steal syndrome, and reinterventions were collected and analyzed using standard statistical and survival analyses. RESULTS: A total of 369 accesses were created during the study period, including 61 endovascular accesses, 171 radiocephalic accesses, and 137 brachiocephalic accesses (median follow-up, 17 months; range, 1-71 months). Maturation failure at the end of follow-up was 27% ± 6%, 27% ± 5%, and 18% ± 4% for endovascular, radiocephalic, and brachiocephalic accesses, respectively (P = .049 for brachiocephalic vs endovascular accesses). Primary patencies at 12 and 24 months were 42% ± 5% and 32% ± 7% for endovascular accesses, 43% ± 4% and 24% ± 4% for radiocephalic accesses, and 42% ± 4% and 29% ± 4% for brachiocephalic accesses (P = .906). Secondary patencies at 12 and 24 months were 68% ± 6% and 60% ± 7% for endovascular accesses, 75% ± 3% and 67% ± 4% for radiocephalic accesses, and 91% ± 3% and 81% ± 4% for brachiocephalic accesses (P = .006 for brachiocephalic vs endovascular accesses). There were no statistically significant differences in ischemic steal syndrome (3.3%, 4.1%, and 8.0%; P = .229) or total reinterventions/year (1.0 ± 3.1, 0.9 ± 1.8, and 1.2 ± 1.8; P = .289) for endovascular, radiocephalic, or brachiocephalic arteriovenous accesses, respectively. CONCLUSIONS: EndoAVF compare favorably with respect to maturation and patency compared with surgically created accesses in a real-world cohort. Outcomes and reintervention rates are similar to conventional radiocephalic arteriovenous accesses, but are inferior with respect to patency and maturation to brachiocephalic accesses.


Asunto(s)
Derivación Arteriovenosa Quirúrgica/métodos , Procedimientos Endovasculares/efectos adversos , Oclusión de Injerto Vascular/epidemiología , Diálisis Renal/métodos , Anciano , Derivación Arteriovenosa Quirúrgica/efectos adversos , Arteria Braquial/cirugía , Femenino , Estudios de Seguimiento , Oclusión de Injerto Vascular/etiología , Humanos , Masculino , Persona de Mediana Edad , Arteria Radial/cirugía , Reoperación/estadística & datos numéricos , Estudios Retrospectivos , Medición de Riesgo/estadística & datos numéricos , Factores de Riesgo , Resultado del Tratamiento , Grado de Desobstrucción Vascular
3.
J Vasc Surg ; 75(3): 1038-1046.e3, 2022 03.
Artículo en Inglés | MEDLINE | ID: mdl-34601046

RESUMEN

BACKGROUND: Percutaneous devices for creation of native arteriovenous fistulae offer an alternative to traditional open surgical techniques. The 4F WavelinQ EndoAVF System was developed as a lower profile alternative to facilitate access through smaller vessels and minimize access site complications; The current report is the original first experience of this device, assessing outcome in 120 patients followed for 6 months. METHODS: The use of the 4F WavelinQ system in three studies, EASE (32 patients), EASE-2 (24 patients), and the EU postmarket clinical follow-up study (64 patients) was aggregated and analyzed. Patients were followed with duplex ultrasound at discharge and follow-up visits at 1, 3, and 6 months. Primary, assisted primary, and secondary patency rates were evaluated as Kaplan-Meier estimates and standard errors. Time to maturity and time to successful cannulation were defined as the mean ± standard deviation days from the procedure in patients enrolled on dialysis. RESULTS: Procedural success was achieved in 116 patients (96.7%). Primary, assisted-primary, and secondary 6-month patency rates were 71.9% ± 4.5%, 80.7% ± 4.1%, and 87.8% ± 3.3%, respectively. Time to maturity averaged 41 ± 17 days. Time to successful cannulation averaged 68 ± 51 days. Device-related serious adverse events were reported in 3 of 120 patients (2.5%) and procedure-related serious adverse events occurred in 7 of 120 patients (5.8%). Arterial or venous access complications were not reported in any of the patients. Access circuit reinterventions were performed in 23 patients (19.2%), split between those performed for EndoAVF maturation (13/120 [10.8%]) and maintenance (11/120 [9.2%]). CONCLUSIONS: Percutaneous creation of native dialysis fistulae with the 4F WavelinQ EndoAVF System is safe and effective, with favorable durability and a low rate of serious complications and reinterventions through 6-month follow-up. Use of the 4F device allows for percutaneous fistula creation between the radial artery and radial vein or the ulnar artery and ulnar vein. These findings suggest that the 4F device is a useful percutaneous alternative to open surgical AVF or endovascular AVF with larger bore devices.


Asunto(s)
Derivación Arteriovenosa Quirúrgica/instrumentación , Implantación de Prótesis Vascular/instrumentación , Prótesis Vascular , Diálisis Renal , Insuficiencia Renal Crónica/terapia , Extremidad Superior/irrigación sanguínea , Adulto , Anciano , Anciano de 80 o más Años , Derivación Arteriovenosa Quirúrgica/efectos adversos , Implantación de Prótesis Vascular/efectos adversos , Ensayos Clínicos como Asunto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Diseño de Prótesis , Arteria Radial/cirugía , Insuficiencia Renal Crónica/diagnóstico , Insuficiencia Renal Crónica/fisiopatología , Factores de Tiempo , Resultado del Tratamiento , Arteria Cubital/cirugía , Ultrasonografía Doppler Dúplex , Grado de Desobstrucción Vascular , Adulto Joven
4.
Bioorg Med Chem Lett ; 58: 128518, 2022 02 15.
Artículo en Inglés | MEDLINE | ID: mdl-34979256

RESUMEN

Hepatitis B virus (HBV) core protein, the building block of the HBV capsid, plays multiple roles in viral replication, and is an attractive target for development of antiviral agents with a new mechanism of action. In addition to the heteroaryldihydropyrimidines (HAPs), sulfamoylbenzamides (SBAs), dibenzothiazepine derivatives (DBTs), and sulfamoylpyrrolamides (SPAs) that inhibit HBV replication by modulation of viral capsid assembly and are currently under clinical trials for the treatment of chronic hepatitis B (CHB), other chemical structures with activity to modulate HBV capsid assembly have also been explored. Here we describe our continued optimization of a benzamide originating from our high throughput screening. A new bicyclic carboxamide lead featuring an electron deficient non-planar core structure was discovered. Evaluations of its ADMET (absorption, distribution, metabolism, excretion and toxicity) and pharmacokinetic (PK) profiles demonstrate improved metabolic stability and good bioavailability.


Asunto(s)
Antivirales/farmacología , Virus de la Hepatitis B/efectos de los fármacos , Quinolinas/farmacología , Animales , Antivirales/síntesis química , Antivirales/química , Relación Dosis-Respuesta a Droga , Humanos , Ratones , Pruebas de Sensibilidad Microbiana , Microsomas Hepáticos/química , Microsomas Hepáticos/metabolismo , Estructura Molecular , Quinolinas/síntesis química , Quinolinas/química , Relación Estructura-Actividad , Proteínas del Núcleo Viral , Replicación Viral/efectos de los fármacos
5.
Bioorg Med Chem Lett ; 30(23): 127553, 2020 12 01.
Artículo en Inglés | MEDLINE | ID: mdl-32971261

RESUMEN

Brusatol, a quassinoid natural product, is effective against multiple diseases including hematologic malignancies, as we reported recently by targeting the PI3Kγ isoform, but toxicity limits its further development. Herein, we report the synthesis of a series of conjugates of brusatol with amino acids and short peptides at its enolic hydroxyl at C-3. A number of conjugates with smaller amino acids and peptides demonstrated activities comparable to brusatol. Through in vitro and in vivo evaluations, we identified UPB-26, a conjugate of brusatol with a L- ß-homoalanine, which exhibits good chemical stability at physiological pH's (SGF and SIF), moderate rate of conversion to brusatol in both human and rat plasmas, improved mouse liver microsomal stability, and most encouragingly, enhanced safety compared to brusatol in mice upon IP administration.


Asunto(s)
Aminobutiratos/farmacología , Antineoplásicos/farmacología , Cuassinas/farmacología , Aminobutiratos/síntesis química , Aminobutiratos/metabolismo , Aminobutiratos/toxicidad , Animales , Antineoplásicos/síntesis química , Antineoplásicos/metabolismo , Antineoplásicos/toxicidad , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Masculino , Ratones Endogámicos NOD , Ratones SCID , Microsomas Hepáticos/metabolismo , Estructura Molecular , Cuassinas/síntesis química , Cuassinas/metabolismo , Cuassinas/toxicidad , Ratas , Relación Estructura-Actividad
6.
J Nat Prod ; 83(4): 1043-1050, 2020 04 24.
Artículo en Inglés | MEDLINE | ID: mdl-32227943

RESUMEN

An extract of Galtonia regalis from the Natural Products Discovery Institute showed moderate antiplasmodial activity, with an IC50 value less than 1.25 µg/mL. The two known cholestane glycosides 1 and 2 and the five new cholestane glycosides galtonosides A-E (3-7) were isolated after bioassay-directed fractionation. The structures of the new compounds were determined by interpretation of their NMR and mass spectra. Among these compounds, galtonoside B (4) displayed the most potent antiplasmodial activity, with an IC50 value of 0.214 µM against the drug-resistant Dd2 strain of Plasmodium falciparum.


Asunto(s)
Antimaláricos/química , Colestanos/farmacología , Glicósidos/farmacología , Asparagales/química , Colestanos/química , Colestanos/aislamiento & purificación , Glicósidos/química , Glicósidos/aislamiento & purificación , Humanos , Extractos Vegetales/química , Extractos Vegetales/aislamiento & purificación , Plasmodium falciparum/química
7.
J Nat Prod ; 83(3): 569-577, 2020 03 27.
Artículo en Inglés | MEDLINE | ID: mdl-31577436

RESUMEN

In our continuing search for novel natural products with antiplasmodial activity, an extract of Aniba citrifolia was found to have good activity, with an IC50 value less than 1.25 µg/mL. After bioassay-directed fractionation, the known indolizinium alkaloid anibamine (1) and the new indolizinium alkaloid anibamine B (2) were isolated as the major bioactive constituents, with antiplasmodial IC50 values of 0.170 and 0.244 µM against the drug-resistant Dd2 strain of Plasmodium falciparum. The new coumarin anibomarin A (3), the new norneolignan anibignan A (5), and six known neolignans (7-12) were also obtained. The structures of all the isolated compounds were determined based on analyses of 1D and 2D NMR spectroscopic and mass spectrometric data, and the absolute configuration of anibignan A (5) was assigned from its ECD spectrum. Evaluation of a library of 28 anibamine analogues (13-40) indicated that quaternary charged analogues had IC50 values as low as 58 nM, while uncharged analogues were inactive or significantly less active. Assessment of the potential effects of anibamine and its analogues on the intraerythrocytic stages and morphological development of P. falciparum revealed substantial activity against ring stages for compounds with two C-10 side chains, while those with only one C-10 side chain exhibited substantial activity against trophozoite stages, suggesting different mechanisms of action.


Asunto(s)
Alcaloides/farmacología , Antimaláricos/farmacología , Lauraceae/química , Plasmodium falciparum/efectos de los fármacos , Piridinas/farmacología , Línea Celular Tumoral , Guyana , Humanos , Estructura Molecular , Fitoquímicos/farmacología
8.
Ann Vasc Surg ; 60: 182-192, 2019 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-31075457

RESUMEN

BACKGROUND: The use of arteriovenous fistula (AVF) is hampered by long surgical wait times, slow maturation, and upwards of 60% that do not mature. We describe our clinical experience in using a system with a 4F catheter profile for endovascular AVF creation in patients on hemodialysis. METHODS: This was a multioperator, single-center, single-arm, prospective study intended to evaluate safety and efficacy of a 4 Fr endovascular AVF (endoAVF) system for the creation of vascular access in hemodialysis patients. The study was performed after institutional review board approval at Italian Hospital (Asuncion, Paraguay). Patients were followed up at regular intervals through 6 months to determine procedural, maturation, and cannulation success as well as intervention rate and patency. RESULTS: From May to November 2016, 32 patients underwent the endoAVF procedure with no device-related adverse events. An endoAVF was successfully created in the proximal forearm for all 32 patients (20 between the radial artery and radial vein; 12 between the ulnar artery and ulnar vein). Wrist access was used for 72% (23/32) of the procedures for the arterial catheter and 59% (19/32) of the procedures for the venous catheter. The device successfully created an endoAVF in every patient for a technical success rate of 100% (32/32). The device- or procedure-related serious adverse event rate was 3% (1/32); one patient experienced a venous guidewire perforation successfully managed with a stent graft. Primary and cumulative patency rates through 6 months were 83% and 87%, respectively, with an intervention rate of 0.21 per patient-year. Physiological suitability, as defined by target flow rates ≥500 ml/min and cannulation vessel diameters ≥4 mm, was achieved in 91% (29/32) of patients by 90 days. Successful 2-needle cannulation was achieved in 78% (21/27) by 90 days, with mean time to cannulation of 43 ± 14 days. Functional cannulation, as defined by successful 2-needle cannulation for two-thirds of the dialysis sessions within 1 month, was achieved in 95% (20/21) of the patients who were successfully cannulated for an overall rate of 74% (20/27). All patients who achieved functional cannulation had their central venous catheters (CVCs) removed before the 90-day follow-up for a CVC removal rate of 74% (20/27). CONCLUSIONS: The 4 Fr endoAVF system allowed for multiple access and fistula creation site options to tailor the procedure to individual patient anatomy. Furthermore, the outcomes are comparable to previous generation endoAVF technology, with a potentially improved safety profile because of the use of arteries at the wrist for access.


Asunto(s)
Derivación Arteriovenosa Quirúrgica/instrumentación , Procedimientos Endovasculares/instrumentación , Diálisis Renal , Extremidad Superior/irrigación sanguínea , Dispositivos de Acceso Vascular , Adulto , Anciano , Derivación Arteriovenosa Quirúrgica/efectos adversos , Procedimientos Endovasculares/efectos adversos , Diseño de Equipo , Femenino , Humanos , Masculino , Persona de Mediana Edad , Paraguay , Factores de Riesgo , Factores de Tiempo , Resultado del Tratamiento , Grado de Desobstrucción Vascular
9.
Bioorg Med Chem Lett ; 28(20): 3368-3371, 2018 11 01.
Artículo en Inglés | MEDLINE | ID: mdl-30219526

RESUMEN

Bioassay-guided fractionation of an extract of Carpha glomerata (Cyperaceae) led to the isolation of seven compounds. Compounds 1 (carphorin A), 3 (carphorin C), 4 (carphorin D), and 5 (carphabene) are new compounds, and compound 2 (8-(3″-hydroxyisoamyl)-naringenin) was isolated for the first time as a natural product. All structures were elucidated based on analyses of their HR-ESIMS and 1D and 2D NMR data. Compounds 1, 2, and 6, which have prenyl or hydroxyprenyl side chains, exhibited antiplasmodial activities with IC50 values of 5.2 ±â€¯0.6, 3.4 ±â€¯0.4, and 6.7 ±â€¯0.8 µM against the drug-resistant Dd2 strain of Plasmodium falciparum. In addition the prenylated stilbene 5 also showed good activity, with IC50 5.8 ±â€¯0.7 µM.


Asunto(s)
Antimaláricos/farmacología , Cyperaceae/química , Flavanonas/farmacología , Estilbenos/farmacología , Antimaláricos/química , Antimaláricos/aislamiento & purificación , Flavanonas/química , Flavanonas/aislamiento & purificación , Plasmodium falciparum/efectos de los fármacos , Estilbenos/química , Estilbenos/aislamiento & purificación
10.
Bioorg Med Chem Lett ; 28(1): 40-42, 2018 01 01.
Artículo en Inglés | MEDLINE | ID: mdl-29162457

RESUMEN

A bioassay-guided fractionation and chemical investigation of Amaryllis belladonna Steud. bulbs resulted in the isolation and identification of the new crinane alkaloid 1,4-dihydroxy-3-methoxy powellan (1), along with the 3 known crinane alkaloids 2-4 and the two lycorane alkaloids 5-6. The structures were elucidated by interpretation of combined HR-ESIMS, CD and 2D NMR spectroscopic data. Among these isolated compounds the lycorane-type alkaloid acetylcaranine (5) exhibited strong antiplasmodial activity, while compounds 3 and 4 were moderately active, and compounds 1 and 6 were inactive.


Asunto(s)
Alcaloides/química , Alcaloides de Amaryllidaceae/química , Antimaláricos/química , Asparagales/química , Alcaloides/aislamiento & purificación , Alcaloides/farmacología , Alcaloides de Amaryllidaceae/aislamiento & purificación , Alcaloides de Amaryllidaceae/farmacología , Antimaláricos/aislamiento & purificación , Antimaláricos/farmacología , Asparagales/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Dicroismo Circular , Humanos , Espectroscopía de Resonancia Magnética , Conformación Molecular , Extractos Vegetales/química , Raíces de Plantas/química , Raíces de Plantas/metabolismo , Plasmodium falciparum/efectos de los fármacos , Espectrometría de Masa por Ionización de Electrospray
11.
J Nat Prod ; 81(3): 475-483, 2018 03 23.
Artículo en Inglés | MEDLINE | ID: mdl-29048892

RESUMEN

Nine new compounds containing either a chromane or chromene ring moiety were isolated from the monotypic plant Koeberlinia spinosa. Compounds 1-4 are chromanes with all possible E and Z isomers of the isoprenoid side chain, with compound 5 a methylated derivative of 1. Compounds 6 and 7 were assigned as diastereomeric cyclized derivatives of 2 and were probably artifacts formed during the extraction or the isolation processes. Compounds 8 and 9 were characterized as new chromenes. Structure elucidation of 1-9 was conducted via 1D and 2D NMR spectroscopic data interpretation, and absolute configurations were determined by ECD spectroscopic analysis. Compounds 2, 5, 6, and 7 had weak antiplasmodial activity, while none of the compounds exhibited antiproliferative activity. The isolation, structure elucidation, and biological evaluation of these compounds are presented.


Asunto(s)
Antimaláricos/farmacología , Benzopiranos/farmacología , Magnoliopsida/química , Plasmodium falciparum/efectos de los fármacos , Animales , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Espectroscopía de Resonancia Magnética/métodos
12.
Am J Kidney Dis ; 70(4): 486-497, 2017 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-28624422

RESUMEN

BACKGROUND: Hemodialysis arteriovenous fistulas (AVFs) are suboptimally used primarily due to problems with maturation, early thrombosis, and patient nonacceptance. An endovascular approach to fistula creation without open surgery offers another hemodialysis vascular access option. STUDY DESIGN: Prospective, single-arm, multicenter study (Novel Endovascular Access Trial [NEAT]). SETTINGS & PARTICIPANTS: Consecutive adult non-dialysis-dependent and dialysis-dependent patients referred for vascular access creation at 9 centers in Canada, Australia, and New Zealand. INTERVENTION: Using catheter-based endovascular technology and radiofrequency energy, an anastomosis was created between target vessels, resulting in an endovascular AVF (endoAVF). OUTCOMES: Safety, efficacy, functional usability, and patency end points. MEASUREMENTS: Safety as percentage of device-related serious adverse events; efficacy as percentage of endoAVFs physiologically suitable (brachial artery flow ≥ 500mL/min, vein diameter ≥ 4mm) for dialysis within 3 months; functional usability of endoAVFs to provide prescribed dialysis via 2-needle cannulation; primary and cumulative endoAVF patencies per standardized definitions. RESULTS: 80 patients were enrolled (20 roll-in and 60 participants in the full analysis set; the latter are reported). EndoAVFs were created in 98% of participants; 8% had a serious procedure-related adverse event (2% device related). 87% were physiologically suitable for dialysis (eg, mean brachial artery flow, 918mL/min; endoAVF vein diameter, 5.2mm [cephalic vein]). EndoAVF functional usability was 64% in participants who received dialysis. 12-month primary and cumulative patencies were 69% and 84%, respectively. LIMITATIONS: Due to the unique anatomy and vessels used to create endoAVFs, this was a single-arm study without a surgical comparator. CONCLUSIONS: An endoAVF can be reliably created using a radiofrequency magnetic catheter-based system, without open surgery and with minimal complications. The endoAVF can be successfully used for hemodialysis and demonstrated high 12-month cumulative patencies. It may be a viable alternative option for achieving AVFs for hemodialysis patients in need of vascular access.


Asunto(s)
Derivación Arteriovenosa Quirúrgica/métodos , Procedimientos Endovasculares , Diálisis Renal , Adulto , Anciano , Anciano de 80 o más Años , Fístula Arteriovenosa , Femenino , Antebrazo/irrigación sanguínea , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos
13.
Nat Commun ; 15(1): 5356, 2024 Jun 25.
Artículo en Inglés | MEDLINE | ID: mdl-38918378

RESUMEN

Type 1 polyketides are a major class of natural products used as antiviral, antibiotic, antifungal, antiparasitic, immunosuppressive, and antitumor drugs. Analysis of public microbial genomes leads to the discovery of over sixty thousand type 1 polyketide gene clusters. However, the molecular products of only about a hundred of these clusters are characterized, leaving most metabolites unknown. Characterizing polyketides relies on bioactivity-guided purification, which is expensive and time-consuming. To address this, we present Seq2PKS, a machine learning algorithm that predicts chemical structures derived from Type 1 polyketide synthases. Seq2PKS predicts numerous putative structures for each gene cluster to enhance accuracy. The correct structure is identified using a variable mass spectral database search. Benchmarks show that Seq2PKS outperforms existing methods. Applying Seq2PKS to Actinobacteria datasets, we discover biosynthetic gene clusters for monazomycin, oasomycin A, and 2-aminobenzamide-actiphenol.


Asunto(s)
Espectrometría de Masas , Familia de Multigenes , Sintasas Poliquetidas , Policétidos , Policétidos/metabolismo , Policétidos/química , Sintasas Poliquetidas/genética , Sintasas Poliquetidas/metabolismo , Espectrometría de Masas/métodos , Minería de Datos/métodos , Aprendizaje Automático , Actinobacteria/genética , Actinobacteria/metabolismo , Genoma Bacteriano , Algoritmos , Productos Biológicos/química , Productos Biológicos/metabolismo
14.
Eur J Med Chem ; 259: 115634, 2023 Nov 05.
Artículo en Inglés | MEDLINE | ID: mdl-37499290

RESUMEN

A key step of hepatitis B virus (HBV) replication is the selective packaging of pregenomic RNA (pgRNA) by core protein (Cp) dimers, forming a nucleocapsid where the reverse transcriptional viral DNA replication takes place. One approach in the development of new anti-HBV drugs is to disrupt the assembly of HBV nucleocapsids by misdirecting Cp dimers to assemble morphologically normal capsids devoid of pgRNA. In this study, we built upon our previous discovery of benzamide-derived HBV capsid assembly modulators by exploring fused bicyclic scaffolds with an exocyclic amide that is ß, γ to the fused ring, and identified 1,2,3,4-tetrahydroquinoxaline derived phenyl ureas as a novel scaffold. Structure-activity relationship studies showed that a favorable hydrophobic substitution can be tolerated at the 2-position of the 1,2,3,4-tetrahydroquinoxaline core, and the resulting compound 88 demonstrated comparable or improved antiviral potencies in mouse and human hepatocyte-derived HBV-replicating cell lines compared to our previously reported benzamide compound, 38017 (8). In addition, a novel bis-urea series based on 1,2,3,4-tetrahydroquinoxaline was also found to inhibit HBV DNA replication with sub-micromolar EC50 values. The mode of action of these compounds is consistent with specific inhibition of pgRNA encapsidation into nucleocapsids in hepatocytes.


Asunto(s)
Virus de la Hepatitis B , Hepatitis B , Humanos , Animales , Ratones , Virus de la Hepatitis B/metabolismo , Replicación Viral , Ensamble de Virus , Replicación del ADN , ARN Viral/genética , ADN Viral , Nucleocápside/metabolismo , Antivirales/química , Benzamidas/farmacología , Hepatitis B/tratamiento farmacológico
15.
Am J Bot ; 99(7): e274-6, 2012 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-22739708

RESUMEN

PREMISE OF THE STUDY: Microsatellite markers were developed in Actaea racemosa to analyze population genetic structure, compare genetic diversity across the species' range, and provide a genetic context for studies of phytochemical variation. METHODS AND RESULTS: A total of seven polymorphic loci were screened in 60 individuals from 12 localities. The number of alleles per locus ranged from three to six, and observed heterozygosity ranged from 0.133 to 0.900. Most of the loci tested cross-amplified in A. pachypoda, A. podocarpa, and A. rubra, indicating the utility of these markers for the genus. CONCLUSIONS: These new loci will provide tools for population genetics studies, including the characterization of genetic variation in A. racemosa and other eastern North American species of Actaea.


Asunto(s)
Cimicifuga/genética , Repeticiones de Microsatélite , Alelos , ADN de Plantas/genética , Marcadores Genéticos , Variación Genética , Genética de Población/métodos , Plantas Medicinales/genética
16.
Emerg Radiol ; 19(4): 317-22, 2012 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-22419058

RESUMEN

Mineral foreign bodies (stones) are infrequent findings in clinical and radiological practice. However, a growing number of reports indicate that they raise clinical and diagnostic concern in ophthalmology, neurosurgery, maxillofacial surgery, otolaryngology, gastroenterology, and vascular surgery. Dense finding in the soft tissue without clear history of foreign body penetration may represent diagnostic challenge mimicking calcifications or bony fragments. The aim of this work is to analyze the appearance of stone foreign bodies on radiographs and computed tomography. A collection of minerals and rocks was used for analysis. The clinical case of a stony foreign body which penetrated into the soft tissue of the leg is used to demonstrate the diagnostic challenge and management. Available literature describing imaging characteristics of stones was reviewed. The results of this work will help in diagnostic interpretation and assessment of stone foreign body composition.


Asunto(s)
Cuerpos Extraños/diagnóstico por imagen , Traumatismos de la Rodilla/diagnóstico por imagen , Tomografía Computarizada por Rayos X/métodos , Accidentes por Caídas , Adolescente , Diagnóstico Diferencial , Cuerpos Extraños/cirugía , Humanos , Traumatismos de la Rodilla/cirugía , Masculino , Ultrasonografía Intervencional
17.
Microorganisms ; 10(11)2022 Nov 15.
Artículo en Inglés | MEDLINE | ID: mdl-36422330

RESUMEN

New therapeutic agents for cryptosporidiosis are a critical medical need. The marine organic compound, tartrolon E (trtE), is highly effective against multiple apicomplexan parasites, including Cryptosporidium. Understanding the mechanism of action of trtE is required to advance in the drug development pipeline. Here, we validate using Nluc C. parvum parasites for the study of trtE and pinpoint the life stage targeted by trtE. Results show that trtE kills Nluc and wild type C. parvum with equal efficiency, confirming the use of the Nluc C. parvum to study this compound. Results revealed that trtE kills the parasite within an hour of treatment and while the compound has no effect on viability of sporozoites, trtE does inhibit establishment of infection. Targeting treatment at particular life cycle stages demonstrated that trtE is effective against asexual of the parasite but has reduced efficacy against mature sexual stages. Gene expression analysis shows that trtE inhibits the early sexual stage of the parasite. Results from these studies will aid the development of trtE as a therapeutic for cryptosporidiosis.

18.
AJR Am J Roentgenol ; 195(2): W96-104, 2010 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-20651180

RESUMEN

OBJECTIVE: The purpose of this work was to show the radiologic signs named after weapons and munitions along with their military counterparts to help radiologists recognize these signs, which will allow confident interpretation and diagnosis. CONCLUSION: Numerous pathologic conditions have classic radiologic manifestations that resemble weapons and ammunition. Most of these signs are highly memorable and easy to recognize. However, the names of the weapons (some of them antique and some not commonly known) may confuse radiologists who are not familiar with the appearance of such weapons as the scimitar, bayonet, or dagger. The value of the signs is reduced if the radiologist is unfamiliar with the appearance of the corresponding weapon.


Asunto(s)
Diagnóstico por Imagen/clasificación , Sustancias Explosivas , Terminología como Asunto , Armas , Humanos
19.
J Can Dent Assoc ; 76: a3, 2010.
Artículo en Inglés | MEDLINE | ID: mdl-20633336

RESUMEN

BACKGROUND AND OBJECTIVE: Disk displacement frequently causes dysfunction of the temporomandibular joint (TMJ). Magnetic resonance imaging (MRI) of the TMJ is 95% accurate in the assessment of disk position and form. Various restorative procedures are used for treatment of disk displacement. However, several authors have noted a lack of correlation between MRI findings of disk displacement and the extent of pain and dysfunction of the TMJ. The purpose of this study was to evaluate whether MRI findings of various degrees of disk displacement could be correlated with the presence of clinical signs and symptoms in patients with a clinical disorder of the TMJ. MATERIALS AND METHODS: One hundred and forty-four TMJs (in 72 patients) were imaged. Displacement of the posterior band in relation to the condyle was quantified as mild or significant. RESULTS: Disk displacement was found in 45 (54%) of the 84 symptomatic joints and 13 (22%) of the 60 asymptomatic joints. Among the 84 symptomatic joints, 31 (37%) had disk displacement with reduction and 14 (17%) had disk displacement without reduction. In the latter group, 11 (79%) of the 14 joints had significant displacement of the posterior band (8 or 9 o'clock) and 21% had mild displacement of the posterior band (10 o'clock). Of the 60 clinically asymptomatic joints, 47 (78%) had no signs of disk displacement on MRI, whereas 13 (22%) had disk displacement with reduction. None of the asymptomatic joints had disk displacement without reduction. The difference in occurrence of disk displacement between symptomatic and asymptomatic joints was statistically significant (54% vs. 22%; p < 0.001). However, the difference in occurrence of disk displacement with reduction of the disk on mouth opening was not statistically significant (37% vs. 22%; p = 0.06). CONCLUSIONS: Disk displacement on MRI correlated well with clinical symptoms in cases of significant disk displacement and in cases of disk displacement without reduction. When disk displacement with reduction was mild, there was no statistically significant difference between symptomatic and asymptomatic joints, which suggests that other causes should be considered.


Asunto(s)
Luxaciones Articulares/patología , Disco de la Articulación Temporomandibular/patología , Trastornos de la Articulación Temporomandibular/patología , Adulto , Anciano , Anciano de 80 o más Años , Humanos , Luxaciones Articulares/complicaciones , Luxaciones Articulares/diagnóstico por imagen , Imagen por Resonancia Magnética , Persona de Mediana Edad , Variaciones Dependientes del Observador , Radiografía , Reproducibilidad de los Resultados , Estudios Retrospectivos , Sensibilidad y Especificidad , Índice de Severidad de la Enfermedad , Estadística como Asunto , Disco de la Articulación Temporomandibular/diagnóstico por imagen , Trastornos de la Articulación Temporomandibular/complicaciones , Trastornos de la Articulación Temporomandibular/diagnóstico por imagen , Adulto Joven
20.
Antibiotics (Basel) ; 9(6)2020 Jun 11.
Artículo en Inglés | MEDLINE | ID: mdl-32545188

RESUMEN

Listeria monocytogenes is a foodborne pathogen responsible for about 1600 illnesses each year in the United States (US) and about 2500 confirmed invasive human cases in European Union (EU) countries. Several technologies and antimicrobials are applied to control the presence of L. monocytogenes in food. Among these, the use of natural antimicrobials is preferred by consumers. This is due to their ability to inhibit the growth of foodborne pathogens but not prompt negative safety concerns. Among natural antimicrobials, plant extracts are used to inactivate L. monocytogenes. However, there is a large amount of these types of extracts, and their active compounds remain unexplored. The aim of this study was to evaluate the antibacterial activity against L. monocytogenes of about 800 plant extracts derived from plants native to different countries worldwide. The minimal inhibitory concentrations (MICs) were determined, and scanning electron microscopy (SEM) was used to verify how the plant extracts affected L. monocytogenes at the microscopic level. Results showed that 12 of the plant extracts had inhibitory activity against L. monocytogenes. Future applications of this study could include the use of these plant extracts as new preservatives to reduce the risk of growth of pathogens and contamination in the food industry from L. monocytogenes.

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