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1.
Nature ; 584(7822): 614-618, 2020 08.
Artículo en Inglés | MEDLINE | ID: mdl-32612233

RESUMEN

Oral antiretroviral agents provide life-saving treatments for millions of people living with HIV, and can prevent new infections via pre-exposure prophylaxis1-5. However, some people living with HIV who are heavily treatment-experienced have limited or no treatment options, owing to multidrug resistance6. In addition, suboptimal adherence to oral daily regimens can negatively affect the outcome of treatment-which contributes to virologic failure, resistance generation and viral transmission-as well as of pre-exposure prophylaxis, leading to new infections1,2,4,7-9. Long-acting agents from new antiretroviral classes can provide much-needed treatment options for people living with HIV who are heavily treatment-experienced, and additionally can improve adherence10. Here we describe GS-6207, a small molecule that disrupts the functions of HIV capsid protein and is amenable to long-acting therapy owing to its high potency, low in vivo systemic clearance and slow release kinetics from the subcutaneous injection site. Drawing on X-ray crystallographic information, we designed GS-6207 to bind tightly at a conserved interface between capsid protein monomers, where it interferes with capsid-protein-mediated interactions between proteins that are essential for multiple phases of the viral replication cycle. GS-6207 exhibits antiviral activity at picomolar concentrations against all subtypes of HIV-1 that we tested, and shows high synergy and no cross-resistance with approved antiretroviral drugs. In phase-1 clinical studies, monotherapy with a single subcutaneous dose of GS-6207 (450 mg) resulted in a mean log10-transformed reduction of plasma viral load of 2.2 after 9 days, and showed sustained plasma exposure at antivirally active concentrations for more than 6 months. These results provide clinical validation for therapies that target the functions of HIV capsid protein, and demonstrate the potential of GS-6207 as a long-acting agent to treat or prevent infection with HIV.


Asunto(s)
Fármacos Anti-VIH/farmacología , Fármacos Anti-VIH/uso terapéutico , Proteínas de la Cápside/antagonistas & inhibidores , VIH-1/efectos de los fármacos , Adolescente , Adulto , Fármacos Anti-VIH/química , Proteínas de la Cápside/genética , Proteínas de la Cápside/metabolismo , Línea Celular , Células Cultivadas , Farmacorresistencia Viral/genética , Femenino , VIH-1/crecimiento & desarrollo , Humanos , Masculino , Persona de Mediana Edad , Modelos Moleculares , Replicación Viral/efectos de los fármacos , Adulto Joven
2.
Clin Infect Dis ; 72(11): e815-e824, 2021 06 01.
Artículo en Inglés | MEDLINE | ID: mdl-33043969

RESUMEN

BACKGROUND: Treatment with vesatolimod, an investigational, oral, toll-like receptor 7 (TLR7) agonist, leads to sustained viral remission in some non-human primates when combined with anti-envelope antibodies or therapeutic vaccines. We report results of a Phase Ib study evaluating safety, pharmacokinetics, and pharmacodynamics of vesatolimod in adults living with human immunodeficiency virus (HIV)-1. METHODS: In this double-blind, multicenter, placebo-controlled trial, participants on antiretroviral therapy with screening plasma HIV-1 RNA levels <50 copies/mL were randomized (6:2) to receive 6-10 doses of vesatolimod (1-12 mg) or matching placebo orally every other week in sequential dose-escalation cohorts. The primary study objectives included establishing the safety and virologic effects of vesatolimod (change from baseline in plasma HIV-1 RNA). Pharmacokinetics and pharmacodynamic/immunologic activity were assessed as secondary objectives. RESULTS: A total of 48 individuals were randomly assigned to vesatolimod (n = 36) or placebo (n = 12). Vesatolimod was generally well tolerated, with no study drug-related serious adverse events or adverse events leading to study drug discontinuation. There were no statistically significant changes from baseline in plasma HIV-1 RNA in the vesatolimod groups, compared to placebo.Vesatolimod plasma exposures increased dose proportionally; consistent responses in cytokines, interferon-stimulated gene expression, and lymphocyte activation were observed with increasing dose levels above 4 mg. Peak elevations 24 hours after receipt of a 6 mg dose were >3.9-fold higher for interferon gamma-induced protein 10 (IP-10), interleukin-1 receptor antagonist (IL-1RA), interferon-inducible T-cell alpha chemoattractant (ITAC) when compared to baseline values. CONCLUSIONS: Vesatolimod was well tolerated at doses ranging from 1 to 12 mg. Immune stimulation was observed at doses above 4 mg, providing rationale for future combination trials in people living with HIV. CLINICAL TRIALS REGISTRATION: NCT02858401.


Asunto(s)
Infecciones por VIH , VIH-1 , Antivirales/uso terapéutico , Método Doble Ciego , Infecciones por VIH/tratamiento farmacológico , Humanos , Pteridinas/uso terapéutico , Receptor Toll-Like 7
3.
Clin Pharmacokinet ; 63(2): 241-253, 2024 02.
Artículo en Inglés | MEDLINE | ID: mdl-38236562

RESUMEN

BACKGROUND AND OBJECTIVE: Lenacapavir (LEN) is a novel, first-in-class, multistage, selective inhibitor of human immunodeficiency virus type 1 (HIV-1) capsid function recently approved for the treatment of HIV-1 infection in heavily treatment-experienced adults with multidrug-resistant HIV-1 infection. The purpose of this multicohort study was to evaluate the pharmacokinetics, metabolism, excretion, safety, and tolerability of LEN following a single intravenous (IV) infusion of 10 mg LEN or 20 mg [14C]LEN in healthy participants. METHODS: Twenty-one healthy adult participants were enrolled into the study and received either a single IV dose of 10 mg LEN (n = 8 active, n = 3 placebo; cohort 1) or a single IV dose of 20 mg [14C]LEN containing 200 µCi (n = 10; cohort 2). Blood, urine, and feces samples (when applicable) were collected after dosing, and radioactivity (cohort 2) was assessed using liquid scintillation counting in both plasma and excreta. LEN in plasma was quantified by liquid chromatography (LC) tandem mass spectroscopy (MS/MS) method bioanalysis. Metabolite profiling in plasma and excreta were performed using LC-fraction collect (FC)-high-resolution MS and LC-FC-accelerator mass spectrometry in plasma. RESULTS: Between the 10 mg and 20 mg doses of LEN, the observed plasma exposure of LEN doubled, while the elimination half-life was similar. Following administration of 20 mg [14C]LEN (200 µCi), the mean cumulative recovery of [14C] radioactivity was 75.9% and 0.24% from feces and urine, respectively. The mean whole [14C] blood-to-plasma concentration ratio was 0.5-0.7, which showed a low distribution of LEN to red blood cells. Intact LEN was the predominant circulating species in plasma (representing 68.8% of circulating radioactivity), and no single metabolite contributed to > 10% of total radioactivity exposure through 1176 h postdose. Similarly, intact LEN was the most abundant component (32.9% of administered dose; 75.9% of recovered dose) measured in feces, with metabolites accounting for trace amounts. These results suggest metabolism of LEN is not a primary pathway of elimination. Of the metabolites observed in the feces, the three most abundant metabolites were direct phase 2 conjugates (glucuronide, hexose, and pentose conjugates), with additional metabolites formed to a lesser extent via other pathways. The administered LEN IV doses were generally safe and well-tolerated across participants in this study. CONCLUSIONS: The results of this mass balance study indicated that LEN was majorly eliminated as intact LEN via the feces. The renal pathway played a minor role in LEN elimination (0.24%). In addition, no major circulating metabolites in plasma or feces were found, indicating minimal metabolism of LEN.


Asunto(s)
Fármacos Anti-VIH , VIH-1 , Adulto , Humanos , Infusiones Intravenosas , Cápside , Voluntarios Sanos , Espectrometría de Masas en Tándem , Biotransformación , Heces/química , Administración Oral
4.
Front Immunol ; 13: 899617, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35720389

RESUMEN

COVID-19 emergency use authorizations and approvals for vaccines were achieved in record time. However, there remains a need to develop additional safe, effective, easy-to-produce, and inexpensive prevention to reduce the risk of acquiring SARS-CoV-2 infection. This need is due to difficulties in vaccine manufacturing and distribution, vaccine hesitancy, and, critically, the increased prevalence of SARS-CoV-2 variants with greater contagiousness or reduced sensitivity to immunity. Antibodies from eggs of hens (immunoglobulin Y; IgY) that were administered the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein were developed for use as nasal drops to capture the virus on the nasal mucosa. Although initially raised against the 2019 novel coronavirus index strain (2019-nCoV), these anti-SARS-CoV-2 RBD IgY surprisingly had indistinguishable enzyme-linked immunosorbent assay binding against variants of concern that have emerged, including Alpha (B.1.1.7), Beta (B.1.351), Delta (B.1.617.2), and Omicron (B.1.1.529). This is different from sera of immunized or convalescent patients. Culture neutralization titers against available Alpha, Beta, and Delta were also indistinguishable from the index SARS-CoV-2 strain. Efforts to develop these IgY for clinical use demonstrated that the intranasal anti-SARS-CoV-2 RBD IgY preparation showed no binding (cross-reactivity) to a variety of human tissues and had an excellent safety profile in rats following 28-day intranasal delivery of the formulated IgY. A double-blind, randomized, placebo-controlled phase 1 study evaluating single-ascending and multiple doses of anti-SARS-CoV-2 RBD IgY administered intranasally for 14 days in 48 healthy adults also demonstrated an excellent safety and tolerability profile, and no evidence of systemic absorption. As these antiviral IgY have broad selectivity against many variants of concern, are fast to produce, and are a low-cost product, their use as prophylaxis to reduce SARS-CoV-2 viral transmission warrants further evaluation. Clinical Trial Registration: https://www.clinicaltrials.gov/ct2/show/NCT04567810, identifier NCT04567810.


Asunto(s)
COVID-19 , SARS-CoV-2 , Animales , Anticuerpos Antivirales , COVID-19/prevención & control , Pollos , Femenino , Humanos , Inmunoglobulinas , Ratas , Glicoproteína de la Espiga del Coronavirus
5.
Clin Pharmacol Drug Dev ; 10(4): 376-383, 2021 04.
Artículo en Inglés | MEDLINE | ID: mdl-32989920

RESUMEN

Filgotinib (FIL) is a potent and selective JAK1 inhibitor in clinical development for treatment of severe inflammatory diseases. A drug-drug interaction study to evaluate the potential effect of FIL on the pharmacokinetics (PK) of the oral contraceptive levonorgestrel (LEVO)/ethinyl estradiol (EE) was conducted. This was a phase 1, open-label, randomized, crossover study in healthy female subjects (N = 24). Subjects received a single dose of LEVO (150 µg)/EE (30 µg) alone (reference), or in combination with multiple-dose FIL (200 mg once daily for 15 days; test). Intensive PK sampling was conducted, and safety was assessed throughout the study. PK interactions were evaluated using 90% confidence intervals of the geometric least squares mean ratios of the test versus reference treatments. All 24 subjects enrolled completed study treatments. Coadministration of FIL with the oral contraceptive did not alter the PK of LEVO and EE; the 90% confidence intervals of the geometric least squares mean ratios were contained within bioequivalence bounds (80%-125%). Exposures of FIL were consistent with observed clinical exposure data. Study treatments were generally well tolerated. All adverse events were mild. Coadministration with FIL did not alter the PK of LEVO/EE, and hormonal contraceptives can serve as an effective contraception method for subjects on FIL treatment.


Asunto(s)
Anticonceptivos Hormonales Orales/farmacocinética , Etinilestradiol/farmacocinética , Inhibidores de las Cinasas Janus/farmacología , Levonorgestrel/farmacocinética , Piridinas/farmacología , Triazoles/farmacología , Adulto , Anticonceptivos Hormonales Orales/efectos adversos , Estudios Cruzados , Combinación de Medicamentos , Interacciones Farmacológicas , Etinilestradiol/efectos adversos , Femenino , Humanos , Janus Quinasa 1/antagonistas & inhibidores , Inhibidores de las Cinasas Janus/efectos adversos , Levonorgestrel/efectos adversos , Persona de Mediana Edad , Piridinas/efectos adversos , Triazoles/efectos adversos , Adulto Joven
6.
Sci Transl Med ; 13(599)2021 06 23.
Artículo en Inglés | MEDLINE | ID: mdl-34162752

RESUMEN

Toll-like receptor 7 (TLR7) agonists, in combination with other therapies, can induce sustained control of simian-human immunodeficiency virus (SHIV) or simian immunodeficiency virus (SIV) in nonhuman primates. Here, we report the results of a randomized, double-blind, placebo-controlled phase 1b clinical trial of an oral TLR7 agonist, vesatolimod, in HIV-1-infected controllers on antiretroviral therapy (ART). We randomized participants 2:1 to receive vesatolimod (n = 17) or placebo (n = 8) once every other week for a total of 10 doses while continuing on ART. ART was then interrupted, and the time to viral rebound was analyzed using the Kaplan-Meier method. Vesatolimod was associated with induction of immune cell activation, decreases in intact proviral DNA during ART, and a modest increase in time to rebound after ART was interrupted. The delayed viral rebound was predicted by the lower intact proviral DNA at the end of vesatolimod treatment (13 days after the final dose). Inferred pathway analysis suggested increased dendritic cell and natural killer cell cross-talk and an increase in cytotoxicity potential after vesatolimod dosing. Larger clinical studies will be necessary to assess the efficacy of vesatolimod-based combination therapies aimed at long-term control of HIV infection.


Asunto(s)
Infecciones por VIH , Síndrome de Inmunodeficiencia Adquirida del Simio , Virus de la Inmunodeficiencia de los Simios , Animales , Antirretrovirales/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Humanos , Pteridinas , Síndrome de Inmunodeficiencia Adquirida del Simio/tratamiento farmacológico , Receptor Toll-Like 7 , Carga Viral
7.
J Acquir Immune Defic Syndr ; 78(4): 465-472, 2018 08 01.
Artículo en Inglés | MEDLINE | ID: mdl-29649076

RESUMEN

BACKGROUND: Tenofovir alafenamide (TAF), a prodrug of the nucleotide analogue tenofovir (TFV), is an antiretroviral (ARV) agent approved either as a complete regimen [elvitegravir/cobicistat/emtricitabine (F)/TAF, rilpivirine/F/TAF, bictegravir/F/TAF], or for use with other ARVs (F/TAF), for treatment of HIV. TAF is a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) transporters. Disposition of TAF may be altered by comedications that can inhibit or induce P-gp or BCRP transporters. The effects of ARVs on the pharmacokinetics of TAF were evaluated in 3 studies. METHODS: Healthy participants received TAF administered alone or with rilpivirine in study 1, with dolutegravir, ritonavir-boosted atazanavir (ATV + RTV), lopinavir (LPV/RTV), or darunavir (DRV + RTV) in study 2, and with the pharmacokinetic enhancer cobicistat or efavirenz in study 3. RESULTS: Across the 3 studies, 98 participants received treatment with TAF and a coadministered agent (n = 10-34/cohort). All study treatments were well tolerated. TAF and TFV exposures were unaffected after co-administration with rilpivirine and dolutegravir. Coadministration with P-gp/BCRP inhibitors such as cobicistat or PI-based regimens (ATV + RTV, LPV/r, or DRV + RTV) resulted in a range of 6%-183% increases in TAF and 105%-316% increases in TFV exposure, whereas coadministration with a P-gp inducer, efavirenz, resulted in a 15%-24% decrease in TAF and TFV exposure. CONCLUSIONS: Evaluation of the drug interaction between TAF and other commonly prescribed boosted and unboosted ARVs provides characterization of the susceptibility of TAF and/or TFV pharmacokinetics to inhibitors or inducers of P-gp/BCRP transporters.


Asunto(s)
Adenina/análogos & derivados , Antirretrovirales/farmacocinética , Interacciones Farmacológicas , Adenina/administración & dosificación , Adenina/farmacocinética , Adolescente , Adulto , Alanina , Antirretrovirales/administración & dosificación , Quimioterapia Combinada/métodos , Femenino , Voluntarios Sanos , Humanos , Masculino , Persona de Mediana Edad , Tenofovir/análogos & derivados , Adulto Joven
8.
Circulation ; 111(1): 44-50, 2005 Jan 04.
Artículo en Inglés | MEDLINE | ID: mdl-15611364

RESUMEN

BACKGROUND: We previously showed that a selective activator peptide of epsilon-protein kinase C (PKC), psi(epsilon)RACK, conferred cardioprotection against ischemia-reperfusion when delivered ex vivo before the ischemic event. Here, we tested whether in vivo continuous systemic delivery of psi(epsilon)RACK confers sustained cardioprotection against ischemia-reperfusion in isolated mouse hearts and whether psi(epsilon)RACK treatment reduces infarct size or lethal arrhythmias in porcine hearts in vivo. METHODS AND RESULTS: After psi(epsilon)RACK was systemically administered in mice either acutely or continuously, hearts were subjected to ischemia-reperfusion in an isolated perfused model. Whereas psi(epsilon)RACK-induced cardioprotection lasted 1 hour after a single intraperitoneal injection, continuous treatment with psi(epsilon)RACK induced a sustained preconditioned state during the 10 days of delivery. There was no desensitization to the therapeutic effect, no downregulation of epsilonPKC, and no adverse effects after sustained psi(epsilon)RACK delivery. Porcine hearts were subjected to ischemia-reperfusion in vivo, and psi(epsilon)RACK was administered by intracoronary injection during the first 10 minutes of ischemia. psi(epsilon)RACK treatment reduced infarct size (34+/-2% versus 14+/-1%, control versus psi(epsilon)RACK) and resulted in fewer cases of ventricular fibrillation during ischemia-reperfusion (87.5% versus 50%, control versus psi(epsilon)RACK). CONCLUSIONS: The epsilonPKC activator psi(epsilon)RACK induced cardioprotection both in vivo and ex vivo, reduced the incidence of lethal arrhythmia during ischemia-reperfusion, and did not cause desensitization or downregulation of epsilonPKC after sustained delivery. Thus, psi(epsilon)RACK may be useful for patients with ischemic heart disease. In addition, the psi(epsilon)RACK peptide should be a useful pharmacological agent for animal studies in which systemic and sustained modulation of epsilonPKC in vivo is needed.


Asunto(s)
Antiarrítmicos/uso terapéutico , Cardiotónicos/uso terapéutico , Infarto del Miocardio/tratamiento farmacológico , Isquemia Miocárdica/tratamiento farmacológico , Daño por Reperfusión Miocárdica/prevención & control , Oligopéptidos/uso terapéutico , Proteína Quinasa C/efectos de los fármacos , Fibrilación Ventricular/prevención & control , Animales , Antiarrítmicos/administración & dosificación , Antiarrítmicos/farmacología , Cardiotónicos/administración & dosificación , Cardiotónicos/farmacología , Vasos Coronarios , Evaluación Preclínica de Medicamentos , Activación Enzimática/efectos de los fármacos , Inducción Enzimática/efectos de los fármacos , Femenino , Productos del Gen tat/administración & dosificación , Bombas de Infusión Implantables , Inyecciones Intraarteriales , Inyecciones Intraperitoneales , Ratones , Infarto del Miocardio/patología , Isquemia Miocárdica/enzimología , Oligopéptidos/administración & dosificación , Oligopéptidos/farmacología , Fragmentos de Péptidos/administración & dosificación , Proteína Quinasa C/metabolismo , Proteína Quinasa C-epsilon , Transporte de Proteínas , Sus scrofa , Fibrilación Ventricular/etiología , Productos del Gen tat del Virus de la Inmunodeficiencia Humana
9.
Am J Physiol Heart Circ Physiol ; 289(4): H1343-50, 2005 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-15894568

RESUMEN

Diabetes mellitus is complicated by the development of a primary cardiomyopathy, which contributes to the excess morbidity and mortality of this disorder. The protein kinase C (PKC) family of isozymes plays a key role in the cardiac phenotype expressed during postnatal development and in response to pathological stimuli. Hyperglycemia is an activating signal for cardiac PKC isozymes that modulate a myriad of cell events including cell death and survival. The epsilon-isozyme of the PKC family transmits a powerful survival signal in cardiac muscle cells. Accordingly, to test the hypothesis that endogenous activation of cardiac PKC-epsilon will protect against hyperglycemic cell injury and left ventricular dysfunction, diabetes mellitus was induced using streptozotocin in genetically engineered mice with cardiac-specific expression of the PKC-epsilon translocation activator [psiepsilon-receptors for activated C kinase (psiepsilon-RACK)]. The results demonstrate a striking PKC-epsilon cardioprotective phenotype in diabetic psiepsilon-RACK (epsilon-agonist) mice that is characterized by inhibition of the hyperglycemia apoptosis signal, attenuation of hyperglycemia-mediated oxidative stress, and preservation of parameters of left ventricular pump function. Hearts of diabetic epsilon-agonist mice exhibited selective trafficking of PKC-epsilon to membrane and mitochondrial compartments, phosphorylation/inactivation of the mitochondrial Bad protein, and inhibition of cytochrome c release. We conclude that activation of endogenous PKC-epsilon in hearts of diabetic epsilon-agonist mice promotes the survival phenotype, attenuates markers of oxidative stress, and inhibits the negative inotropic properties of chronic hyperglycemia.


Asunto(s)
Cardiomiopatías/metabolismo , Diabetes Mellitus Experimental/metabolismo , Miocardio/enzimología , Proteína Quinasa C/metabolismo , Transducción de Señal/fisiología , Animales , Apoptosis , Cardiomiopatías/etiología , Cardiomiopatías/patología , Citocromos c/metabolismo , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Experimental/patología , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Hiperglucemia/metabolismo , Hiperglucemia/patología , Ratones , Ratones Mutantes , Miocardio/patología , Estrés Oxidativo/fisiología , Fosforilación , Proteína Quinasa C/genética , Proteína Quinasa C-epsilon , Función Ventricular Izquierda
10.
Biochem Biophys Res Commun ; 318(4): 949-54, 2004 Jun 11.
Artículo en Inglés | MEDLINE | ID: mdl-15147964

RESUMEN

Intracellularly acting peptide modulators of signaling enzymes provide a powerful means to regulate signaling events. Delivery of peptides into cells is facilitated by conjugation to carrier peptides, such as Tat. When peptides are irreversibly conjugated to Tat, Tat-mediated subcellular localization may predominate, resulting in mislocalization of the peptide cargo. We have used intracellularly acting peptides, conjugated to Tat by a disulfide bond, to modulate protein kinase C (PKC) signaling; these PKC-modulating peptides are released from Tat upon intracellular delivery. Previously, the distribution of these peptides within tissue and throughout the body had not been demonstrated. We show here intravascular delivery of a PKC-peptide, reversibly conjugated to Tat, resulted in distribution throughout cardiac tissue. In addition, a single injection resulted in selective modulation of PKC activity in many organs. Therefore, intracellularly acting peptide modulators of signaling enzymes, reversibly conjugated to Tat, have extensive biodistribution and can be used to modulate signaling pathways in vivo.


Asunto(s)
Productos del Gen tat/farmacocinética , Péptidos/farmacocinética , Proteína Quinasa C/metabolismo , Secuencia de Aminoácidos , Animales , Transporte Biológico , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacocinética , Inhibidores Enzimáticos/farmacología , Fluoresceína-5-Isotiocianato/análogos & derivados , Fluoresceína-5-Isotiocianato/metabolismo , Productos del Gen tat/química , Inyecciones Intraperitoneales , Isoenzimas , Miocardio/metabolismo , Péptidos/química , Péptidos/farmacología , Fosforilación , Proteína Quinasa C/antagonistas & inhibidores , Proteína Quinasa C/genética , Ratas , Distribución Tisular , Xantenos/metabolismo
11.
Dev Biol ; 247(1): 127-36, 2002 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-12074557

RESUMEN

In Caenorhabditis elegans, let-60 Ras controls many cellular processes, such as differentiation of vulval epithelial cells, function of chemosensory neurons, and meiotic progression in the germ line. Although much is known about the let-60 Ras signaling pathway, relatively little is understood about the target genes induced by let-60 Ras signaling that carry out terminal effector functions leading to morphological change. We have used DNA microarrays to identify 708 genes that change expression in response to activated let-60 Ras.


Asunto(s)
Proteínas de Caenorhabditis elegans , Caenorhabditis elegans/genética , Regulación del Desarrollo de la Expresión Génica , Proteínas ras/genética , Animales , Caenorhabditis elegans/embriología , Proteínas del Helminto/genética , Análisis de Secuencia por Matrices de Oligonucleótidos , Transducción de Señal/genética
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