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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.
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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 JovenRESUMEN
Lenacapavir (LEN), a long-acting injectable, is the first approved human immunodeficiency virus type 1 capsid inhibitor and one of a few FDA-approved drugs that exhibit atropisomerism. LEN exists as a mixture of two class 2 atropisomers that interconvert at a fast rate (t1/2 <2 hours) with a ratio that is stable over time and unaffected by enzymes or binding to proteins in plasma. LEN exhibits low systemic clearance (CL) in nonclinical species and humans; however, in all species the observed CL was higher than the in vitro predicted CL. The volume of distribution was moderate in nonclinical species and consistent with the tissue distribution observed by whole body autoradiography in rats. LEN does not distribute to brain, consistent with being a P-glycoprotein (P-gp) substrate. Mechanistic drug disposition studies with [14C]LEN in IV-dosed BDC rats and dogs showed a substantial amount of unchanged LEN (31 - 60% of dose) excreted in feces, indicating that intestinal excretion (IE) was a major clearance pathway for LEN in both species. Coadministration of oral elacridar, a P-gp inhibitor, in rats decreased CL and IE of LEN. Renal excretion was <1% of dose in both species. In plasma, almost all radioactivity was unchanged LEN. Low levels of metabolites in excreta included LEN-conjugates with glutathione, pentose, and glucuronic acid, which were consistent with metabolites formed in vitro in Hµrel® hepatocyte cocultures and those observed in human. Our studies highlight the importance of IE for efflux substrates that are highly metabolically stable compounds with slow elimination rates. Significance Statement LEN is a long-acting injectable that exists as conformationally stable atropisomers. Due to an atropisomeric interconversion rate that significantly exceeds the in vivo elimination rate, the atropisomer ratio of LEN remains constant in circulation. The disposition of LEN highlights that intestinal excretion has a substantial part in the elimination of compounds that are metabolically highly stable and efflux transporter substrates.
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Lenacapavir (LEN) is a picomolar first-in-class capsid inhibitor of human immunodeficiency virus type 1 (HIV-1) with a multistage mechanism of action and no known cross resistance to other existing antiretroviral (ARV) drug classes. LEN exhibits a low aqueous solubility and exceptionally low systemic clearance following intravenous (IV) administration in nonclinical species and humans. LEN formulated in an aqueous suspension or a PEG/water solution formulation showed sustained plasma exposure levels with no unintended rapid drug release following subcutaneous (SC) administration to rats and dogs. A high total fraction dose release was observed with both formulations. The long-acting pharmacokinetics (PK) were recapitulated in humans following SC administration of both formulations. The SC PK profiles displayed two-phase absorption kinetics in both animals and humans with an initial fast-release absorption phase, followed by a slow-release absorption phase. Noncompartmental and compartmental analyses informed the LEN systemic input rate from the SC depot and exit rate from the body. Modeling-enabled deconvolution of the input rates from two processes: absorption of the soluble fraction (minor) from a direct fast-release process leading to the early PK phase and absorption of the precipitated fraction (major) from an indirect slow-release process leading to the later PK phase. LEN SC PK showed flip-flop kinetics due to the input rate being substantially slower than the systemic exit rate. LEN input rates via the slow-release process in humans were slower than those in both rats and dogs. Overall, the combination of high potency, exceptional stability, and optimal release rate from the injection depot make LEN well suited for a parenteral long-acting formulation that can be administered once up to every 6 months in humans for the prevention and treatment of HIV-1.
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Fármacos Anti-VIH , VIH-1 , Humanos , Ratas , Animales , Perros , Antirretrovirales , Cápside , Fármacos Anti-VIH/farmacología , Proteínas de la CápsideRESUMEN
Learning how to speak a second language (i.e., becoming a bilingual) and learning how to play a musical instrument (i.e., becoming a musician) are both thought to increase executive control through experience-dependent plasticity. However, evidence supporting this effect is mixed for bilingualism and limited for musicianship. In addition, the combined effects of bilingualism and musicianship on executive control are unknown. To determine whether bilingualism, musicianship, and combined bilingualism and musicianship improve executive control, we tested 219 young adults belonging to one of four groups (bilinguals, musicians, bilingual musicians, and controls) on a nonlinguistic, nonmusical, visual-spatial Simon task that measured the ability to ignore an irrelevant and misinformative cue. Results revealed that bilinguals, musicians, and bilingual musicians showed an enhanced ability to ignore a distracting cue relative to controls, with similar levels of superior performance among bilinguals, musicians, and bilingual musicians. These results indicate that bilingualism and musicianship improve executive control and have implications for educational and rehabilitation programs that use music and foreign language instruction to boost cognitive performance.
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Cognición/fisiología , Función Ejecutiva/fisiología , Multilingüismo , Música , Adolescente , Adulto , Femenino , Humanos , Masculino , Pruebas Neuropsicológicas , Adulto JovenRESUMEN
Chronic hepatitis B (CHB) virus infection afflicts hundreds of millions of people and causes nearly one million deaths annually. The high levels of circulating viral surface antigen (HBsAg) that characterize CHB may lead to T-cell exhaustion, resulting in an impaired antiviral immune response in the host. Agents that suppress HBsAg could help invigorate immunity toward infected hepatocytes and facilitate a functional cure. A series of dihydropyridoisoquinolizinone (DHQ) inhibitors of human poly(A) polymerases PAPD5/7 were reported to suppress HBsAg in vitro. An example from this class, RG7834, briefly entered the clinic. We set out to identify a potent, orally bioavailable, and safe PAPD5/7 inhibitor as a potential component of a functional cure regimen. Our efforts led to the identification of a dihydropyridophthalazinone (DPP) core with improved pharmacokinetic properties. A conformational restriction strategy and optimization of core substitution led to GS-8873, which was projected to provide deep HBsAg suppression with once-daily dosing.
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Musical experience may benefit learning of a new language by increasing the fidelity with which the auditory system encodes sound. In the current study, participants with varying degrees of musical experience were exposed to two statistically defined languages consisting of auditory Morse code sequences that varied in difficulty. We found an advantage for highly skilled musicians, relative to lower-skilled musicians, in learning novel Morse code-based words. Furthermore, in the more difficult learning condition, performance of lower-skilled musicians was mediated by their general cognitive abilities. We suggest that musical experience may improve processing of statistical information and that musicians' enhanced ability to learn statistical probabilities in a novel Morse code language may extend to natural language learning.
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Percepción Auditiva , Formación de Concepto , Modelos Estadísticos , Multilingüismo , Música/psicología , Aprendizaje Verbal , Comprensión , Femenino , Humanos , Masculino , Pruebas Neuropsicológicas/estadística & datos numéricos , Psicometría , Escalas de Wechsler/estadística & datos numéricos , Adulto JovenRESUMEN
[This corrects the article DOI: 10.3389/fpsyg.2023.1149062.].
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PURPOSE: To improve the credibility, reproducibility, and clinical utility of research findings, many scientific fields are implementing transparent and open research practices. Such open science practices include researchers making their data publicly available and preregistering their hypotheses and analyses. A way to enhance the adoption of open science practices is for journals to encourage or require submitting authors to participate in such practices. Accordingly, the American Speech-Language-Hearing Association's Journals Program has recently announced their intention to promote open science practices. Here, we quantitatively assess the extent to which several journals in communication sciences and disorders (CSD) encourage or require participation in several open science practices by using the Transparency and Openness Promotion (TOP) Factor metric. METHOD: TOP Factors were assessed for 34 CSD journals, as well as several journals in related fields. TOP Factors measure the level of implementation across 10 open science-related practices (e.g., data transparency, analysis plan preregistration, and replication) for a total possible score of 29 points. RESULTS: Collectively, CSD journals had very low TOP Factors (M = 1.4, range: 0-8). The related fields of Psychology (M = 4.0), Rehabilitation (M = 3.2), Linguistics (M = 1.7), and Education (M = 1.6) also had low scores, though Psychology and Rehabilitation had higher scores than CSD. CONCLUSION: CSD journals currently have low levels of encouraging or requiring participation in open science practices, which may impede adoption. Open Science Form: https://doi.org/10.23641/asha.21699458.
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Publicaciones Periódicas como Asunto , Humanos , Reproducibilidad de los Resultados , Comunicación , Lenguaje , AudiciónRESUMEN
How we remember the things that we see can be shaped by our prior experiences. Here, we examine how linguistic and sensory experiences interact to influence visual memory. Objects in a visual search that shared phonology (cat-cast) or semantics (dog-fox) with a target were later remembered better than unrelated items. Phonological overlap had a greater influence on memory when targets were cued by spoken words, while semantic overlap had a greater effect when targets were cued by characteristic sounds. The influence of overlap on memory varied as a function of individual differences in language experience -- greater bilingual experience was associated with decreased impact of overlap on memory. We conclude that phonological and semantic features of objects influence memory differently depending on individual differences in language experience, guiding not only what we initially look at, but also what we later remember.
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Lenguaje , Lingüística , Humanos , Memoria , Recuerdo Mental , SemánticaRESUMEN
How we perceive and learn about our environment is influenced by our prior experiences and existing representations of the world. Top-down cognitive processes, such as attention and expectations, can alter how we process sensory stimuli, both within a modality (e.g., effects of auditory experience on auditory perception), as well as across modalities (e.g., effects of visual feedback on sound localization). Here, we demonstrate that experience with different types of auditory input (spoken words vs. environmental sounds) modulates how humans remember concurrently-presented visual objects. Participants viewed a series of line drawings (e.g., picture of a cat) displayed in one of four quadrants while listening to a word or sound that was congruent (e.g., "cat" or
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How does the mind process linguistic and non-linguistic sounds? The current study assessed the different ways that spoken words (e.g., "dog") and characteristic sounds (e.g.,
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Percepción Auditiva/fisiología , Formación de Concepto/fisiología , Psicolingüística , Tecnología de Seguimiento Ocular , Femenino , Humanos , Masculino , Percepción del Habla/fisiología , Factores de Tiempo , Adulto JovenRESUMEN
OBJECTIVE: The purpose of the study was to determine whether listeners were less likely to believe a statement that is produced in an atypical voice, as compared to a typical voice. It was hypothesized that an atypical voice, characterized by abnormal roughness, strain, and pitch, would elicit increased skepticism. This hypothesis was based on previous evidence that there are negative stereotypes against individuals who have a voice disorder, and that increased difficulty processing an utterance can lead to disbelief. METHODS: In Experiment 1, 36 listeners rated obscure trivia statements (such as "the elephant is the only mammal that cannot jump" and "the first public library was opened in Vienna in 1745") as definitely false, probably false, probably true, or definitely true. The statements were produced by a speaker who used their typical voice and simulated an atypical voice (of severe deviance according to the CAPE-V), as well as two additional control speakers with typical voices. Experiment 2 was a replication of Experiment 1 with a new set of 36 listeners and a new set of speakers. In addition, Experiment 2 examined whether reduced credibility was due to negative stereotypes and/or processing difficulty, through questionnaire data and correlation analyses. RESULTS: The results were largely consistent with the hypothesis that statements produced in an atypical voice would be perceived as less credible. In both experiments, the percentage of definitely false ratings was higher for the atypical voice than for the typical voice and control voices, with a large effect size in Experiment 1 and a medium effect size in Experiment 2. Further, Experiment 2 suggested that reduced credibility was due to negative stereotypes but not processing difficulty. CONCLUSION: The current study reveals a social consequence of having a voice disorder, i.e., decreased perceived credibility, with implications for job-related success.
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Percepción del Habla , Confianza/psicología , Trastornos de la Voz , Voz , Humanos , Percepción Social , Encuestas y CuestionariosRESUMEN
Language is often present when people are encoding visual memories. For bilinguals, this language context can have different forms (i.e., Language A, Language B, or both Language A and B), and can change over the course of events. The current study examined whether a change in language context during a visual event or between visual events affects a bilingual's ability to remember visual information. English-Spanish bilinguals and control participants encoded three lists of novel shapes amid different task-irrelevant language contexts. Following each list, participants completed a free recall test in which they drew the novel shapes they remembered. Results indicated that a change in language context between events, but not during events, affected visual memory. Specifically, the switch in language context between the second and third event (such as an English context in list 2 switching to a Spanish context in list 3) produced a reliable memory advantage for the English-Spanish bilinguals (relative to the control participants). The results offer preliminary evidence that task-irrelevant language context can influence a bilingual's ability to remember non-linguistic information, as well as further evidence for context effects and multi-sensory effects in memory.
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People living with HIV (PLWH) have expressed concern about the life-long burden and stigma associated with taking pills daily and can experience medication fatigue that might lead to suboptimal treatment adherence and the emergence of drug-resistant viral variants, thereby limiting future treatment options1-3. As such, there is strong interest in long-acting antiretroviral (ARV) agents that can be administered less frequently4. Herein, we report GS-CA1, a new archetypal small-molecule HIV capsid inhibitor with exceptional potency against HIV-2 and all major HIV-1 types, including viral variants resistant to the ARVs currently in clinical use. Mechanism-of-action studies indicate that GS-CA1 binds directly to the HIV-1 capsid and interferes with capsid-mediated nuclear import of viral DNA, HIV particle production and ordered capsid assembly. GS-CA1 selects in vitro for unfit GS-CA1-resistant capsid variants that remain fully susceptible to other classes of ARVs. Its high metabolic stability and low solubility enabled sustained drug release in mice following a single subcutaneous dosing. GS-CA1 showed high antiviral efficacy as a long-acting injectable monotherapy in a humanized mouse model of HIV-1 infection, outperforming long-acting rilpivirine. Collectively, these results demonstrate the potential of ultrapotent capsid inhibitors as new long-acting agents for the treatment of HIV-1 infection.
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Fármacos Anti-VIH/farmacología , Proteínas de la Cápside/antagonistas & inhibidores , Infecciones por VIH/tratamiento farmacológico , VIH-1/efectos de los fármacos , Indazoles/farmacología , Piridinas/farmacología , Bibliotecas de Moléculas Pequeñas/farmacología , Animales , Fármacos Anti-VIH/uso terapéutico , Cápside/efectos de los fármacos , Cápside/metabolismo , Proteínas de la Cápside/genética , ADN Viral/efectos de los fármacos , Preparaciones de Acción Retardada , Farmacorresistencia Viral/efectos de los fármacos , Infecciones por VIH/genética , Infecciones por VIH/virología , VIH-1/genética , VIH-1/patogenicidad , VIH-2/efectos de los fármacos , VIH-2/patogenicidad , Humanos , Indazoles/uso terapéutico , Cumplimiento de la Medicación , Ratones , Piridinas/uso terapéuticoRESUMEN
We examined how well typical adult listeners remember the speech of a person with a voice disorder (relative to that of a person without a voice disorder). Participants (n = 40) listened to two lists of words (one list uttered in a disordered voice and the other list uttered in a normal voice). After each list, participants completed a free recall test, in which they tried to remember as many words as they could. While the total number of words recalled did not differ between the disordered voice condition and the normal voice condition, an investigation of the serial-position curve revealed a difference. In the normal voice condition, a parabolic (i.e., u-shaped) serial-position curve was observed, with a significant primacy effect (i.e., the beginning of the list was remembered better than the middle) and a significant recency effect (i.e., the end of the list was remembered better than the middle). In contrast, in the disordered voice condition, while there was a significant recency effect, no primacy effect was present. Thus, the increased ability to remember the first words uttered by a speaker (relative to subsequent words) may disappear when the speaker has a voice disorder. Explanations and implications of this finding are discussed.
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Can experience change perception? Here, we examine whether language experience shapes the way individuals process auditory and visual information. We used the McGurk effect—the discovery that when people hear a speech sound (e.g., “ba”) and see a conflicting lip movement (e.g., “ga”), they recognize it as a completely new sound (e.g., “da”). This finding suggests that the brain fuses input across auditory and visual modalities demonstrates that what we hear is profoundly influenced by what we see. We find that cross-modal integration is affected by language background, with bilinguals experiencing the McGurk effect more than monolinguals. This increased reliance on the visual channel is not due to decreased language proficiency, as the effect was observed even among highly proficient bilinguals. Instead, we propose that the challenges of learning and monitoring multiple languages have lasting consequences for how individuals process auditory and visual information.
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AIMS AND OBJECTIVES: The objectives of the present research were to examine the cognitive consequences of trilingualism and explain them relative to the cognitive consequences of bilingualism. APPROACH: A comparison of cognitive abilities in trilinguals and bilinguals was conducted. In addition, we proposed a cognitive plasticity framework to account for cognitive differences and similarities between trilinguals and bilinguals. DATA AND ANALYSIS: Three aspects of cognition were analyzed: (1) cognitive reserve in older adults, as measured by age of onset of Alzheimer's disease and mild cognitive impairment; (2) inhibitory control in children and younger adults, as measured by response times on behavioral Simon and flanker tasks; and (3) memory generalization in infants and toddlers, as measured by accuracy on behavioral deferred imitation tasks. Results were considered within a framework of cognitive plasticity, which took into account several factors that may affect plasticity, including the age of learning a third language and the extent to which additional cognitive resources are needed to learn the third language. FINDINGS: A mixed pattern of results was observed. In some cases, such as cognitive reserve in older adults, trilinguals showed larger advantages than bilinguals. On other measures, for example inhibitory control in children and younger adults, trilinguals were found to exhibit the same advantages as bilinguals. In still other cases, like memory generalization in infants and toddlers, trilinguals did not demonstrate the advantages seen in bilinguals. ORIGINALITY: This study is the first comprehensive analysis of how learning a third language affects the cognitive abilities that are modified by bilingual experience, and the first to propose a cognitive plasticity framework that can explain and predict trilingual-bilingual differences. SIGNIFICANCE: This research shows that the cognitive consequences of trilingualism are not simply an extension of bilingualism's effects; rather, trilingualism has distinct consequences, with theoretical implications for our understanding of linguistic and cognitive processes and their plasticity, as well as applied-science implications for using second and third language learning in educational and rehabilitative contexts to foster successful cognitive development and aging.
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Most of the world's population has knowledge of at least two languages. Many of these bilinguals are also exposed to and identify with at least two cultures. Because language knowledge enables participation in cultural practices and expression of cultural beliefs, bilingual experience and cultural identity are interconnected. However, the specific links between bilingualism and cultural identity remain largely unidentified. The current study examined which aspects of bilingualism relate to identification with first- and second-language cultures. Two-hundred-and-nine bilinguals completed a questionnaire probing linguistic background and cultural affiliations. Regression analyses indicated that cultural identification was predicted by age of language acquisition, language proficiency, foreign-accentedness, and contexts of long-term language immersion and current language exposure. Follow-up analyses revealed that the language-culture relations were mediated by the age and manner in which the second language was acquired. These findings are situated within a proposed framework of bilingual cultural identity. By identifying features of bilingualism that are relevant for cultural identity, the current research increases our understanding of the relationship between language and culture.