Neurosyphilis is characterized by a compartmentalized and robust neuroimmune response but not by neuronal injury.

BACKGROUND: Neurosyphilis is increasing in prevalence but its pathophysiology remains incompletely understood. This study assessed for CNS-specific immune responses during neurosyphilis compared to syphilis without neurosyphilis and compared these immune profiles to those observed in other neuroinflammatory diseases. METHODS: Participants with syphilis were categorized as having neurosyphilis if their cerebrospinal fluid (CSF)-venereal disease research laboratory (VDRL) test was reactive and as having syphilis without neurosyphilis if they had a non-reactive CSF-VDRL test and a white blood cell count <5/µL. Neurosyphilis and syphilis without neurosyphilis participants were matched by rapid plasma reagin titer and HIV status. CSF and plasma were assayed for markers of neuronal injury and glial and immune cell activation. Bulk RNA sequencing was performed on CSF cells, with results stratified by the presence of neurological symptoms. FINDINGS: CSF neopterin and five CSF chemokines had levels significantly higher in individuals with neurosyphilis compared to those with syphilis without neurosyphilis, but no markers of neuronal injury or astrocyte activation were significantly elevated. The CSF transcriptome in neurosyphilis was characterized by genes involved in microglial activation and lipid metabolism and did not differ in asymptomatic versus symptomatic neurosyphilis cases. CONCLUSIONS: The CNS immune response observed in neurosyphilis was comparable to other neuroinflammatory diseases and was present in individuals with neurosyphilis regardless of neurological symptoms, yet there was minimal evidence for neuronal or astrocyte injury. These findings support the need for larger studies of the CSF inflammatory response in asymptomatic neurosyphilis. FUNDING: This work was funded by the National Institutes of Health, grants K23MH118999 (S.F.F.) and R01NS082120 (C.M.M.).

Introducing a common taxonomy to support learning from failure in conservation.

Although some sectors have made significant progress in learning from failure, there is currently limited consensus on how a similar transition could best be achieved in conservation and what is required to facilitate this. One of the key enabling conditions for other sectors is a widely accepted and standardized classification system for identifying and analyzing root causes of failure. We devised a comprehensive taxonomy of root causes of failure affecting conservation projects. To develop this, we solicited examples of real-life conservation efforts that were deemed to have failed in some way, identified their underlying root causes of failure, and used these to develop a generic, 3-tier taxonomy of the ways in which projects fail, at the top of which are 6 overarching cause categories that are further divided into midlevel cause categories and specific root causes. We tested the taxonomy by asking conservation practitioners to use it to classify the causes of failure for conservation efforts they had been involved in. No significant gaps or redundancies were identified during this testing phase. We then analyzed the frequency that particular root causes were encountered by projects within this test sample, which suggested that some root causes were more likely to be encountered than others and that a small number of root causes were more likely to be encountered by projects implementing particular types of conservation action. Our taxonomy could be used to improve identification, analysis, and subsequent learning from failed conservation efforts, address some of the barriers that currently limit the ability of conservation practitioners to learn from failure, and contribute to establishing an effective culture of learning from failure within conservation.

Introducción de una taxonomía común como apoyo al aprendizaje a partir del fracaso en la conservación Resumen Mientras que algunos sectores han progresado significativamente en el aprendizaje a partir del fracaso, actualmente hay un consenso limitado sobre cómo podría lograrse una transición similar en la conservación y qué se requiere para facilitarla. Una de las condiciones habilitantes más importantes en otros sectores es un sistema de clasificación estandarizado y aceptado por la mayoría para la identificación y análisis de las causas fundamentales del fracaso. Diseñamos una taxonomía completa de las causas fundamentales del fracaso que afecta a los proyectos de conservación. Para desarrollarla, solicitamos ejemplos de esfuerzos de conservación reales que de alguna manera se consideraron como fracasos, identificamos las causas fundamentales no aparentes de su fracaso y luego las usamos para desarrollar una taxonomía genérica de tres niveles de las maneras en las que fracasan los proyectos, en cuyo nivel superior están seis categorías de causas generales que después se dividen en categorías de nivel medio de categorías de causas y causas fundamentales específicas. Pusimos a prueba la taxonomía al pedirle a los practicantes de la conservación que la usaran para clasificar las causas del fracaso de los esfuerzos de conservación en los que han participado. No identificamos vacíos o redundancias importantes durante esta fase de prueba. Después, analizamos la frecuencia con la que los proyectos de esta muestra se enfrentaron a causas fundamentales particulares, lo que sugirió que algunas causas fundamentales tienen mayor probabilidad de ocurrir y que un número reducido de causas fundamentales tiene mayor probabilidad de ocurrir en proyectos que implementan ciertos tipos de acciones de conservación. Nuestra taxonomía podría usarse para mejorar el análisis, identificación y aprendizaje subsecuente a partir del fracaso de los esfuerzos de conservación; tratar algunas de las barreras que en la actualidad limitan a los practicantes de la conservación a aprender del fracaso; y contribuir al establecimiento de una cultura efectiva del aprendizaje a partir del fracaso dentro de la conservación.

Recognizing reflexivity among conservation practitioners.

When deciding how to conserve biodiversity, practitioners navigate diverse missions, sometimes conflicting approaches, and uncertain trade-offs. These choices are based not only on evidence, funders' priorities, stakeholders' interests, and policies, but also on practitioners' personal experiences, backgrounds, and values. Calls for greater reflexivity-an individual or group's ability to examine themselves in relation to their actions and interactions with others-have appeared in the conservation science literature. But what role does reflexivity play in conservation practice? We explored how self-reflection can shape how individuals and groups conserve nature. To provide examples of reflexivity in conservation practice, we conducted a year-long series of workshop discussions and online exchanges. During these, we examined cases from the peer-reviewed and gray literature, our own experiences, and conversations with 10 experts. Reflexivity among practitioners spanned individual and collective levels and informal and formal settings. Reflexivity also encompassed diverse themes, including practitioners' values, emotional struggles, social identities, training, cultural backgrounds, and experiences of success and failure. Reflexive processes also have limitations, dangers, and costs. Informal and institutionalized reflexivity requires allocation of limited time and resources, can be hard to put into practice, and alone cannot solve conservation challenges. Yet, when intentionally undertaken, reflexive processes might be integrated into adaptive management cycles at multiple points, helping conservation practitioners better reach their goals. Reflexivity could also play a more transformative role in conservation by motivating practitioners to reevaluate their goals and methods entirely. Reflexivity might help the conservation movement imagine and thus work toward a better world for wildlife, people, and the conservation sector itself.

Reconocimiento de la reflexividad entre los practicantes de la conservación Resumen Cuando se decide cómo conservar la biodiversidad, quienes la practican sortean varias misiones, algunas veces con enfoques contrastantes y compensaciones inciertas. Estas elecciones no se basan solamente en las evidencias, prioridades de los financiadores, los intereses de los actores y las políticas, sino también en las experiencias personales, formación y valores de los practicantes. En la literatura sobre las ciencias de la conservación han surgido llamados para una mayor reflexividad - la habilidad individual o grupal para examinarse a sí mismo en relación con sus acciones e interacciones con otros. Pero ¿cuál es el papel de la reflexividad en la práctica de la conservación? Para responder esto, exploramos cómo la autorreflexión puede determinar cómo ocurre la conservación individual y grupal de la naturaleza. Realizamos una serie de talleres de discusión e intercambios virtuales durante un año para ejemplificar la reflexividad en la práctica de la conservación. Durante estas sesiones examinamos casos de la literatura gris y revisada por pares, nuestras propias experiencias y conversaciones con diez expertos. La reflexividad de los practicantes abarcó niveles individuales y colectivos y escenarios formales e informales. La reflexividad también comprendió diferentes aspectos de los practicantes, como los valores, conflictos emocionales, identidad social, preparación, contexto cultural y experiencias exitosas y fallidas. Los procesos reflexivos también tienen limitaciones, riesgos y costos. La reflexividad informal e institucionalizada requiere la distribución de tiempo y recursos limitados, puede ser difícil de poner en práctica y no puede resolver los retos de conservación por sí sola. Aun así, cuando se realizan intencionalmente, los procesos reflexivos pueden integrarse a los ciclos de manejo adaptativo en varios puntos, lo que ayuda a quienes practican la conservación a lograr sus metas de mejor manera. La reflexividad también podría tener un papel transformador en la conservación al motivar a los practicantes a reevaluar completamente sus metas y métodos. La reflexividad podría ayudar al movimiento de conservación a imaginar, y por lo tanto trabajar para tener, un mundo mejor para la vida silvestre, las personas y el propio sector de la conservación.

Inhibition of a Chromatin and Transcription Modulator, SLTM, Increases HIV-1 Reactivation Identified by a CRISPR Inhibition Screen.

Despite effective antiretroviral therapy, HIV-1 persistence in latent reservoirs remains a major obstacle to a cure. We postulate that HIV-1 silencing factors suppress HIV-1 reactivation and that inhibition of these factors will increase HIV-1 reactivation. To identify HIV-1 silencing factors, we conducted a genome-wide CRISPR inhibition (CRISPRi) screen using four CRISPRi-ready, HIV-1-d6-GFP-infected Jurkat T cell clones with distinct integration sites. We sorted cells with increased green fluorescent protein (GFP) expression and captured single guide RNAs (sgRNAs) via targeted deep sequencing. We identified 18 HIV-1 silencing factors that were significantly enriched in HIV-1-d6-GFPhigh cells. Among them, SLTM (scaffold attachment factor B-like transcription modulator) is an epigenetic and transcriptional modulator having both DNA and RNA binding capacities not previously known to affect HIV-1 transcription. Knocking down SLTM by CRISPRi significantly increased HIV-1-d6-GFP expression (by 1.9- to 4.2-fold) in three HIV-1-d6-GFP-Jurkat T cell clones. Furthermore, SLTM knockdown increased the chromatin accessibility of HIV-1 and the gene in which HIV-1 is integrated but not the housekeeping gene POLR2A. To test whether SLTM inhibition can reactivate HIV-1 and further induce cell death of HIV-1-infected cells ex vivo, we established a small interfering RNA (siRNA) knockdown method that reduced SLTM expression in CD4+ T cells from 10 antiretroviral therapy (ART)-treated, virally suppressed, HIV-1-infected individuals ex vivo. Using limiting dilution culture, we found that SLTM knockdown significantly reduced the frequency of HIV-1-infected cells harboring inducible HIV-1 by 62.2% (0.56/106 versus 1.48/106 CD4+ T cells [P = 0.029]). Overall, our study indicates that SLTM inhibition reactivates HIV-1 in vitro and induces cell death of HIV-1-infected cells ex vivo. Our study identified SLTM as a novel therapeutic target. IMPORTANCE HIV-1-infected cells, which can survive drug treatment and immune cell killing, prevent an HIV-1 cure. Immune recognition of infected cells requires HIV-1 protein expression; however, HIV-1 protein expression is limited in infected cells after long-term therapy. The ways in which the HIV-1 provirus is blocked from producing protein are unknown. We identified a new host protein that regulates HIV-1 gene expression. We also provided a new method of studying HIV-1-host factor interactions in cells from infected individuals. These improvements may enable future strategies to reactivate HIV-1 in infected individuals so that infected cells can be killed by immune cells, drug treatment, or the virus itself.

Measuring the size and decay dynamics of the HIV-1 latent reservoir.

Measuring HIV-1 latent reservoir is essential for HIV-1 cure strategies. Levy et al.1 developed a multiplex droplet digital PCR (ddPCR) assay-5-target intact proviral DNA assay-to detect multiple regions of HIV-1 proviral genome and increase accuracy.

Black swans, cognition, and the power of learning from failure.

Failure carries undeniable stigma and is difficult to confront for individuals, teams, and organizations. Disciplines such as commercial and military aviation, medicine, and business have long histories of grappling with it, beginning with the recognition that failure is inevitable in every human endeavor. Although conservation may arguably be more complex, conservation professionals can draw on the research and experience of these other disciplines to institutionalize activities and attitudes that foster learning from failure, whether they are minor setbacks or major disasters. Understanding the role of individual cognitive biases, team psychological safety, and organizational willingness to support critical self-examination all contribute to creating a cultural shift in conservation to one that is open to the learning opportunity that failure provides. This new approach to managing failure is a necessary next step in the evolution of conservation effectiveness.

Using prosody to infer discourse prominence in cochlear-implant users and normal-hearing listeners.

Cochlear implants (CIs) provide speech perception to adults with severe-to-profound hearing loss, but the acoustic signal remains severely degraded. Limited access to pitch cues is thought to decrease sensitivity to prosody in CI users, but co-occurring changes in intensity and duration may provide redundant cues. The current study investigates how listeners use these cues to infer discourse prominence. CI users and normal-hearing (NH) listeners were presented with sentences varying in prosody (accented vs. unaccented words) while their eye-movements were measured to referents varying in discourse status (given vs. new categories). In Experiment 1, all listeners inferred prominence when prosody on nouns distinguished categories ("SANDWICH"→not sandals). In Experiment 2, CI users and NH listeners presented with natural speech inferred prominence when prosody on adjectives implied contrast across both categories and properties ("PINK horse"→not the orange horse). In contrast, NH listeners presented with simulated CI (vocoded) speech were sensitive to acoustic differences in prosody, but did not use these cues to infer discourse status. Together, this suggests that exploiting redundant cues for comprehension varies with the demands of language processing and prior experience with the degraded signal.