Search

Every year between 20 and 25,000 people ‘go missing’ in São Paulo state in Brazil. But in Brazilian law disappearance is just a fato atípico; an ‘atypical occurrence’. There is no causal relationship between act and violence to be legally found. Nor, it seems, is there a pursuit to know. In a region well recognised for political disappearance, I ask for a deeper and historicised consideration of how disappearance has worked politically, and why it might be acutely important at the current juncture where mass graves have a kind of axiomatic enigma. Doing so allows for a thorough disaggregation of how conditions of passive government and a lack of pursuit – letting disappear – shape the terrain of both extreme suffering and contemporary political ordering.

Acute exercise can modulate the excitability of the nonexercised upper limb representation in the primary motor cortex (M1). Measures of M1 excitability using transcranial magnetic stimulation (TMS) are modulated after various forms of acute exercise in young adults, including high-intensity interval training (HIIT). However, the impact of HIIT on M1 excitability in older adults is currently unknown. Therefore, the purpose of the current study was to investigate the effects of lower limb cycling HIIT on bilateral upper limb M1 excitability in older adults.We assessed the impact of acute lower limb HIIT or rest on bilateral corticospinal excitability, intracortical inhibition and facilitation, and interhemispheric inhibition of the nonexercised upper limb muscle in healthy older adults (mean age 66 ± 8 yr). We used single and paired-pulse TMS to assess motor evoked potentials, short-interval intracortical inhibition, intracortical facilitation, and the ipsilateral silent period. Two groups of healthy older adults completed either HIIT exercise or seated rest for 23 min, with TMS measures performed before (T0), immediately after (T1), and 30 min after (T2) HIIT/rest.Motor evoked potentials were significantly increased after HIIT exercise at T2 compared with T0 in the dominant upper limb. Contrary to our hypothesis, we did not find any significant change in short-interval intracortical inhibition, intracortical facilitation, or ipsilateral silent period after HIIT.Our findings demonstrate that corticospinal excitability of the nonexercised upper limb is increased after HIIT in healthy older adults. Our results indicate that acute HIIT exercise impacts corticospinal excitability in older adults, without affecting intracortical or interhemispheric circuitry. These findings have implications for the development of exercise strategies to potentiate neuroplasticity in healthy older and clinical populations.

SUMMARYPlants use electrical and chemical signals for systemic communication. Herbivory, for instance, appears to trigger local apoplasmic glutamate accumulation, systemic electrical signals and calcium waves that travel to report insect damage to neighboring leaves and initiate defense. To monitor extra- and intracellular glutamate concentrations in plants, we generated Arabidopsis lines expressing genetically encoded fluorescent glutamate sensors. In contrast to cytosolically localized sensors, extracellularly displayed variants inhibited plant growth and proper development. Phenotypic analyses of high-affinity display sensor lines revealed that root meristem development, particularly the quiescent center (QC), number of lateral roots, vegetative growth and floral architecture were impacted. Notably, the severity of the phenotypes was positively correlated with the affinity of the display sensors, intimating that their ability to sequester glutamate at the surface of the plasma membrane was responsible for the defects. Root growth defects were suppressed by supplementing culture media with low levels of glutamate. Together, the data indicate that sequestration of glutamate at the cell surface either disrupts the supply of glutamate to meristematic cells and/or impairs localized glutamatergic signaling important for developmental processes.SIGNIFICANCE STATEMENTGlutamate is an important signaling molecule in animals and plants. The affinity-dependent effects of surface-displayed glutamate sensors on plant development intimate that glutamate levels in the vicinity of the plasma membrane play important roles in signaling in plants.

On the basis of a qualitative study of three different operational oil and gas and petrochemical sites, in the Middle East, Asia-Pacific and Europe, we examine how actors construe error prevention and error management and how they reconcile these approaches in their everyday practice. Our repertory grid data reveal that actors recognise the importance of error prevention, but also appreciate that emergent and unexpected issues require error management in order to trap, address or mitigate problems in the making. Errors are also regarded to play an important role in adaptation, innovation and learning. However, our interview data and analysis of incident investigation reports reflect a narrower range of factors and indicates a strongly institutionalised predisposition towards error prevention. There are practical implications for the management of process safety and for incident analysis, which may be overlooking the importance of error management, and also for individuals at the sharp end who may be coping with the gap between what they believe is important in terms of process safety and what they bring to the surface, share and document.

Antibiotics are a routine part of everyday life in many contexts, contributing to the development of antimicrobial resistance (AMR). Our ethnographic research documents the ways that antibiotics have become a key part of everyday life for precariously employed urban day-wage workers living in a large informal settlement in Kampala, Uganda. We found that for many people, their daily work and ongoing health was entangled with antibiotic use; that is, people showed us how their antibiotic use cannot be separated from the realities of living in a politically, economically and environmentally degraded ‘informal’ landscape. Thinking through entanglement as itself a politics, we show how limited political power, inability to demand change, and inequitable access to good health care, are associated with high rates of infection and disease, precarious work, and polluted environments. Antibiotics, we argue, have become a way to negotiate the inequalities written into these informal urban landscapes; their use entangled with ongoing relations with labour, environment and bodily suffering. Through this approach, we show how antimicrobials are used in society, with an attention to how vulnerabilities, risks, and forms of abandonment and exclusion shape their everyday use. Antibiotic use is entangled with everyday life in informal settlements, and the politics that produce ‘informality’. In Kampala today, the entanglement of antibiotics with life in informal settlements reveals how forms of urban segregation, life in ‘slums’ and their everyday acceptance, shape the pathways and uses of antimicrobials.

Renal cell carcinoma (RCC) is considered an immunogenic tumour with a prominent dysfunctional immune cell infiltrate, unable to control tumour growth. Although tyrosine kinase inhibitors and immunotherapy have improved the outlook for some patients, many individuals are non-responders or relapse despite treatment, and then develop progressive disease, cancer symptoms and will have a reduced life expectancy. Following the limited success of cytokine therapy, immunotherapy using ipililumab/nivolumab combination or nivolumab single agent checkpoint-inhibitor therapy has been transformational and reiterated the potential for immune manipulation to significantly impact this disease. There is an urgent need to further improve the potential efficacy of these new targeted immunotherapies as not all patients derive benefit. The immune environment created by the tumour recapitulates that present in chronic viral infections in which inappropriate and excessive antigen stimulation leads to intra-tumoural T-cell exhaustion. These exhausted T-cells exhibit defective proliferative capacities and cytokine production and display an overall phenotype of metabolic insufficiency, characterized by extensive mitochondrial alterations. We set out to comprehensively identify mitochondrial defects in exhausted RCC tumour infiltrating lymphocytes (TILs) and correlate these findings with the clinicopathological characteristics of the tumour and the metabolic tumour microenvironment. The emergence of exhausted RCC CD8 + TILs upon progression into p3-4 advanced stage disease coincided with a significant decrease in expression of PPARGC1A, a key regulator of mitochondrial biogenesis. Down-regulation of PPARGC1A during ccRCC disease progression thus represents a ‘tipping point’ promoting immune dysfunction, cancer progression and poor outcomes from this disease.

Resumen Introducción: El noroeste de Costa Rica representa un área con una alta riqueza geológica que evidencia rocas generadas en diferentes ambientes, como plano abisal, talud continental, plataforma continental, volcánicos continentales efusivos y explosivos, volcánicos submarinos, costeros, erosivos fluviales, erosivos gravitatorios, de intrusión y el manto terrestre. Objetivo: Describir el contexto geológico actual del noroeste de Costa Rica, mediante el análisis y recopilación de datos de campo, geoquímicos, petrológicos, estructurales, paleontológicos y radiométricos con el fin de reconstruir los eventos y etapas de deformación desde el Jurásico a la actualidad. Métodos: Se hizo una recopilación bibliográfica de estudios en diversas ramas geológicas para establecer un estado del arte del extremo noroeste de Costa Rica. Resultados: La historia geológica representa el registro en rocas desde el Jurásico al Holoceno - actualidad con once etapas definidas a partir de interpretaciones petrológicas, estructurales, geocronológicas, estratigráficas y paleontológicas agrupadas en tres etapas de depositación y afectadas por cuatro fases tectónicas compresivas. Conclusiones: Las etapas de depositación corresponden con una primera etapa magmática con afinidad oceánica entre el Jurásico y el Cretácico Superior, una segunda etapa predominantemente sedimentaria con un rango de edad entre el Cretácico Superior y el Oligoceno, y por último una etapa volcánica efusiva - explosiva ubicada desde el Plioceno hasta la actualidad. Las fases tectónicas se asocian con diferentes eventos entre placas. La primera se dio en el Cretácico Inferior y su principal resultado visible fue la emersión de la Ofiolita de Santa Elena; la segunda sucedió del Cretácico Superior temprano al Campaniano y su reconocimiento está ligado a la posición actual de la Ofiolita de Santa Elena y sus estructuras circundantes; la tercera fase aconteció desde el Eoceno Superior hasta el Mioceno y su principal producto fue la generación del tren de pliegues sedimentarios del Golfo de Santa Elena a bahía de Salinas; y por último se presenta una fase Cuaternaria que originó el eje de basculamiento de los productos piroclásticos frente a la cordillera volcánica de Guanacaste. Abstract Introduction: The Costa Rican northwestern coastline has a wide geological uniqueness that exhibits rocks from different environments such as abyssal plane, continental slope, continental platform, volcanic eruptions (effusive, explosive, and submarine), coastal, erosional (fluvial and gravitatory), intrusions, and upper mantle rocks. Objective: To present the geologic state of the art of the northwestern coastline of Costa Rica through the bibliographic review of geochemical, petrologic, structural, paleontological and geochronological data. Methods: A bibliographic revision was done to propose a state of the art of northwestern coastline of Costa Rica. Results: The geologic record shows eleven stages from the Jurassic to the Holocene. These stages were regrouped from petrologic, structural, geochronologic, stratigraphic and paleontological interpretations in three depositional stages and four compressive tectonic phases. Conclusions: The first depositional stage is volcanic with oceanic affinity between the Jurassic and Upper Cretaceous. The second has a sedimentary predominance with an age range between the Upper Cretaceous and the Miocene. The last depositional stage is a volcanic (effusive and explosive) from the Pliocene until the present. The tectonic phases are associate with different interactions between tectonic plates. The first phase triggered the Santa Elena Ophiolite obduction during the Early Cretaceous. The second phase occurred in the Early Upper Cretaceous - Campanian and is recognized by its current position and surrounding structures. The third phase lasted from the Upper Eocene until the Miocene and its main result was the folding of the Bahía de Salinas sedimentary rocks. Finally, the Quaternary phase created a tilt axis and the aperture for the deposition of pyroclastic density currents in front of the Guanacaste volcanic ridge.

Receptor-interacting serine/threonine protein kinase 2 (RIPK2) is an important kinase of the innate immune system. Herein, we describe the optimization of a series of RIPK2 PROTACs which recruit members of the inhibitor of apoptosis (IAP) family of E3 ligases. Our PROTAC optimization strategy focused on reducing the lipophilicity of the early lead which resulted in the identification of analogues with improved solubility and increased human and rat microsomal stability. We identified a range of IAP binders that were successfully incorporated into potent RIPK2 PROTACs with attractive pharmacokinetic profiles. Compound 20 possessed the best overall profile with good solubility, potent degradation of RIPK2, and associated inhibition of TNFα release. A proof-of-concept study utilizing a slow release matrix demonstrated the feasibility of a long-acting parenteral formulation with >1 month duration. This represents an attractive alternative dosing paradigm to oral delivery, especially for chronic diseases where compliance can be challenging.