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Bruton's tyrosine kinase (BTK) is a Tec family kinase that plays an essential role in B-cell receptor (BCR) signaling as well as Fcγ receptor signaling in leukocytes. Pharmacological inhibition of BTK has been shown to be effective in treating hematological malignancies and is hypothesized to provide an effective strategy for the treatment of autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus. We report the discovery and preclinical properties of JNJ-64264681 (

Spatial memory studies often employ static images depicting a scene, an array of objects, or environmental features from one perspective and then following a perspective-shift-prompt memory either of the scene or objects within the scene. The current study investigated a previously reported systematic bias in spatial memory where, following a perspective shift from encoding to recall, participants indicated the location of an object farther to the direction of the shift. In Experiment 1, we aimed to replicate this bias by asking participants to encode the location of an object in a virtual room and then indicate it from memory following a perspective shift induced by camera translation and rotation. In Experiment 2, we decoupled the influence of camera translations and rotations and examined whether adding additional objects to the virtual room would reduce the bias. Overall, our results indicate that camera translations result in greater systematic bias than camera rotations. We propose that the accurate representation of camera translations requires more demanding mental computations than camera rotations, leading to greater uncertainty regarding the location of an object in memory. This uncertainty causes people to rely on an egocentric anchor, thereby giving rise to the systematic bias in the direction of camera translation.

Luminescence is ubiquitous in biology research and medicine. Conceptually simple, the detection of luminescence nonetheless faces technical challenges because relevant signals can exhibit exceptionally low radiant power densities. Although low light detection is well-established in centralized laboratory settings, the cost, size, and environmental requirements of high-performance benchtop luminometers are not compatible with geographically-distributed global health studies or resource-constrained settings. Here we present the design and application of a ~$700 US handheld, battery-powered luminometer with performance on par with high-end benchtop instruments. By pairing robust and inexpensive Silicon Photomultiplier (SiPM) sensors with a low-profile shutter system, our design compensates for sensor non-idealities and thermal drift, achieving a limit of detection of 1.6E-19 moles of firefly luciferase, or approximately 1fW of radiant optical power. Using these devices, we performed split luciferase serology studies to monitor sars-cov-2 antibodies in a cohort in the United States, as well as a field study in Bangladesh.

The cultural and geographical properties of the environment have been shown to deeply influence cognition and mental health1-6. Living near green spaces has been found to be strongly beneficial7-11, and urban residence has been associated with a higher risk of some psychiatric disorders12-14-although some studies suggest that dense socioeconomic networks found in larger cities provide a buffer against depression15. However, how the environment in which one grew up affects later cognitive abilities remains poorly understood. Here we used a cognitive task embedded in a video game16 to measure non-verbal spatial navigation ability in 397,162 people from 38 countries across the world. Overall, we found that people who grew up outside cities were better at navigation. More specifically, people were better at navigating in environments that were topologically similar to where they grew up. Growing up in cities with a low street network entropy (for example, Chicago) led to better results at video game levels with a regular layout, whereas growing up outside cities or in cities with a higher street network entropy (for example, Prague) led to better results at more entropic video game levels. This provides evidence of the effect of the environment on human cognition on a global scale, and highlights the importance of urban design in human cognition and brain function.

Recent advances in gene editing are enabling the engineering of cells with an unprecedented level of scale. To capitalize on this opportunity, new methods are needed to accelerate the different steps required to manufacture and handle engineered cells. Here, we describe the development of an integrated software and hardware platform to automate Fluorescence-Activated Cell Sorting (FACS), a central step for the selection of cells displaying desired molecular attributes. Sorting large numbers of samples is laborious, and, to date, no automated system exists to sequentially manage FACS samples, likely owing to the need to tailor sorting conditions (“gating”) to each individual sample. Our platform is built around a commercial instrument and integrates the handling and transfer of samples to and from the instrument, autonomous control of the instrument’s software, and the algorithmic generation of sorting gates, resulting in walkaway functionality. Automation eliminates operator errors, standardizes gating conditions by eliminating operator-to-operator variations, and reduces hands-on labor by 93%. Moreover, our strategy for automating the operation of a commercial instrument control software in the absence of an Application Program Interface (API) exemplifies a universal solution for other instruments that lack an API. Our software and hardware designs are fully open-source and include step-by-step build documentation to contribute to a growing open ecosystem of tools for high-throughput cell biology.

Cognitive abilities can vary widely. Some people excel in certain skills, others struggle. However, not all those who describe themselves as gifted are. One possible influence on self-estimates is the surrounding culture. Some cultures may amplify self-assurance and others cultivate humility. Past research has shown that people in different countries can be grouped into a set of consistent cultural clusters with similar values and tendencies, such as attitudes to masculinity or individualism. Here we explored whether such cultural dimensions might relate to the extent to which populations in 46 countries overestimate or underestimate their cognitive abilities in the domain of spatial navigation. Using the Sea Hero Quest navigation test and a large sample (N = 383,187) we found cultural clusters of countries tend to be similar in how they self-rate ability relative to their actual performance. Across the world population sampled, higher self-ratings were associated with better performance. However, at the national level, higher self-ratings as a nation were not associated with better performance as a nation. Germanic and Near East countries were found to be most overconfident in their abilities and Nordic countries to be most under-confident in their abilities. Gender stereotypes may play a role in mediating this pattern, with larger national positive attitudes to male stereotyped roles (Hofstede's masculinity dimension) associated with a greater overconfidence in performance at the national level. We also replicate, with higher precision than prior studies, evidence that older men tend to overestimate their navigation skill more than other groups. These findings give insight into how culture and demographics may impact self-estimates of our abilities., Scientific Reports, 13 (1), ISSN:2045-2322

The present study demonstrates similarities between route learning and classical tests of serial order memory. Here, we investigated serial memory for landmarks in a route learning task, in younger and older adults. We analysed data from a route learning task with 12 landmarks, reported by Hilton et al. (2021). Participants (88 younger and 77 older) learned a route using either a Fixed Learning (3 exposures to the route) or Flexible Learning (repeated exposures until successful navigation was achieved) procedure. Following route learning, participants completed Immediate Free Recall (IFR) and Free Reconstruction of Order (Free RoO) of the landmarks. We show clear acquisition of sequence memory for landmarks for both age groups, with Free RoO producing a bowed serial position curve. IFR produced recency effects but no primacy effects in fixed learning, with recency reduced following flexible learning for both age groups. Younger adults displayed a primacy bias for the first item recalled in both learning conditions, as did the older adults in the flexible learning condition. In contrast, older adults displayed a recency bias in the fixed learning condition. Evidence of contiguity in IFR was present only for younger adults in the flexible learning condition. Findings are broadly consistent with results from typical short-term list learning procedures and support the universality of sequence learning effects, which we demonstrate are generalisable to a navigation context.

[Image: see text] Bruton’s tyrosine kinase (BTK) is a cytoplasmic tyrosine kinase that plays a critical role in the activation of B cells, macrophages, and osteoclasts. Given the key role of these cell types in the pathology of autoimmune disorders, BTK inhibitors have the potential to improve treatment outcomes in multiple diseases. Herein, we report the discovery and characterization of a novel potent and selective covalent 4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide BTK inhibitor chemotype. Compound 27 irreversibly inhibits BTK by targeting a noncatalytic cysteine residue (Cys481) for covalent bond formation. Compound 27 is characterized by selectivity for BTK, potent in vivo BTK occupancy that is sustained after it is cleared from systemic circulation, and dose-dependent efficacy at reducing joint inflammation in a rat collagen-induced arthritis model.

In the current study, we investigated whether the introduction of perspective shifts in a spatial memory task results in systematic biases in object location estimations. To do so, we asked participants to first encode the position of an object in a virtual room and then to report its position from memory or perception following a perspective shift. Overall, our results showed that participants made systematic errors in estimating object positions in the same direction as the perspective shift. Notably, this bias was present in both memory and perception conditions. We propose that the observed systematic bias was driven by difficulties in understanding the perspective shifts that led participants to use an egocentric representation of object positions as an anchor when estimating the object location following a perspective shift., Attention, Perception, & Psychophysics, 84 (4), ISSN:1943-393X, ISSN:1943-3921

Living with dementia can adversely affect people's spatial (orientation and navigation) and reality (time, date and place) orientation, which can detrimentally impact on their sense of social inclusion and wellbeing. This is an important challenge to address within United Kingdom (UK) care homes where around 70 per cent of the residents are living with dementia or severe memory problems. Care home managers have some autonomy in decision-making that impacts on the daily functioning of residents and are key in enacting the orientation and navigation agenda within a care home environment. Yet a paucity of literature explores their understanding and experiences of this issue. Contributing to this knowledge gap, our exploratory study examined managers’ current practice of supporting residents with dementia to minimise disorientation and their knowledge of dementia-friendly design principles, guidelines and audit tools. Semi-structured telephone interviews with 12 UK care home managers were conducted. Questions started generally targeting residents’ orientation and navigation abilities, followed by specific questions to draw out strategies used to support residents. Thematic analysis identified three higher-order themes: aligning strategies with needs, intuitive learning and managing within the wider business context. The findings demonstrated that managers perceive dementia to impact on a person's spatial and reality orientation. Consequently, the strategies they chose to adopt were tailored towards alleviating both challenges. However, although managers were aware of some design principles, they frequently relied on intuitive learning and past experiences to inform their choice of interventions, reporting a lack of knowledge and/or time to seek out orientation-specific training and guidance, resulting in a low uptake of guidelines and audit tools in practice. This gap between theory and practice highlights a need for accessible guidelines that integrate strategies with neuropsychological theory, and appropriate training to improve orientation and navigation in care home environments. Managers, staff, business owners, architects and designers all play a key role in implementing orientation guidelines into practice and ensuring dementia-friendly care home environments for residents.

Ageing is associated with declines in spatial memory, however, the source of these deficits remains unclear. Here we used eye-tracking to investigate age-related differences in spatial encoding strategies and the cognitive processes underlying the age-related deficits in spatial memory tasks. To do so we asked young and older participants to encode the locations of objects in a virtual room shown as a picture on a computer screen. The availability and utility of room-based landmarks were manipulated by removing landmarks, presenting identical landmarks rendering them uninformative, or by presenting unique landmarks that could be used to encode object locations. In the test phase, participants viewed a second picture of the same room taken from the same (0°) or a different perspective (30°) and judged whether the objects occupied the same or different locations in the room. We found that the introduction of a perspective shift and swapping of objects between encoding and testing impaired performance in both age groups. Furthermore, our results revealed that although older adults performed the task as well as younger participants, they relied on different visual encoding strategies to solve the task. Specifically, gaze analysis revealed that older adults showed a greater preference towards a more categorical encoding strategy in which they formed relationships between objects and landmarks.

Many older people, both with and without dementia, eventually move from their familiar home environments into unfamiliar surroundings, such as sheltered housing or care homes. Age-related declines in wayfinding skills can make it difficult to learn to navigate in these new, unfamiliar environments. To facilitate the transition to their new accommodation, it is therefore important to develop retirement complexes and care homes specifically designed to reduce the wayfinding difficulties of older people and those with Alzheimer’s disease (AD). Residential complexes that are designed to support spatial orientation and that compensate for impaired navigation abilities would make it easier for people with dementia to adapt to their new living environment. This would improve the independence, quality of life and well-being of residents, and reduce the caregivers’ workload. Based on these premises, this opinion paper considers how evidence from cognitive psychology, neuropsychology and environmental psychology can contribute to ageing- and dementia-friendly design with a view to minimising spatial disorientation. After an introduction of the cognitive mechanisms and processes involved in spatial navigation, and the changes that occur in typical and atypical ageing, research from the field of environmental psychology is considered, highlighting design factors likely to facilitate (or impair) indoor wayfinding in complex buildings. Finally, psychological theories and design knowledge are combined to suggest ageing- and dementia-friendly design guidelines that aim to minimise spatial disorientation by focusing on residual navigation skills.

Age-related spatial navigation decline is more pronounced in patients with mild cognitive impairment (MCI) and Alzheimer’s disease (AD) dementia. We used a realistic-looking virtual navigation test suite to analyze different aspects of visuospatial processing in typical and atypical aging. A total of 219 older adults were recruited from the Czech Brain Aging Study cohort. Cognitively normal older adults (CN, n = 78), patients with amnestic MCI (n = 75), and those with mild AD dementia (n = 66) underwent three navigational tasks, cognitive assessment, and brain MRI. Route learning and wayfinding/perspective-taking tasks distinguished the groups as performance and learning declined and specific visuospatial strategies were less utilized with increasing cognitive impairment. Increased perspective shift and utilization of non-specific strategies were associated with worse task performance across the groups. Primacy and recency effects were observed across the groups in the route learning and the wayfinding/perspective-taking task, respectively. In addition, a primacy effect was present in the wayfinding/perspective-taking task in the CN older adults. More effective spatial navigation was associated with better memory and executive functions. The results demonstrate that a realistic and ecologically valid spatial navigation test suite can reveal different aspects of visuospatial processing in typical and atypical aging.

The integration of intersecting routes is an important process for the formation of cognitive maps and thus successful navigation. Here we present a novel task to study route integration and the effects that landmark information and cognitive ageing have on this process. We created two virtual environments, each comprising five places and one central intersection but with different landmark settings: in the Identical Landmark environment, the intersection contained visually monotonic features whereas the intersection contained visually distinctive features in the Different Landmarks environment. In both environments young and older participants were presented with two short routes that both traversed through the shared intersection. To test route integration, participants were asked to either repeat the learning routes, to navigate the routes from the destination to the starting place or to plan novel routes. As expected, results demonstrate better performance when repeating or retracing routes than when planning novel routes. Performance was better in younger than older participants and in the Different Landmark environment which does not require detailed knowledge of the spatial configuration of all places in the environment. A subgroup of the older participants who performed lower on a screening test for cognitive impairments could not successfully complete the experiment or did not reach the required performance criterion. These results demonstrate that strategically placed landmarks support the integration of route knowledge into spatial representations that allow for goal-dependent flexible navigation behaviour and that earliest signs of atypical cognitive ageing affect this process of route integration. Electronic supplementary material The online version of this article (10.1007/s00426-020-01401-5) contains supplementary material, which is available to authorized users.

The aim of the current study was to develop a novel task that allows for the quick assessment of spatial memory precision with minimal technical and training requirements. In this task, participants memorized the position of an object in a virtual room and then judged from a different perspective, whether the object has moved to the left or to the right. Results revealed that participants exhibited a systematic bias in their responses that we termed the reversed congruency effect. Specifically, they performed worse when the camera and the object moved in the same direction than when they moved in opposite directions. Notably, participants responded correctly in almost 100% of the incongruent trials, regardless of the distance by which the object was displaced. In Experiment 2, we showed that this effect cannot be explained by the movement of the object on the screen, but that it relates to the perspective shift and the movement of the object in the virtual world. We also showed that the presence of additional objects in the environment reduces the reversed congruency effect such that it no longer predicts performance. In Experiment 3, we showed that the reversed congruency effect is greater in older adults, suggesting that the quality of spatial memory and perspective-taking abilities are critical. Overall, our results suggest that this effect is driven by difficulties in the precise encoding of object locations in the environment and in understanding how perspective shifts affect the projected positions of the objects in the two-dimensional image., Attention, Perception, & Psychophysics, 83 (5), ISSN:1943-393X, ISSN:1943-3921

Drosophila sechellia is a dietary specialist fruit fly that evolved from a generalist ancestor to specialize on the toxic fruit of Morinda citrifolia. This species pair has been the subject of numerous studies where the goal has largely been to determine the genetic basis of adaptations associated with host specialization. Because one of the most striking features of M. citrifolia fruit is the production of toxic volatile compounds that kill insects, most genomic studies in D. sechellia to date have focused on gene expression responses to the toxic compounds in its food. In this study, we aim to identify new genes important for host specialization by profiling gene expression response to 3,4-dihydroxyphenylalanine (L-DOPA). Recent work found it to be highly abundant in M. citrifolia, critical for reproductive success of D. sechellia, and supplementation of diet with the downstream pathway product dopamine can influence toxin resistance phenotypes in related species. Here we used a combination of functional genetics and genomics techniques to identify new genes that are important for D. sechellia ecological adaptation to this new niche. We show that L-DOPA exposure can affect toxin resistance phenotypes, identify genes with plastic responses to L-DOPA exposure, and functionally test an identified candidate gene. We found that knock-down of Esterase 6 (Est6) in a heterologous species alters toxin resistance suggesting Est6 may play an important role in D. sechellia host specialization.

Most research groups studying human navigational behavior with virtual environment (VE) technology develop their own tasks and protocols. This makes it difficult to compare results between groups and to create normative data sets for any specific navigational task. Such norms, however, are prerequisites for the use of navigation assessments as diagnostic tools-for example, to support the early and differential diagnosis of atypical aging. Here we start addressing these problems by presenting and evaluating a new navigation test suite that we make freely available to other researchers ( https://osf.io/mx52y/ ). Specifically, we designed three navigational tasks, which are adaptations of earlier published tasks used to study the effects of typical and atypical aging on navigation: a route-repetition task that can be solved using egocentric navigation strategies, and route-retracing and directional-approach tasks that both require allocentric spatial processing. Despite introducing a number of changes to the original tasks to make them look more realistic and ecologically valid, and therefore easy to explain to people unfamiliar with a VE or who have cognitive impairments, we replicated the findings from the original studies. Specifically, we found general age-related declines in navigation performance and additional specific difficulties in tasks that required allocentric processes. These findings demonstrate that our new tasks have task demands similar to those of the original tasks, and are thus suited to be used more widely.