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In debates over the regulation of communication related to dual-use research, the risks that such communication creates must be weighed against against the value of scientific autonomy. The censorship of such communication seems justifiable in certain cases, given the potentially catastrophic applications of some dual-use research. This conclusion however, gives rise to another kind of danger: that regulators will use overly simplistic cost-benefit analysis to rationalize excessive regulation of scientific research. In response to this, we show how institutional design principles and normative frameworks from free speech theory can be used to help extend the argument for regulating dangerous dual-use research beyond overly simplistic cost-benefit reasoning, but without reverting to an implausibly absolutist view of scientific autonomy.

When science contradicts people’s experiences, they often deny the science. Psychological science may be particularly prone to denialism because of its relatively high relevance to people’s lives. In two sets of studies ( N = 637 from university students and Mechanical Turk workers), we tested whether perceived and actual incongruence between one’s personality and scientific findings predict psychological discomfort and science denialism. Participants rated the incongruence (subjective incongruence) between their own personality responses and science, as well as their comfort and denial of the science. Those who experienced more subjective incongruence experienced greater discomfort and reported more science denialism. Those whose personality characteristics were objectively incongruent with the science also experienced greater subjective incongruence (all studies), discomfort (Studies 1A, 1B, and 1C), and science denialism (Studies 1A, 1C, and 2B) compared with those with congruent characteristics. Implications regarding denialism of psychological science, and science more broadly, are discussed.

The study of how to build ethical autonomous vehicles (AVs) initially focused on the trolley problem and on questions about who to harm, but it has evolved to consider how to distribute the risk of harm. This chapter examines that evolution and argue that it signals a change in the kinds of philosophical, metaphilosophical, and empirical tools that should be marshalled to solve pressing ethical issues in AVs. We show this by examining cases in which AVs are required to make judgments under conditions of moral uncertainty, and when thinking about the widespread distribution of risks and benefits from AVs.

Background Machine learning (ML) models can handle large data sets without assuming underlying relationships and can be useful for evaluating disease characteristics, yet they are more commonly used for predicting individual disease risk than for identifying factors at the population level. We offer a proof of concept applying random forest (RF) algorithms to Candida-positive hospital encounters in an electronic health record database of patients in the United States. Methods Candida-positive encounters were extracted from the Cerner HealthFacts database; invasive infections were laboratory-positive sterile site Candida infections. Features included demographics, admission source, care setting, physician specialty, diagnostic and procedure codes, and medications received before the first positive Candida culture. We used RF to assess risk factors for 3 outcomes: any invasive candidiasis (IC) vs non-IC, within-species IC vs non-IC (eg, invasive C. glabrata vs noninvasive C. glabrata), and between-species IC (eg, invasive C. glabrata vs all other IC). Results Fourteen of 169 (8%) variables were consistently identified as important features in the ML models. When evaluating within-species IC, for example, invasive C. glabrata vs non-invasive C. glabrata, we identified known features like central venous catheters, intensive care unit stay, and gastrointestinal operations. In contrast, important variables for invasive C. glabrata vs all other IC included renal disease and medications like diabetes therapeutics, cholesterol medications, and antiarrhythmics. Conclusions Known and novel risk factors for IC were identified using ML, demonstrating the hypothesis-generating utility of this approach for infectious disease conditions about which less is known, specifically at the species level or for rarer diseases.

So-called ‘gain-of-function’ (GOF) research is virological research that results in a virus substantially more virulent or transmissible than its wild antecedent. GOF research has been subject to ethical analysis in the past, but the methods of GOF research have to date been underexamined by philosophers in these analyses. Here, we examine the typical animal used in influenza GOF experiments, the ferret, and show how despite its longstanding use, it does not easily satisfy the desirable criteria for ananimal model. We then discuss the limitations of the ferret model, and how those epistemic limitations bear on ethical and policy questions around the risks and benefits of GOF research. We conclude with a reflection on how philosophy of science can contribute to ethical and policy debates around the risks, benefits and relative priority of life sciences research.

A combination of ultrahigh-speed optical imaging (5 × 106 frames/s), B-mode ultrasound and passive cavitation detection was used to study the vaporization process and determine both the acoustic droplet vaporization (ADV) and inertial cavitation (IC) thresholds of phospholipid-coated perfluorobutane nanodroplets (PFB NDs, diameter = 237 ± 16 nm). PFB NDs have not previously been studied with ultrahigh-speed imaging and were observed to form individual microbubbles (1–10 μm) within two to three cycles and subsequently larger bubble clusters (10–50 μm). The ADV and IC thresholds did not statistically significantly differ and decreased with increasing pulse length (20–20,000 cycles), pulse repetition frequency (1–100 Hz), concentration (108–1010 NDs/mL), temperature (20°C–45°C) and decreasing frequency (1.5–0.5 MHz). Overall, the results indicate that at frequencies of 0.5, 1.0 and 1.5 MHz, PFB NDs can be vaporized at moderate peak negative pressures (

Nostalgia is an emotion that confers psychological benefits. The literature has neglected romantic nostalgia—that is, nostalgia specifically for past experiences shared with one’s partner—and its potential advantages for relationships. We examined romantic nostalgia in one correlational study, two experiments, and one daily diary study ( N = 638). Romantic nostalgia was positively associated with greater relationship commitment, satisfaction, and closeness (Study 1). Additionally, inducing romantic nostalgia via a writing task (Study 2) or music (Study 3) strengthened relational benefits. Finally, participants reported more positive relationship-specific experiences on days when they felt greater romantic nostalgia (Study 4). We discuss contributions to the nostalgia and relationships literatures.

Improved walking function is a priority among persons with motor-incomplete spinal cord injury (PwMISCI). Accessibility and cost limit long-term participation in locomotor training offered in specialized centers. Intensive motor training that facilitates neuroplastic mechanisms that support skill learning and can be implemented in the home/community may be advantageous for promoting long-term restoration of walking function. Additionally, increasing corticospinal drive via transcranial direct current stimulation (tDCS) may enhance training effects. In this pilot study, we investigated whether a moderate-intensity motor skill training (MST) circuit improved walking function in PwMISCI and whether augmenting training with tDCS influenced outcomes.Twenty-five adults (chronic, motor-incomplete spinal cord injury) were randomized to a 3-day intervention of a locomotor-related MST circuit and concurrent application of sham tDCS (MST+tDCS sham ) or active tDCS (MST+tDCS). The primary outcome was overground walking speed. Secondary outcomes included walking distance, cadence, stride length, and step symmetry index (SI).Analyses revealed significant effects of the MST circuit on walking speed, walking distance, cadence, and bilateral stride length but no effect on interlimb SI. No significant between-groups differences were observed. Post hoc analyses revealed within-groups change in walking speed (ΔM = 0.13 m/s, SD = 0.13) that app-roached the minimally clinically important difference of 0.15 m/s.Brief, intensive MST involving locomotor-related activities significantly increased walking speed, walking distance, and spatiotemporal measures in PwMISCI. Significant additive effects of tDCS were not observed; however, participation in only 3 days of MST was associated with changes in walking speed that were comparable to longer locomotor training studies.Video Abstract available for more insights from the authors (see the Video, Supplemental Digital Content 1, available at: http://links.lww.com/JNPT/A386 ).

Synthetic clays are promising biomaterials for delivery of therapeutic molecules in regenerative medicine. However, before their use can be translated into clinical applications, their safety must be assessed in human volunteers. The aim of this study was to test the hypothesis that a synthetic nanoclay (LAPONITE) does not cause irritation to the human skin. To achieve this, a nanoclay gel at two different concentrations (1.5 and 3% w/v) was applied on the forearm of healthy volunteers for 24 h. 1% sodium lauryl sulfate (SLS) and 3% (w/v) polyacrylic acid were used as the positive and negative controls, respectively. The compromise in the skin barrier function was measured by trans-epidermal water loss (TEWL), erythema by spectroscopic measurements, and skin inflammatory biomarkers (IL-1α and IL-1RA) by the enzyme-linked immunosorbent assay. We found that the nanoclay caused no prolonged increase in TEWL, erythema, or induction of inflammatory cytokines. This was in contrast to 1% SLS, a known irritant, which induced significant increases in both skin erythema and TEWL. We conclude that the nanoclay is not an irritant and is thus suitable for therapeutic interventions at the skin surface.

People often reflect nostalgicallyon the momentous occasions of their relationships. Experiencing romantic nostalgia-nostalgia for shared experiences with one's current romantic partner-likely confers relationship-specific benefits. Indeed, prior research indirectly hints at this assumed outcome by looking at relationship narratives. More recent work provides direct evidence that romantic nostalgia is both positively correlated with and causally enhances relationship-specific benefits. We describe such research and discuss avenues for future investigations that address mechanisms and potential downsides of romantic nostalgia while exploring translational possibilities.

Abstract. Empathy and perspective taking play important roles in interpersonal functioning. As prior research has linked metaphor use to emotional understanding, it is likely that metaphor use is also involved in empathy and perspective taking. In two daily diary studies ( N = 225; Obs. = 1,849), we predicted that on days in which empathy and perspective taking were high, participants would also report higher metaphor use. In Study 1, we found support for our hypotheses, such that daily metaphor use was positively associated with daily empathy and perspective taking. In Study 2, we replicated these results. We place this work within the current literature and discuss the promise of an interpersonal function of metaphor use.

LAPONITE® clay nanoparticles are known to exert osteogenic effects on human bone marrow stromal cells (HBMSCs), most characteristically, an upregulation in alkaline phosphatase activity and increased calcium deposition. The specific properties of LAPONITE® that impart its bioactivity are not known. In this study the role of lithium, a LAPONITE® degradation product, was investigated through the use of lithium salts and lithium modified LAPONITE® formulations. In contrast to intact particles, lithium ions applied at concentrations equivalent to that present in LAPONITE®, failed to induce any significant increase in alkaline phosphatase (ALP) activity. Furthermore, no significant differences were observed in ALP activity with modified clay structures and the positive effect on osteogenic gene expression did not correlate with the lithium content of modified clays. These results suggest that other properties of LAPONITE® nanoparticles, and not their lithium content, are responsible for their bioactivity.

Brain organoids grown from human pluripotent stem cells self-organize into cytoarchitectures resembling the developing human brain. These three-dimensional models offer an unprecedented opportunity to study human brain development and dysfunction. Characterization currently sacrifices spatial information for single-cell or histological analysis leaving whole-tissue analysis mostly unexplored. Here, we present the SCOUT pipeline for automated multiscale comparative analysis of intact cerebral organoids. Our integrated technology platform can rapidly clear, label, and image intact organoids. Algorithmic- and convolutional neural network-based image analysis extract hundreds of features characterizing molecular, cellular, spatial, cytoarchitectural, and organoid-wide properties from fluorescence microscopy datasets. Comprehensive analysis of 46 intact organoids and ~ 100 million cells reveals quantitative multiscale “phenotypes" for organoid development, culture protocols and Zika virus infection. SCOUT provides a much-needed framework for comparative analysis of emerging 3D in vitro models using fluorescence microscopy.

A detailed understanding of the anatomical and molecular architectures of cells and their system-wide connectivity is essential for interrogating system function and dysfunction. Extensive efforts have been made toward characterizing cells through various approaches, and have established invaluable databases yielding new insights. However, we still lack technologies for mapping the combined multi-scale anatomical and molecular details of individual cells in the human organ-scale system. To address this challenge, we developed a fully integrated technology platform for simultaneously extracting spatial, molecular, morphological, and connectivity information of individual cells from the same human brain at single-fiber resolution. We accomplished this by seamlessly integrating new chemical, mechanical, and computational tools to enable 3D multi-scale proteomic reconstruction of human organ tissues. We developed a novel microtome, termed MEGAtome, that enables ultra-precision slicing of whole-mount intact human brain hemispheres and large arrays of organs from other species with no loss of intra- and inter-slice cellular connectivity. To preserve structural and molecular information within intact human brain slabs and to enable multiplexed multiscale imaging, we developed a tissue-gel technology, termed mELAST, that transforms human brain tissues into an elastic and reversibly expandable tissue-hydrogel. To reconstruct the 3D connectivity of axonal networks across multiple brain slabs, we developed a computational pipeline termed UNSLICE. Using the technology platform, we analyzed Alzheimer’s disease (AD) pathology at multiple scales from overall cytoarchitecture to individual synapses. Finally, we demonstrated the feasibility of scalable neural connectivity mapping in human brain, establishing a path for probing brain connectivity and its alterations in diseases.One-Sentence SummaryWe developed an integrated scalable platform for highly multiplexed multi-scale phenotyping and connectivity mapping in the same human brain tissue, which includes novel tissue processing, labeling, imaging, and computational reconstruction technologies.

Frailty is a distinctive health state in which the ability of older people to cope with acute stressors is compromised by an increased vulnerability brought by age-associated declines in physiological reserve and function across multiple organ systems. Although closely associated with age, multimorbidity, and disability, frailty is a discrete syndrome that is associated with poorer outcomes across a range of medical conditions. However, its role in cerebrovascular disease and stroke has received limited attention. The estimated rise in the prevalence of frailty associated with changing demographics over the coming decades makes it an important issue for stroke practitioners, cerebrovascular research, clinical service provision, and stroke survivors alike. This review will consider the concept and models of frailty, how frailty is common in cerebrovascular disease, the impact of frailty on stroke risk factors, acute treatments, and rehabilitation, and considerations for future applications in both cerebrovascular clinical and research settings.

The complex connectivity of the mammalian brain underlies its function, but understanding how interconnected brain regions interact in neural processing remains a formidable challenge. Here we address this problem by introducing a genetic probe that permits selective functional imaging of distributed neural populations defined by viral labeling techniques. The probe is an engineered enzyme that transduces cytosolic calcium dynamics of probe-expressing cells into localized hemodynamic responses that can be specifically visualized by functional magnetic resonance imaging. Using a viral vector that undergoes retrograde transport, we apply the probe to characterize a brain-wide network of presynaptic inputs to the striatum activated in a deep brain stimulation paradigm in rats. The results reveal engagement of surprisingly diverse projection sources and inform an integrated model of striatal function relevant to reward behavior and therapeutic neurostimulation approaches. Our work thus establishes a strategy for mechanistic analysis of multiregional neural systems in the mammalian brain.

Organoids can shed light on the dynamic interplay between complex tissues and rare cell types within a controlled microenvironment. Here, we develop gut organoid cocultures with type-1 innate lymphoid cells (ILC1) to dissect the impact of their accumulation in inflamed intestines. We demonstrate that murine and human ILC1 secrete transforming growth factor β1, driving expansion of CD44v6 + epithelial crypts. ILC1 additionally express MMP9 and drive gene signatures indicative of extracellular matrix remodelling. We therefore encapsulated human epithelial–mesenchymal intestinal organoids in MMP-sensitive, synthetic hydrogels designed to form efficient networks at low polymer concentrations. Harnessing this defined system, we demonstrate that ILC1 drive matrix softening and stiffening, which we suggest occurs through balanced matrix degradation and deposition. Our platform enabled us to elucidate previously undescribed interactions between ILC1 and their microenvironment, which suggest that they may exacerbate fibrosis and tumour growth when enriched in inflamed patient tissues.

BACKGROUND Stroke remains a devastating complication of cardiac surgery. The aim of this study was to characterize the incidence of stroke and analyze the impact of stroke on patient outcomes and survival. METHODS A retrospective analysis was performed of patients with a computed tomography-confirmed stroke diagnosis between 1 January 2015 and 31 March 2019 at a single center. 2:1 propensity matching was performed to identify a control population. RESULTS Over the period 165 patients suffered a stroke (1.99%), with an incidence ranging from 0.85% for coronary artery bypass grafting to 8.14% for aortic surgery. The mean age was 70.3 years and 58.8% were male. 18% had experienced a previous stroke or transient ischemic attack. Compared to the comparison group, patients experiencing postoperative stroke had a significantly prolonged period of intensive care unit admission (8.0 vs 1.1 days P

Objectives This study determined whether in vivo positron emission tomography (PET) of arterial inflammation (18F-fluorodeoxyglucose [18F-FDG]) or microcalcification (18F-sodium fluoride [18F-NaF]) could predict restenosis following PTA. Background Restenosis following lower limb percutaneous transluminal angioplasty (PTA) is common, unpredictable, and challenging to treat. Currently, it is impossible to predict which patient will suffer from restenosis following angioplasty. Methods In this prospective observational cohort study, 50 patients with symptomatic peripheral arterial disease underwent 18F-FDG and 18F-NaF PET/computed tomography (CT) imaging of the superficial femoral artery before and 6 weeks after angioplasty. The primary outcome was arterial restenosis at 12 months. Results Forty subjects completed the study protocol with 14 patients (35%) reaching the primary outcome of restenosis. The baseline activities of femoral arterial inflammation (18F-FDG tissue-to-background ratio [TBR] 2.43 [interquartile range (IQR): 2.29 to 2.61] vs. 1.63 [IQR: 1.52 to 1.78]; p, Central Illustration

ObjectivesTimely thrombolysis of ischaemic stroke improves functional recovery, yet its delivery nationally is challenging due to shortages in the stroke specialist workforce and large geographical areas. One solution is remote stroke specialist input to regional centres via telemedicine. This study evaluates the usage and key metrics of performance of the East of England Stroke Telemedicine Partnership—the largest telestroke service in the UK—in providing hyperacute stroke care.DesignProspective observational study.SettingThe East of England Stroke Telemedicine Partnership provides a horizontal ‘hubless’ model of out-of-hours hyperacute stroke care to a population of 6.2 million across a 7500 square mile semirural region.ParticipantsAll (2709) telestroke consultations between 1 January 2014 and 31 December 2019.Main outcome measuresThrombolysis decision, pre-thrombolysis and post-thrombolysis stroke severity (National Institutes of Health Stroke Scale, NIHSS), haemorrhagic complications, and hyperacute pathway timings.ResultsOver the period, 1149 (42.4%) individuals were thrombolysed. Thrombolysis rates increased from 147/379 (38.8%) in 2014 to 225/490 (45.9%) in 2019. Median (IQR) pre-thrombolysis NIHSS was 10 (6–17), reducing to 6 (2–14) 24-hour post-thrombolysis (pConclusionsThe results from this large hyperacute telestroke cohort indicate two important points for clinical practice. First, telemedicine via a hubless horizontal model provides a clinically effective and safe method for delivering hyperacute stroke thrombolysis. Second, improved door-to-needle times were offset by a concerning rise in prehospital timings. These findings indicate that although telemedicine may benefit in-hospital hyperacute stroke care, improvements across the whole stroke pathway are essential.

Guttiferones belong to the polyisoprenylated benzophenone, a class of compounds, a very restricted group of natural plant products, especially in the Clusiaceae family. They are commonly found in bark, stem, leaves, and fruits of plants of the genus Garcinia and Symphonia. Guttiferones have the following classifications according to their chemical structure: A, B, C, D, E, F, G, H, I, J, K, L, M, N, O, P, Q, R, S, and T. All of them have received growing attention due to its multiple biological activities. This review provides a first comprehensive approach to plant sources, phytochemical profile, specific pharmacological effects, and mechanisms of guttiferones already described. Studies indicate a broad spectrum of pharmacological activities, such as: anti-inflammatory, immunomodulatory, antioxidant, antitumor, antiparasitic, antiviral, and antimicrobial. Despite the low toxicity of these compounds in healthy cells, there is a lack of studies in the literature related to toxicity in general. Given their beneficial effects, guttiferones are expected to be great potential drug candidates for treating cancer and infectious and transmissible diseases. However, further studies are needed to elucidate their toxicity, specific molecular mechanisms and targets, and to perform more in-depth pharmacokinetic studies. This review highlights chemical properties, biological characteristics, and mechanisms of action so far, offering a broad view of the subject and perspectives for the future of guttiferones in therapeutics.

An off-axis Schmidt telescope based remote imaging system is under development for in-situ viewing of high-energy proton beam distribution at the Spallation Neutron Source. The optical architecture, design parameters and challenges of this design will be discussed.

Melioidosis caused by the facultative intracellular pathogen Burkholderia pseudomallei is difficult to treat due to poor intracellular bioavailability of antibiotics and antibiotic resistance. In the absence of novel compounds, polymersome (PM)-encapsulation may increase the efficacy of existing antibiotics and reduce antibiotic resistance by promoting targeted, infection-specific intracellular uptake. In this study we developed PMs composed of widely available polyethylene oxide-polycaprolactone (PEO-PCL) block co-polymers and demonstrated their delivery to intracellular B. thailandensis infection using multispectral imaging flow cytometry (IFC) and coherent anti-Stokes Raman scattering (CARS) microscopy. Antibiotics were tightly sequestered in PMs and did not inhibit the growth of free-living B. thailandensis. However, on uptake of antibiotic-loaded PMs by infected macrophages, IFC demonstrated PM co-localisation with intracellular B. thailandensis and a significant inhibition of their growth. We conclude that PMs are a viable approach for the targeted antibiotic treatment of persistent intracellular Burkholderia infection.

Highlights • Increasing the volumetric concentration of PFP led to an increase in the size of lipid-coated PFP NDs. • Increasing sonication intensity and time led to a decrease in ND size. • The ND coating layer can be labelled with lipophilic fluorophores without affecting the overall ND size. • NDs were stable at 4 °C for one week, and at 37 °C for 110 min. • Ultrasound (0.5 MHz, 2–4 MPa) caused vaporisation of NDs within a tissue-mimicking phantom., Liquid perfluorocarbon nanodroplets (NDs) are an attractive alternative to microbubbles (MBs) for ultrasound-mediated therapeutic and diagnostic applications. ND size and size distribution have a strong influence on their behaviour in vivo, including extravasation efficiency, circulation time, and response to ultrasound stimulation. Thus, it is desirable to identify ways to tailor the ND size and size distribution during manufacturing. In this study phospholipid-coated NDs, comprising a perfluoro-n-pentane (PFP) core stabilised by a DSPC/PEG40s (1,2-distearoyl-sn-glycero-3-phosphocholine and polyoxyethylene(40)stearate, 9:1 molar ratio) shell, were produced in phosphate-buffered saline (PBS) by sonication. The effect of the following production-related parameters on ND size was investigated: PFP concentration, power and duration of sonication, and incorporation of a lipophilic fluorescent dye. ND stability was also assessed at both 4 °C and 37 °C. When a sonication pulse of 6 s and 15% duty cycle was employed, increasing the volumetric concentration of PFP from 5% to 15% v/v in PBS resulted in an increase in ND diameter from 215.8 ± 16.8 nm to 408.9 ± 171.2 nm. An increase in the intensity of sonication from 48 to 72 W (with 10% PFP v/v in PBS) led to a decrease in ND size from 354.6 ± 127.2 nm to 315.0 ± 100.5 nm. Increasing the sonication time from 20 s to 40 s (using a pulsed sonication with 30% duty cycle) did not result in a significant change in ND size (in the range 278–314 nm); however, when it was increased to 60 s, the average ND diameter reduced to 249.7 ± 9.7 nm, which also presented a significantly lower standard deviation compared to the other experimental conditions investigated (i.e., 9.7 nm vs. > 49.4 nm). The addition of the fluorescent dye DiI at different molar ratios did not affect the ND size distribution. NDs were stable at 4 °C for up to 6 days and at 37 °C for up to 110 min; however, some evidence of ND-to-MB phase transition was observed after 40 min at 37 °C. Finally, phase transition of NDs into MBs was demonstrated using a tissue-mimicking flow phantom under therapeutic ultrasound exposure conditions (ultrasound frequency: 0.5 MHz, acoustic pressure: 2–4 MPa, and pulse repetition frequency: 100 Hz).

Alongside the use of metal cations and π–π stacking, hydrogen bonding is one of the major templating interactions used to prepare rotaxanes and catenanes. In this review, a brief summary of key historical milestones will be followed by discussion of developments from over the last decade in both synthetic methodology and application of hydrogen bond templated interlocked molecules. Hydrogen bond templation can allow for rapid access to interlocked molecules in high yields, with select examples having been put to useful purpose, in applications such as organocatalysis and cellular imaging.

Understanding complex biological systems requires the system-wide characterization of both molecular and cellular features. Existing methods for spatial mapping of biomolecules in intact tissues suffer from information loss caused by degradation and tissue damage. We report a tissue transformation strategy named stabilization under harsh conditions via intramolecular epoxide linkages to prevent degradation (SHIELD), which uses a flexible polyepoxide to form controlled intra- and intermolecular cross-link with biomolecules. SHIELD preserves protein fluorescence and antigenicity, transcripts and tissue architecture under a wide range of harsh conditions. We applied SHIELD to interrogate system-level wiring, synaptic architecture, and molecular features of virally labeled neurons and their targets in mouse at single-cell resolution. We also demonstrated rapid three-dimensional phenotyping of core needle biopsies and human brain cells. SHIELD enables rapid, multiscale, integrated molecular phenotyping of both animal and clinical tissues.