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For ease of instruction in the classroom, the one-way analysis of variance F statistic is rewritten in terms of pairwise differences in individual sample means instead of differences of individual sample means from the overall sample mean. Likewise, the Kruskal–Wallis statistic may be rewritten in terms of pairwise differences in individual average ranks rather than differences of individual average ranks from the overall average rank. In unbalanced designs, it is seen that the contribution to either test statistic from a pair of samples is related to the product of the sample sizes multiplied by the square of the relevant pairwise difference. Supplementary materials for this article are available online.

Introduction: This study aims to assess the understandability, actionability, and quality of online resources for the self-management (SM) of bipolar spectrum disorders in adults. Methods: An online search using Google, Bing, and Yahoo! search engines was conducted to identify resources for bipolar disorder. Those that were published in English, discussed at least 1 method directed at improving an SM task, and were within the first 25 nonadvertisement results for each search were included. Resources directed specifically at adolescents were excluded. Understandability and actionability of the online resources were evaluated using the Patient Education Materials Assessment Tool (PEMAT). Quality of the online resources was evaluated using the DISCERN instrument. The number of SM tasks each resource discussed was also evaluated. Overall mean appropriateness was calculated by averaging the percentage scores of understandability, actionability, and quality. Results: Fifty-two resources were included. The mean sample scores were 8.4 (SD, 2.1; range, 2-13; maximum, 15) for understandability, 2.2 (SD, 1.2; range, 0-4; maximum, 5) for actionability, and 46.1 (SD, 8.9; range, 30-57; maximum, 75) for quality. The overall mean appropriateness percentage was 53.5% (SD, 11.7%; range, 18%-77%), with a goal of at least 70%. Included resources addressed a mean of 7.1 tasks (SD, 2.5; range, 1-14; maximum, 20). Discussion: Most online resources for the SM of bipolar disorder scored poorly for understandability and actionability based on PEMAT scores and had low to moderate scores for quality using the DISCERN instrument. Future online resources should be designed with the goal of increasing appropriateness for patients.

In this paper, we present a full spatially resolved polarization map for the Vela pulsar wind nebula (PWN) observed by IXPE. By employing effective background discrimination techniques, our results show a remarkably high degree of local polarization in the outskirt region, exceeding 60% (55%) with a probability of 95% (99%), which approaches the upper limit predicted by the synchrotron emission mechanism. The high degree of polarization suggests that the turbulent magnetic energy is at most 33% of the ordered one. In addition, the X-ray polarization map exhibits a toroidal magnetic field pattern that is consistent with the field revealed by radio observations across the entire nebula. This consistency reveals that the observed X-ray and radio emissions are radiated by electrons from the same magnetic field. Different from the Crab PWN, the consistency observed in the Vela PWN may be attributed to the interaction between the reverse shock of the supernova blast wave and the PWN, which leads to a displacement between the synchrotron-cooled nebula and the fresh nebula close to the pulsar. These findings deepen our understanding of the structure and evolution of the Vela PWN and the magnetohydrodynamic interaction in PWNe.

We report the first detection of the X-ray polarization of the bright transient Swift J1727.8−1613 with the Imaging X-ray Polarimetry Explorer. The observation was performed at the beginning of the 2023 discovery outburst, when the source resided in the bright hard state. We find a time- and energy-averaged polarization degree of 4.1% ± 0.2% and a polarization angle of 2.°2 ± 1.°3 (errors at 68% confidence level; this translates to ∼20 σ significance of the polarization detection). This finding suggests that the hot corona emitting the bulk of the detected X-rays is elongated, rather than spherical. The X-ray polarization angle is consistent with that found in submillimeter wavelengths. Since the submillimeter polarization was found to be aligned with the jet direction in other X-ray binaries, this indicates that the corona is elongated orthogonal to the jet.

The Imaging X-ray Polarimetry Explorer (IXPE) observed the black hole X-ray binary 4U 1630–47 in the steep power-law (or very high) state. The observations reveal a linear polarization degree of the 2–8 keV X-rays of 6.8% ± 0.2% at a position angle of 21.°3 ± 0.°9 east of north (all errors at 1 σ confidence level). Whereas the polarization degree increases with energy, the polarization angle stays constant within the accuracy of our measurements. We compare the polarization of the source in the steep power-law state with the previous IXPE measurement of the source in the high soft state. We find that, even though the source flux and spectral shape are significantly different between the high soft state and the steep power-law state, their polarization signatures are similar. Assuming that the polarization of both the thermal and power-law emission components are constant over time, we estimate the power-law component polarization to be 6.8%–7.0% and note that the polarization angle of the thermal and power-law components must be approximately aligned. We discuss the implications for the origin of the power-law component and the properties of the emitting plasma.

BackgroundIndividuals with type 1 diabetes represent a population with important vulnerabilities to dynamic physiological, behavioral, and psychological interactions, as well as cognitive processes. Ecological momentary assessment (EMA), a methodological approach used to study intraindividual variation over time, has only recently been used to deliver cognitive assessments in daily life, and many methodological questions remain. The Glycemic Variability and Fluctuations in Cognitive Status in Adults with Type 1 Diabetes (GluCog) study uses EMA to deliver cognitive and self-report measures while simultaneously collecting passive interstitial glucose in adults with type 1 diabetes. ObjectiveWe aimed to report the results of an EMA optimization pilot and how these data were used to refine the study design of the GluCog study. An optimization pilot was designed to determine whether low-frequency EMA (3 EMAs per day) over more days or high-frequency EMA (6 EMAs per day) for fewer days would result in a better EMA completion rate and capture more hypoglycemia episodes. The secondary aim was to reduce the number of cognitive EMA tasks from 6 to 3. MethodsBaseline cognitive tasks and psychological questionnaires were completed by all the participants (N=20), followed by EMA delivery of brief cognitive and self-report measures for 15 days while wearing a blinded continuous glucose monitor. These data were coded for the presence of hypoglycemia (80% EMA completion. However, more hypoglycemia episodes were captured during the schedule with the 3 EMAs per day than during the schedule with 6 EMAs per day. ConclusionsThe results from this EMA optimization pilot guided key design decisions regarding the EMA frequency and study duration for the main GluCog study. The present report responds to the urgent need for systematic and detailed information on EMA study designs, particularly those using cognitive assessments coupled with physiological measures. Given the complexity of EMA studies, choosing the right instruments and assessment schedules is an important aspect of study design and subsequent data interpretation.

The lower-energy peak of the spectral energy distribution of blazars has commonly been ascribed to synchrotron radiation from relativistic particles in the jets. Despite the consensus regarding jet emission processes, the particle acceleration mechanism is still debated. Here, we present the first X-ray polarization observations of PG 1553+113, a high-synchrotron-peak blazar observed by the Imaging X-ray Polarimetry Explorer (IXPE). We detect an X-ray polarization degree of (10 ± 2)% along an electric-vector position angle of ψ _X = 86° ± 8°. At the same time, the radio and optical polarization degrees are lower by a factor of ∼3. During our IXPE pointing, we observed the first orphan optical polarization swing of the IXPE era, as the optical angle of PG 1553+113 underwent a smooth monotonic rotation by about 125°, with a rate of ∼17° day ^–1 . We do not find evidence of a similar rotation in either radio or X-rays, which suggests that the X-ray and optically emitting regions are separate or, at most, partially cospatial. Our spectropolarimetric results provide further evidence that the steady-state X-ray emission in blazars originates in a shock-accelerated and energy-stratified electron population.

This paper reports the first detection of polarization in the X-rays for atoll-source 4U 1820−303, obtained with the Imaging X-ray Polarimetry Explorer (IXPE) at 99.999% confidence level (CL). Simultaneous polarimetric measurements were also performed in the radio with the Australia Telescope Compact Array. The IXPE observations of 4U 1820−303 were coordinated with Swift X-ray Telescope, Neutron Star Interior Composition Explorer, and Nuclear Spectroscopic Telescope Array aiming to obtain an accurate X-ray spectral model covering a broad energy interval. The source shows a significant polarization above 4 keV, with a polarization degree of 2.0% ± 0.5% and a polarization angle of −55° ± 7° in the 4–7 keV energy range, and a polarization degree of 10% ± 2% and a polarization angle of −67° ± 7° in the 7–8 keV energy bin. This polarization also shows a clear energy trend with polarization degree increasing with energy and a hint for a position-angle change of ≃90° at 96% CL around 4 keV. The spectro-polarimetric fit indicates that the accretion disk is polarized orthogonally to the hard spectral component, which is presumably produced in the boundary/spreading layer. We do not detect linear polarization from the radio counterpart, with a 3 σ upper limit of 50% at 7.25 GHz.

We report the first >99% confidence detection of X-ray polarization in BL Lacertae. During a recent X-ray/ γ -ray outburst, a 287 ks observation (2022 November 27–30) was taken using the Imaging X-ray Polarimetry Explorer (IXPE), together with contemporaneous multiwavelength observations from the Neil Gehrels Swift observatory and XMM-Newton in soft X-rays (0.3–10 keV), NuSTAR in hard X-rays (3–70 keV), and optical polarization from the Calar Alto and Perkins Telescope observatories. Our contemporaneous X-ray data suggest that the IXPE energy band is at the crossover between the low- and high-frequency blazar emission humps. The source displays significant variability during the observation, and we measure polarization in three separate time bins. Contemporaneous X-ray spectra allow us to determine the relative contribution from each emission hump. We find >99% confidence X-ray polarization ${{\rm{\Pi }}}_{2\mbox{--}4\mathrm{keV}}={21.7}_{-7.9}^{+5.6} \% $ and electric vector polarization angle ψ _2–4keV = −28.°7 ± 8.°7 in the time bin with highest estimated synchrotron flux contribution. We discuss possible implications of our observations, including previous IXPE BL Lacertae pointings, tentatively concluding that synchrotron self-Compton emission dominates over hadronic emission processes during the observed epochs.

The radiation from accreting X-ray pulsars was expected to be highly polarized, with some estimates for the polarization degree of up to 80%. However, phase-resolved and energy-resolved polarimetry of X-ray pulsars is required in order to test different models and to shed light on the emission processes and the geometry of the emission region. Here we present the first results of the observations of the accreting X-ray pulsar Vela X-1 performed with the Imaging X-ray Polarimetry Explorer. Vela X-1 is considered to be the archetypal example of a wind-accreting, high-mass X-ray binary system, consisting of a highly magnetized neutron star accreting matter from its supergiant stellar companion. The spectropolarimetric analysis of the phase-averaged data for Vela X-1 reveals a polarization degree (PD) of 2.3% ± 0.4% at the polarization angle (PA) of −47.°3 ± 5.°4. A low PD is consistent with the results obtained for other X-ray pulsars and is likely related to the inverse temperature structure of the neutron star atmosphere. The energy-resolved analysis shows the PD above 5 keV reaching 6%–10% and a ∼90° difference in the PA compared to the data in the 2–3 keV range. The phase-resolved spectropolarimetric analysis finds a PD in the range 0%–9% with the PA varying between −80° and 40°.

We present the IXPE observation of GRB 221009A, which includes upper limits on the linear polarization degree of both prompt and afterglow emission in the soft X-ray energy band. GRB 221009A is an exceptionally bright gamma-ray burst (GRB) that reached Earth on 2022 October 9 after traveling through the dust of the Milky Way. The Imaging X-ray Polarimetry Explorer (IXPE) pointed at GRB 221009A on October 11 to observe, for the first time, the 2–8 keV X-ray polarization of a GRB afterglow. We set an upper limit to the polarization degree of the afterglow emission of 13.8% at a 99% confidence level. This result provides constraints on the jet opening angle and the viewing angle of the GRB, or alternatively, other properties of the emission region. Additionally, IXPE captured halo-rings of dust-scattered photons that are echoes of the GRB prompt emission. The 99% confidence level upper limit to the prompt polarization degree depends on the background model assumption, and it ranges between ∼55% and ∼82%. This single IXPE pointing provides both the first assessment of X-ray polarization of a GRB afterglow and the first GRB study with polarization observations of both the prompt and afterglow phases.

Magnetars are the most strongly magnetized neutron stars, and one of the most promising targets for X-ray polarimetric measurements. We present here the first Imaging X-ray Polarimetry Explorer observation of the magnetar 1RXS J170849.0-400910, jointly analyzed with a new Swift observation and archival NICER data. The total (energy- and phase-integrated) emission in the 2–8 keV energy range is linerarly polarized, at a ∼35% level. The phase-averaged polarization signal shows a marked increase with energy, ranging from ∼20% at 2–3 keV up to ∼80% at 6–8 keV, while the polarization angle remains constant. This indicates that radiation is mostly polarized in a single direction. The spectrum is well reproduced by a combination of either two thermal (blackbody) components or a blackbody and a power law. Both the polarization degree and angle also show a variation with the spin phase, and the former is almost anticorrelated with the source counts in the 2–8 and 2–4 keV bands. We discuss the possible implications and interpretations, based on a joint analysis of the spectral, polarization, and pulsation properties of the source. A scenario in which the surface temperature is not homogeneous, with a hotter cap covered by a gaseous atmosphere and a warmer region in a condensed state, provides a satisfactory description of both the phase- and energy-dependent spectro-polarimetric data. The (comparatively) small size of the two emitting regions, required to explain the observed pulsations, does not allow to reach a robust conclusion about the presence of vacuum birefringence effects.

Hannah Arendt’s claim that thinking is the last defense against the moral outrages of criminal political regimes sets the problematic of good and evil in relief. Human freedom, Paul Ricœur reminds us, is responsible for evil. The avowal of the evil of violence is thus the condition of our consciousness of the freedom to act anew. Aesthetic experience’s lateral transposition onto the planes of ethics and politics highlights our capacity to respond to exigencies in apposite ways. Exemplary representations of the good, the right, and the justexpress a desire for being. Eros is accordingly the law of every work, word, deed, or act that answers to a difficulty, challenge, or crisis. Bound to living experiences, thought attains its true height through interrogating, demystifying, and vacating frozen norms, standards, and mores. Judgment actualizes thought’s liberating effects in answer to the demands of the situations in which we find ourselves.

Paul Ricœur’s recourse to the metahistorical categories, space of experience and horizon of expectation, invites an inquiry into geography’s role as the guarantor of history. The ontology of the flesh provides the first indication of how one’s body is implicated in the sense of one’s place in the world. In turn, narrative inscriptions of events on the landscape transform the physical topography of a place into an array of sites where memories of ancestral wisdom and historical traumas endure. By anchoring historians’ representations of the past in the places and locales in which events took place, geography constructs a third space analogous to the third time of history. The aporias engendered by the phenomenology of time, however, have no equivalent in the phenomenology of space. The dissymmetry between the dialectic that informs the discourse of space and the one that informs the discourse of time thus keeps in place the reciprocal relation between geography and historiography.

Abstract Bacterial keratitis (BK) is a major cause of corneal blindness globally. This study aimed to develop a novel class of antimicrobial therapy, based on human-derived hybrid host defense peptides (HyHDPs), for treating BK. HyHDPs were rationally designed through combination of functional amino acids in parent HDPs, including LL-37 and human beta-defensin (HBD)-1 to -3. Minimal inhibitory concentrations (MICs) and time-kill kinetics assay were performed to determine the concentration- and time-dependent antimicrobial activity and cytotoxicity was evaluated against human corneal epithelial cells and erythrocytes. In vivo safety and efficacy of the most promising peptide was examined in the corneal wound healing and Staphylococcus aureus (ATCC SA29213) keratitis murine models, respectively. A second-generation HyHDP (CaD23), based on rational hybridization of the middle residues of LL-37 and C-terminal of HBD-2, was developed and was shown to demonstrate good efficacy against methicillin-sensitive and methicillin-resistant S. aureus [MIC = 12.5–25.0 μg/ml (5.2–10.4 μM)] and S. epidermidis [MIC = 12.5 μg/ml (5.2 μM)], and moderate efficacy against P. aeruginosa [MIC = 25-50 μg/ml (10.4–20.8 μM)]. CaD23 (at 25 μg/ml or 2× MIC) killed all the bacteria within 30 min, which was 8 times faster than amikacin (25 μg/ml or 20× MIC). After 10 consecutive passages, S. aureus (ATCC SA29213) did not develop any antimicrobial resistance (AMR) against CaD23 whereas it developed significant AMR (i.e. a 32-fold increase in MIC) against amikacin, a commonly used treatment for BK. Pre-clinical murine studies showed that CaD23 (0.5 mg/ml) achieved a median reduction of S. aureus bioburden by 94% (or 1.2 log10 CFU/ml) while not impeding corneal epithelial wound healing. In conclusion, rational hybridization of human-derived HDPs has led to generation of a potentially efficacious and safe topical antimicrobial agent for treating Gram-positive BK, with no/minimal risk of developing AMR.

Percentage of body fat, age, weight, height, and 14 circumference measurements (e.g., waist) are given for 184 women aged 18–25. Body fat, one measure of health, was accurately determined by an underwater weighing technique which requires special equipment and training of the individuals conducting the process. Modeling body fat percentage using multiple regression provides a convenient method of estimating body fat percentage using measures collected using only a measuring tape and a scale. This dataset can be used to show students the utility of multiple regression and to provide practice in model building.

Introduction: With current goals of increased space exploration and travel to Mars, there has been great interest in understanding the long-term effects of high atomic number, high energy (HZE) ion exposure on various organ systems and the immune system. Little is known about late effects on the immune system after HZE exposure. Therefore, our objective was to determine how natural killer (NK) cell populations were affected in geriatric mice that were exposed to HZE particles during middle-age, thereby representing elderly retired astronauts that undertook deep space missions.Methods: 10 month old male CBA/CaJ mice were whole-body irradiated: sham (control); 150-cGy gamma-rays (delivered in 1 fraction); 40-cGy 1-GeV/nu 28Si14+ ions (delivered in 3 fractions); 40-cGy 1-GeV/nu 16O8+ ions (1 fraction); and 40-cGy 1-GeV/nu 16O8+ ions (3 fractions). The mice were sacrificed 1–1.5 yr post-exposure, and the spleens harvested. Splenocyte effector (E) cells were harvested and added to 51Cr-labeled Yac-1 target (T) cells in E:T ratios of 12:1, 25:1, 50:1, and 100:1. NK cytotoxicity was measured with 51Cr release. In addition, 2 million splenocytes were aliquoted and stained with a seven-antibody cocktail, and flow cytometry was used to determine the percentage of NK, B lymphocytes, and T lymphocytes in the splenocyte population.Results: Mice exposed to either a single fraction of 150-cGy gamma rays or 40-cGy 16O8+ ions in 3 fractions were found to have significant decreases in NK cytotoxicity of approximately 30% and 25%, respectively. No significant differences were observed in NK cytotoxicity for 40-cGy 16O8+ ions delivered in 1 fraction, or 40-cGy 28Si14+ ions delivered in 3 fractions. No significant differences were observed in the percentage of spleen cells that were NK (%NK) amongst the groups.Conclusion: Fractionated HZE ion exposure has the potential to affect the innate arm of the immune system long after exposure, leading to decreases in NK cell function. Therefore, protective countermeasures may need to be considered to decrease the risk of reduced long-term immune function in elderly retired astronauts that undertook deep space missions.

Wastewater-based epidemiology (WBE) is an effective way of tracking the appearance and spread of SARS-COV-2 lineages through communities. Beginning in early 2021, we implemented a targeted approach to amplify and sequence the receptor binding domain (RBD) of SARS-COV-2 to characterize viral lineages present in sewersheds. Over the course of 2021, we reproducibly detected multiple SARS-COV-2 RBD lineages that have never been observed in patient samples in 9 sewersheds located in 3 states in the USA. These cryptic lineages contained between 4 to 24 amino acid substitutions in the RBD and were observed intermittently in the sewersheds in which they were found for as long as 14 months. Many of the amino acid substitutions in these lineages occurred at residues also mutated in the Omicron variant of concern (VOC), often with the same substitutions. One of the sewersheds contained a lineage that appeared to be derived from the Alpha VOC, but the majority of the lineages appeared to be derived from pre-VOC SARS-COV-2 lineages. Specifically, several of the cryptic lineages from New York City appeared to be derived from a common ancestor that most likely diverged in early 2020. While the source of these cryptic lineages has not been resolved, it seems increasingly likely that they were derived from long-term patient infections or animal reservoirs. Our findings demonstrate that SARS-COV-2 genetic diversity is greater than what is commonly observed through routine SARS-CoV-2 surveillance. Wastewater sampling may more fully capture SARS-CoV-2 genetic diversity than patient sampling and could reveal new VOCs before they emerge in the wider human population.

Blood samples were collected from pigs at six abattoirs in the Kampala, Uganda metropolitan area from May 2021 through June 2022, and tested for African swine fever virus. Thirty-one samples with cycle threshold values < 26 from pigs with different geographic origins, clinical and pathologic signs, and Ornithodoros moubata exposure underwent whole genome sequencing. The p72 gene was used to genotype the isolates, and all were found to be genotype IX; whole genome sequences to previous genotype IX isolates confirmed their similarity. Six of the isolates had enough coverage to evaluate single nucleotide polymorphisms (SNPs). Five of the isolates differed from historic regional isolates, but had similar SNPs to one another, and the sixth isolate also differed from historic regional isolates, but also differed from the other five isolates, even though they are all genotype IX. Whole genome sequencing data provide additional detail on viral evolution that can be useful for molecular epidemiology, and understanding the impact of changes in genes to disease phenotypes, and may be needed for vaccine targeting should a commercial vaccine become available. More sequencing of African swine fever virus isolates is needed in Uganda to understand how and when the virus is changing.

BackgroundGenistein is a dietary supplement with phyto-estrogenic properties. Therefore, high intake of genistein during pregnancy may have adverse effects on the genetic integrity of testes and germ cells of male offspring. In this study, we examined whether maternal exposure to genistein during pregnancy induced oxidative DNA damage in the male germline at adolescence.MethodsAtm-ΔSRI mice have lower glucose-6-phosphate dehydrogenase (G6PDH) activity, which is important for maintaining levels of reduced glutathione and therefore these mice have an increased susceptibility to oxidative stress. Parental heterozygous Atm-ΔSRI mice received a genistein-rich or control diet, after which they were mated to obtain offspring. During pregnancy, mothers remained on the respective diets and after delivery all animals received control diets. Redox status and oxidative DNA damage were assessed in testes and sperm of 12 weeks old male offspring. Gene expression of Cyp1b1, Comt, and Nqo1 was assessed in testes, and DNA methylation as possible mechanism for transmission of effects to later life.ResultsIntake of genistein during pregnancy increased oxidative DNA damage in testes of offspring, especially in heterozygous Atm-ΔSRI mice. These increased DNA damage levels coincided with decreased expression of Comt and Nqo1. Heterozygous Atm-ΔSRI mice had higher levels of DNA strand breaks in sperm compared to wild type littermates, and DNA damage was further enhanced by a genistein-rich maternal diet. G6PDH activity was higher in mice with high maternal intake of genistein compared to control diets, suggesting compensation against oxidative stress. A positive correlation was observed between the levels of DNA methylation and oxidative DNA damage in testes.ConclusionThese data indicate that prenatal exposure to genistein altered gene expression and increased DNA damage in testes and sperm of adolescent male offspring. These effects of genistein on DNA damage in later life coincided with alterations in DNA methylation.

Herbal traditional Chinese medicines (TCMs) are an increasingly popular alternative therapy globally. Due to the complex chemical composition of herbal products, and with research showing that consumers from Western countries are more likely to take multiple herbal products at one time, the lack of understanding of the potential side effects of herbal TCM may pose a significant risk to health and wellbeing. This may be particularly so now that herbal preparations are being promoted for the prevention and treatment of COVID-19 symptoms, often in association with Western medicines such as paracetamol. Of interest are the potential adverse effects of herbal TCMs on the kidney. Many factors can lead to the development of renal injury including intrinsic toxicity, plant misidentification, adulteration, contamination, and of increasing importance, interactions with conventional drugs and other herbs. This review evaluates and summarizes some of the key aspects of TCM-induced nephrotoxicity and the current scope of herb-drug and herb-herb interaction that may cause adverse effects.

Sight is arguably the most important sense in human. Being constantly exposed to the environmental stress, irritants and pathogens, the ocular surface – a specialized functional and anatomical unit composed of tear film, conjunctival and corneal epithelium, lacrimal glands, meibomian glands, and nasolacrimal drainage apparatus – serves as a crucial front-line defense of the eye. Host defense peptides (HDPs), also known as antimicrobial peptides, are evolutionarily conserved molecular components of innate immunity that are found in all classes of life. Since the first discovery of lysozyme in 1922, a wide range of HDPs have been identified at the ocular surface. In addition to their antimicrobial activity, HDPs are increasingly recognized for their wide array of biological functions, including anti-biofilm, immunomodulation, wound healing, and anti-cancer properties. In this review, we provide an updated review on: (1) spectrum and expression of HDPs at the ocular surface; (2) participation of HDPs in ocular surface diseases/conditions such as infectious keratitis, conjunctivitis, dry eye disease, keratoconus, allergic eye disease, rosacea keratitis, and post-ocular surgery; (3) HDPs that are currently in the development pipeline for treatment of ocular diseases and infections; and (4) future potential of HDP-based clinical pharmacotherapy for ocular diseases.

The HIV/SIV envelope glycoprotein (Env) cytoplasmic domain contains a highly conserved Tyr-based trafficking signal that mediates both clathrin-dependent endocytosis and polarized sorting. Despite extensive analysis, the role of these functions in viral infection and pathogenesis is unclear. An SIV molecular clone (SIVmac239) in which this signal is inactivated by deletion of Gly-720 and Tyr-721 (SIVmac239ΔGY), replicates acutely to high levels in pigtail macaques (PTM) but is rapidly controlled. However, we previously reported that rhesus macaques and PTM can progress to AIDS following SIVmac239ΔGY infection in association with novel amino acid changes in the Env cytoplasmic domain. These included an R722G flanking the ΔGY deletion and a nine nucleotide deletion encoding amino acids 734-736 (ΔQTH) that overlaps the rev and tat open reading frames. We show that molecular clones containing these mutations reconstitute signals for both endocytosis and polarized sorting. In one PTM, a novel genotype was selected that generated a new signal for polarized sorting but not endocytosis. This genotype, together with the ΔGY mutation, was conserved in association with high viral loads for several months when introduced into naïve PTMs. For the first time, our findings reveal strong selection pressure for Env endocytosis and particularly for polarized sorting during pathogenic SIV infection in vivo.

Abstract The novel coronavirus disease 2019 (COVID-19) has considerably heightened health and financial concerns for many individuals. Similar concerns, such as those associated with poverty, impair performance on cognitive control tasks. If ongoing concerns about COVID-19 substantially increase the tendency to mind wander in tasks requiring sustained attention, these worries could degrade performance on a wide range of tasks, leading, for example, to increased traffic accidents, diminished educational achievement, and lower workplace productivity. In two pre-registered experiments, we investigated the degree to which young adults’ concerns about COVID-19 correlated with their ability to sustain attention. Experiment 1 tested mainly European participants during an early phase of the pandemic. After completing a survey probing COVID-related concerns, participants engaged in a continuous performance task (CPT) over two, 4-min blocks, during which they responded to city scenes that occurred 90% of the time and withheld responses to mountain scenes that occurred 10% of the time. Despite large and stable individual differences, performance on the scene CPT did not significantly correlate with the severity of COVID-related concerns obtained from the survey. Experiment 2 tested US participants during a later phase of the pandemic. Once again, CPT performance did not significantly correlate with COVID concerns expressed in a pre-task survey. However, participants who had more task-unrelated thoughts performed more poorly on the CPT. These findings suggest that although COVID-19 increased anxiety in a broad swath of society, young adults are able to hold these concerns in a latent format, minimizing their impact on performance in a demanding sustained attention task.

Abstract Background Oxford Nanopore Technologies’ instruments can sequence reads of great length. Long reads improve sequence assemblies by unambiguously spanning repetitive elements of the genome. Sequencing reads of significant length requires the preservation of long DNA template molecules through library preparation by pipetting reagents as slowly as possible to minimize shearing. This process is time-consuming and inconsistent at preserving read length as even small changes in volumetric flow rate can result in template shearing. Results We have designed SNAILS (Slow Nucleic Acid Instrument for Long Sequences), a 3D-printable instrument that automates slow pipetting of reagents used in long read library preparation for Oxford Nanopore sequencing. Across six sequencing libraries, SNAILS preserved more reads exceeding 100 kilobases in length and increased its libraries’ average read length over manual slow pipetting. Conclusions SNAILS is a low-cost, easily deployable solution for improving sequencing projects that require reads of significant length. By automating the slow pipetting of library preparation reagents, SNAILS increases the consistency and throughput of long read Nanopore sequencing.

The aporias of time that Paul Ricœur identifies in the conclusion to his three-volume Time and Narrative offer a fecund starting-point from which to consider how the poetics of narrativity figures in a philosophy of the will. By setting the poetics of narrativity against the aporetics of temporality, Ricoeur highlights the narrative art’s operative power in drawing together incidents and events in answer to time’s dispersion across the present, the past, and the future. In turn, the confession of the limits of narrative opens the way to a broader consideration of the idea of the unity of history in the absence of a meta-historical plot. This idea calls for a reflection on the ethical and political imperative of making freedom a reality for all. By taking the theory of freedom’s actualization as a touchstone, I argue that the vision of a reconciled humanity that for Ricœur is the intended object of the poetics of the will acquires the force of a directive idea. The capacity to refashion the real from within thus proves to be decisive for drawing out the connection between the aporetics of temporality, the poetics of narrativity, and Ricœur’s philosophical anthropology.

Abstract Background Cancer-associated fibroblasts (CAFs) are a major component of the cancer stroma, and their response to therapeutic treatments likely impacts the outcome. We tested the hypothesis that CAFs develop unique characteristics that enhance their resistance to ionizing radiation. Methods CAFs were generated through intimate coculture of normal human fibroblasts of skin or lung origin with various human cancer cell types using permeable microporous membrane inserts. Fibroblasts and cancer cells are grown intimately, yet separately, on either side of the insert’s membrane for extended times to generate activated fibroblast populations highly enriched in CAFs. Results The generated CAFs exhibited a decrease in Caveolin-1 protein expression levels, a CAF biomarker, which was further enhanced when the coculture was maintained under in-vivo-like oxygen tension conditions. The level of p21Waf1 was also attenuated, a characteristic also associated with accelerated tumor growth. Furthermore, the generated CAFs experienced perturbations in their redox environment as demonstrated by increases in protein carbonylation, mitochondrial superoxide anion levels, and modulation of the activity of the antioxidants, manganese superoxide dismutase and catalase. Propagation of the isolated CAFs for 25 population doublings was associated with enhanced genomic instability and a decrease in expression of the senescence markers β-galactosidase and p16INK4a. With relevance to radiotherapeutic treatments, CAFs in coculture with cancer cells of diverse origins (breast, brain, lung, and prostate) were resistant to the clastogenic effects of 137Cs γ rays compared to naïve fibroblasts. Addition of repair inhibitors of single- or double-stranded DNA breaks attenuated the resistance of CAFs to the clastogenic effects of γ rays, supporting a role for increased ability to repair DNA damage in CAF radioresistance. Conclusions This study reveals that CAFs are radioresistant and experience significant changes in indices of oxidative metabolism. The CAFs that survive radiation treatment likely modulate the fate of the associated cancer cells. Identifying them together with their mode of communication with cancer cells, and eradicating them, particularly when they may exist at the margin of the radiotherapy planning target volume, may improve the efficacy of cancer treatments. Video Abstract

Introduction: Dosing recommendations for paliperidone long-acting injectable antipsychotic (LAIA) do not include oral antipsychotic (OAP) overlap; however, OAPs are often given concurrently despite limited evidence describing both the risks and benefits of this practice. Methods: A retrospective chart review was conducted in patients initiated on paliperidone palmitate (PP) during a psychiatric hospitalization to compare patients who received OAP overlap versus those who did not. The primary outcome is the proportion of patients who receive prescription claims for benztropine, a medication commonly prescribed for extrapyramidal symptoms, at the time of LAIA discontinuation and 6 months postdischarge. Secondary outcomes include prescription claims for beta blockers and diphenhydramine, number of psychiatric emergency visits and hospitalizations, length of stay of the index hospitalization, frequency of LAIA discontinuation and the time to LAIA discontinuation. Results: There is a significant difference in the proportion of benztropine prescription claims in the OAP overlap group versus the no-overlap group at the time of LAIA discontinuation (30% vs 0%, P =.046) but not at 6 months postdischarge. There are also significant differences in the number of psychiatric emergency visits (0.7 vs 0.1, P =.02) and psychiatric hospitalizations (0.6 vs 0.1, P =.029) at the time of LAIA discontinuation. No other differences are observed in defined secondary outcomes. Discussion: Patients who receive OAP overlap while receiving PP receive more benztropine and have more psychiatric emergency visits and hospitalizations than those treated without OAP. Larger studies with better control for confounding variables are needed to confirm these results.

Florida’s freshwater spring and river ecosystems have been deteriorating due to direct and indirect human impacts. However, while the conservation and restoration strategies employed to mitigate these effects often rely on faunal surveys that go back several decades, the local ecosystem shifts tend to have much deeper roots that predate those faunal surveys by centuries or millennia. Conservation paleobiology, an approach which enhances our understanding of the past states of ecosystems, allows for comparison of modern faunal communities with those prior to significant human impacts. This study examines the historical record of freshwater mollusk assemblages from two spring-fed river systems, the Wakulla and Silver/Ocklawaha Rivers. Specifically, we compared fossil assemblages (latest Pleistocene - early Holocene) and live mollusk assemblages in the two targeted river systems. Bulk sampling of the fossil record (20 sites; 70 samples; 16,314 specimens) documented relatively diverse mollusk assemblages that consist of a suite of native freshwater species that is similar across the studied systems. In contrast, sampling of live communities (24 sites; 138 samples; 7,572 specimens) revealed depauperate species assemblies characterized by the absence of multiple native freshwater species commonly found in fossil samples, the widespread presence of introduced species, and dominance of brackish-tolerant species at the lower Wakulla River sites. Unlike fossil mollusk assemblages, live mollusk assemblages differ notably between the two river systems due to differences in relative abundance of introduced species (Melanoides tuberculata and Corbicula fluminea) and the presence of brackish-tolerant mollusks in the coastally influenced Wakulla River. The diverse, exclusively freshwater mollusk associations comparable across multiple river systems documented in the fossil record provide a historical perspective on the past state of freshwater river ecosystems complementing data provided by modern surveys. The conservation paleobiology approach used in this study reinforces the importance of considering the historical ecology of an ecosystem and the utility of the fossil record in providing a historical perspective on long-term faunal changes.

Background: Paracetamol (acetaminophen) is one of the most accessible pharmaceutical analgesic and antipyretic agents. Similarly, traditional herbal medicines including Psoralea corylifolia, Astragalus propinquus and Atractylodes macrocephala have been used for centuries to treat cold and flu-like symptoms. As herbal medicines are ‘natural and safe’, likelihood of combination with over-the-counter pharmaceuticals is high. Paracetamol and herbal medicines are associated with many adverse effects, hepatotoxicity being a common complication. Purpose: To determine whether concomitant use of paracetamol with phytochemicals commonly found in herbal medicines, including psoralen, astragaloside IV (AST-IV) and atractylenolide I (ATR-I) may produce synergistic hepatotoxicity. Methods: Paracetamol (0–50 mM), psoralen (0–1000 µM) and AST-IV and ATR-I (0–300 µM) were tested on a human hepatocellular carcinoma cell line (HepG2) individually and in combination. Interactions were determined using fixed concentrations of 200 µM psoralen with paracetamol (0 – 50 mM), and 10 mM paracetamol with AST-IV or ATR-I (0 – 300 µM). Results: Paracetamol and psoralen demonstrated significant concentration-dependent toxicity individually (P 0.05). Fixed 200 µM psoralen in 20 mM – 50 mM paracetamol had approximately 20% increase in cell death compared to paracetamol with no psoralen; thus, paracetamol and psoralen demonstrated increased toxicity through synergistic interactions (P

Abstract Fungal phytopathogens secrete extracellular vesicles (EVs) associated with enzymes and phytotoxic metabolites. While these vesicles are thought to promote infection, defining the true contents and functions of fungal EVs, as well as suitable protein markers, is an ongoing process. To expand our understanding of fungal EVs and their possible roles during infection, we purified EVs from the hemibiotrophic phytopathogen Colletotrichum higginsianum, the causative agent of anthracnose disease in multiple plant species, including Arabidopsis thaliana. EVs were purified in large numbers from the supernatant of protoplasts but not the supernatant of intact mycelial cultures. We purified two separate populations of EVs, each associated with over 700 detected proteins, including proteins involved in vesicle transport, cell wall biogenesis and the synthesis of secondary metabolites. We selected two SNARE proteins (Snc1 and Sso2) and one 14‐3‐3 protein (Bmh1) as potential EV markers and generated transgenic strains expressing fluorescent fusions. Each marker was confirmed to be protected inside EVs. Fluorescence microscopy was used to examine the localization of each marker during infection on Arabidopsis leaves. These findings further our understanding of EVs in fungal phytopathogens and will help build an experimental system to study EV interkingdom communication between plants and fungi.

Despite the ubiquitous presence of tactile actuators (tactors) in mobile devices, there is a continuing need for more advanced tactors that can cover the entire frequency range of human tactile perception. Broadband tactors can increase information transmission and enrich sensory experience. The engineering challenges are multifold in that the ideal tactors should exhibit an effective bandwidth of at least 300 Hz, small form factor, robustness, power efficiency and low cost. For wearable applications, there are the additional challenges of ease of mounting and maintaining adequate skin contact during body movements. We propose an approach to interleave narrowband tactile stimuli to achieve broadband effects, taking advantage of the limited spatial resolution of the skin on the torso and limbs. Three psychophysical experiments were conducted to assess the validity of this approach. Participants performed pairwise discriminations of two broadband stimuli delivered using one or two tactors. The broadband stimuli consisted of one mid-frequency and one high-frequency component delivered through one tactor by mixing the two components, or through two tactors (one component per tactor). The first two experiments revealed extraneous cues such as localization and mutual masking of mid- and high-frequency components that were subsequently eliminated in the third experiment. Results from 12 participants confirmed that performance on pairwise comparisons was below the discrimination threshold, confirming that broadband haptic effects can be achieved through narrowband tactors placed within the skin’s two-point limen.

Bovine ischaemic teat necrosis (ITN) is an emerging disease of unknown aetiology that affects the teats of dairy cattle. It causes economic and animal welfare issues with many animals being culled. No effective treatments or epidemiological data to inform control strategies are currently available. The aim of this observational study was to investigate farmer-reported experiences and identify potential farm-level risk factors. In January 2018, a questionnaire was sent to a random sample of 1,855 Great Britain (GB) dairy farmers. A usable response rate of 12.3% was obtained. Fifty-one per cent [95% confidence interval (CI): 44.4–57.8%] of farmers reported having experienced ITN on their farm between 1985 and 2018. Rising numbers of farms indicated that ITN is an emerging disease with 46.3% of farmers reporting the first case in the 3 years up to 2018. At the animal level, 47.3% (95% CI: 38.7–55.9%) of the cases occurred during the first lactation and 78.9% (95% CI: 75.2–82.6%) within the first 90 days in milk. Only 20.8% (95% CI: 15.9–26.4%) of the cases were reported to recover, whereas 22.8% (95% CI: 17.8–28.5%) of the cases required culling. The remaining cases experienced complications such as loss of a teat and/or mastitis. From these data, the cost of ITN, through production losses and expenditure, was estimated to be £1,121 per farm per year. The costs were estimated at £720, £860 and £2,133 for recovered, complicated and culled cases, respectively. Univariable and multivariable logistic regression models were used to explore the associations between the presence of ITN on farm and various risk factors. The presence of udder cleft dermatitis (UCD) (odds ratio 2.80; 95% CI: 1.54–5.07; p < 0.01) and chapped teats (odds ratio 6.07; 95% CI: 1.96–18.76; p < 0.01) in the milking herd was associated with the presence of ITN at the farm level. This is the first national questionnaire of ITN within GB and highlights the association of UCD and chapped teats with ITN at the farm level. While there are many limitations and potential bias around farmer questionnaires, these findings highlight several key areas for further disease investigation and possible intervention.

Abstract Extensive research has shown that practice yields highly specific perceptual learning of simple visual properties such as orientation and contrast. Does this same learning characterize more complex perceptual skills? Here we investigated perceptual learning of complex medical images. Novices underwent training over four sessions to discriminate which of two chest radiographs contained a tumor and to indicate the location of the tumor. In training, one group received six repetitions of 30 normal/abnormal images, the other three repetitions of 60 normal/abnormal images. Groups were then tested on trained and novel images. To assess the nature of perceptual learning, test items were presented in three formats – the full image, the cutout of the tumor, or the background only. Performance improved across training sessions, and notably, the improvement transferred to the classification of novel images. Training with more repetitions on fewer images yielded comparable transfer to training with fewer repetitions on more images. Little transfer to novel images occurred when tested with just the cutout of the cancer region or just the background, but a larger cutout that included both the cancer region and some surrounding regions yielded good transfer. Perceptual learning contributes to the acquisition of expertise in cancer image perception.

The Australian Community Climate and Earth System Simulator (ACCESS) has been extended to include land and ocean carbon cycle components to form an Earth System Model (ESM). The current version, ACCESS-ESM1.5, has been mainly developed to enable Australia to participate in the Coupled Model Intercomparison Project Phase 6 (CMIP6) with an ESM version. Here we describe the model components and changes to the previous version, ACCESS-ESM1. We use the 500-year pre-industrial control run to highlight the stability of the physical climate and the carbon cycle. The long spin-up, negligible drift in temperature and small pre-industrial net carbon fluxes (0.02 and 0.08 PgC year−1 for land and ocean respectively) highlight the suitability of ACCESS-ESM1.5 to explore modes of variability in the climate system and coupling to the carbon cycle. The physical climate and carbon cycle for the present day have been evaluated using the CMIP6 historical simulation by comparing against observations and ACCESS-ESM1. Although there is generally little change in the climate simulation from the earlier model, many aspects of the carbon simulation are improved. An assessment of the climate response to CO2 forcing indicates that ACCESS-ESM1.5 has an equilibrium climate sensitivity of 3.87°C.

Blazars are a class of jet-dominated active galactic nuclei with a typical double-humped spectral energy distribution. It is of common consensus that the synchrotron emission is responsible for the low frequency peak, while the origin of the high frequency hump is still debated. The analysis of X-rays and their polarization can provide a valuable tool to understand the physical mechanisms responsible for the origin of high-energy emission of blazars. We report the first observations of BL Lacertae (BL Lac) performed with the Imaging X-ray Polarimetry Explorer, from which an upper limit to the polarization degree Π _X < 12.6% was found in the 2–8 keV band. We contemporaneously measured the polarization in radio, infrared, and optical wavelengths. Our multiwavelength polarization analysis disfavors a significant contribution of proton-synchrotron radiation to the X-ray emission at these epochs. Instead, it supports a leptonic origin for the X-ray emission in BL Lac.

Background Health and social care workers (HSCWs) are at risk of experiencing adverse mental health outcomes (e.g. higher levels of anxiety and depression) because of the COVID-19 pandemic. This can have a detrimental effect on quality of care, the national response to the pandemic and its aftermath. Aims A longitudinal design provided follow-up evidence on the mental health (changes in prevalence of disease over time) of NHS staff working at a remote health board in Scotland during the COVID-19 pandemic, and investigated the determinants of mental health outcomes over time. Method A two-wave longitudinal study was conducted from July to September 2020. Participants self-reported levels of depression (Patient Health Questionnaire-9), anxiety (Generalised Anxiety Disorder-7) and mental well-being (Warwick-Edinburgh Mental Well-being Scale) at baseline and 1.5 months later. Results The analytic sample of 169 participants, working in community (43%) and hospital (44%) settings, reported substantial levels of depression and anxiety, and low mental well-being at baseline (depression, 30.8%; anxiety, 20.1%; well-being, 31.9%). Although mental health remained mostly constant over time, the proportion of participants meeting the threshold for anxiety increased to 27.2% at follow-up. Multivariable modelling indicated that working with, and disruption because of, COVID-19 were associated with adverse mental health changes over time. Conclusions HSCWs working in a remote area with low COVID-19 prevalence reported substantial levels of anxiety and depression, similar to those working in areas with high COVID-19 prevalence. Efforts to support HSCW mental health must remain a priority, and should minimise the adverse effects of working with, and disruption caused by, the COVID-19 pandemic.

Abstract In July of 2016, abnormal ear development in corn (Zea mays L.) (barbell‐ears, multiple ears per node herein termed as multi‐ears, and short‐husks) was reported in several cornfields that extended from the Texas Panhandle to eastern Colorado and East through Kansas, Nebraska, Iowa, and Illinois. Field surveys were conducted to study these ear abnormalities. Affected and unaffected plants were sampled from 15 farmer fields located in central and eastern Nebraska. Each plant was evaluated for ear type, ear placement, internode length, and grain yield. Along with plant evaluations, management practices and weather information were collected from the surveyed fields. Of the 15 surveyed fields, nine were grouped as affected (more than 10% abnormalities), and six were grouped as checks (