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I. INTRODUCTION In the dramatic months of early 2020, the United States and many other countries abruptly shut down their economies in efforts to prevent widespread contagion and disease due [...], Tax policy can play important roles in limiting the spread of communicable disease and in managing the economic fallout of a pandemic. Taxes on business activities that bring workers or customers into close contact with each other offer efficient alternatives to broad regulatory measures, such as shutdowns, that have been effective but enormously costly. Corrective taxation also helps raise the revenue required to cover elevated government expenditure during a pandemic. Moreover, the restricted consumer choice that accompanies a pandemic reduces the welfare cost of raising tax revenue from higher-income taxpayers, making it a good time for deficit closure. Current U.S. tax measures serve some of these functions, but additional measures could further limit the spread of disease while also addressing government budget deficits. Keywords: taxation, externalities, COVID-19 JEL Codes: H21, H23, H24, H25, H62,118

Gene flow may influence the formation of species range limits, and yet little is known about the patterns of gene flow with respect to environmental gradients or proximity to range limits. With rapid environmental change, it is especially important to understand patterns of gene flow to inform conservation efforts. Here we investigate the species range of the selfing, annual plant, Mimulus laciniatus, in the California Sierra Nevada. We assessed genetic variation, gene flow, and population abundance across the entire elevation-based climate range. Contrary to expectations, within-population plant density increased towards both climate limits. Mean genetic diversity of edge populations was equivalent to central populations; however, all edge populations exhibited less genetic diversity than neighbouring interior populations. Genetic differentiation was fairly consistent and moderate among all populations, and no directional signals of contemporary gene flow were detected between central and peripheral elevations. Elevation-driven gene flow (isolation by environment), but not isolation by distance, was found across the species range. These findings were the same towards high- and low-elevation range limits and were inconsistent with two common centre-edge hypotheses invoked for the formation of species range limits: (i) decreasing habitat quality and population size; (ii) swamping gene flow from large, central populations. This pattern demonstrates that climate, but not centre-edge dynamics, is an important range-wide factor structuring M. laciniatus populations. To our knowledge, this is the first empirical study to relate environmental patterns of gene flow to range limits hypotheses. Similar investigations across a wide variety of taxa and life histories are needed.

BackgroundAs modern humans, we spend the majority of our time in indoor environments. Consequently, environmental exposure to microorganisms has important implications for human health, and a better understanding of the ecological drivers and processes that impact indoor microbial assemblages will be key for expanding our knowledge of the built environment. In the present investigation, we combined recent studies examining the microbiota of the built environment in order to identify unifying community patterns and the relative importance of indoor environmental factors. Ultimately, the present meta-analysis focused on studies of bacteria and archaea due to the limited number of high-throughput fungal studies from the indoor environment. We combined 16S ribosomal RNA (rRNA) gene datasets from 16 surveys of indoor environments conducted worldwide, additionally including 7 other studies representing putative environmental sources of microbial taxa (outdoor air, soil, and the human body).ResultsCombined analysis of subsets of studies that shared specific experimental protocols or indoor habitats revealed community patterns indicative of consistent source environments and environmental filtering. Additionally, we were able to identify several consistent sources for indoor microorganisms, particularly outdoor air and skin, mirroring what has been shown in individual studies. Technical variation across studies had a strong effect on comparisons of microbial community assemblages, with differences in experimental protocols limiting our ability to extensively explore the importance of, for example, sampling locality, building function and use, or environmental substrate in structuring indoor microbial communities.ConclusionsWe present a snapshot of an important scientific field in its early stages, where studies have tended to focus on heavy sampling in a few geographic areas. From the practical perspective, this endeavor reinforces the importance of negative "kit" controls in microbiome studies. From the perspective of understanding mechanistic processes in the built environment, this meta-analysis confirms that broad factors, such as geography and building type, structure indoor microbes. However, this exercise suggests that individual studies with common sampling techniques may be more appropriate to explore the relative importance of subtle indoor environmental factors on the indoor microbiome.

Traumatic brain injury (TBI) is a serious and poorly understood medical condition. Here, the authors show that TBI induces long-lasting deficits in brain lymphatic drainage. They report that defects in this drainage pathway provoke severe TBI pathogenesis that can be rescued with VEGF-C treatment.

Abstract Microfluidic channels moulded from the soft polymer poly(dimethylsiloxane) (PDMS) are widely used as a platform for mimicking biological environments, and can be used for the simulation of fluid filled structures such as blood and lung vessels. The control of pressure and flow rate within these structures is vital to mimic physiological conditions. The flexibility of PDMS leads to pressure-induced deformation under flow, leading to variable flow profiles along a device. Here, we investigate the change in Young’s modulus of microfluidic channels due to infiltration of mineral oil, a PDMS permeable fluid, and how this affects the resulting pressure profile using a novel pressure measurement method. We found a 53% decrease in Young’s modulus of PDMS due to mineral oil absorption over the course of 3 h accounted for lower internal pressure and larger channel deformation compared to fresh PDMS at a given flow rate. Confocal fluorescence microscopy used to image channel profiles before and after the introduction of mineral oil showed a change in pressure-induced deformation after infiltration of the oil. Atomic force microscopy (AFM) nanoindentation was used to measure Young’s modulus of PDMS before ( $$2.80 \pm 0.03$$ 2.80 ± 0.03 MPa) and after ( $$1.32 \pm 0.04$$ 1.32 ± 0.04 MPa) mineral oil absorption. Raman spectroscopy showed the infiltration of mineral oil into PDMS from channel walls and revealed the diffusion coefficient of mineral oil in PDMS.

Abstract Background Syringomyelia (SM) is a debilitating condition in the cavalier King Charles spaniel (CKCS) that results in neuropathic pain and diminished quality of life. Von Frey aesthesiometry (VFA) is a method of mechanical quantitative sensory testing that provides an objective sensory threshold (ST) value and can be used to quantify neuropathic pain (NP) and monitor response to therapy. The utility of VFA has been previously established in client-owned dogs with acute spinal cord injury but the technique has not been evaluated in dogs with SM. The goal of this study was to evaluate ST, as determined by VFA, in dogs with and without SM, to assess the utility of VFA in quantifying NP in SM-affected dogs. We hypothesized the SM-affected CKCS would have lower ST values, consistent with hyperesthesia, when compared to control CKCS. Additionally, we hypothesized that ST values in SM-affected dogs would be inversely correlated with syrinx size on MRI and with owner-derived clinical sign scores. Results ST values for the thoracic and pelvic limbs differed significantly between the SM-affected and control CKCS (p = 0.027; p = 0.0396 respectively). Median ST value (range) for the thoracic limbs was 184.1 g (120.9–552) for control dogs, and 139.9 g (52.6–250.9) for SM-affected dogs. The median ST value (range) for the pelvic limbs was 164.9 g (100.8–260.3) in control dogs and 129.8 g (57.95–168.4) in SM-affected dogs. The ST values in SM-affected dogs did not correlate with syrinx height on MRI (r = 0.314; p = 0.137). Owner-reported clinical sign scores showed an inverse correlation with pelvic limb ST values, where dogs with lower ST values (hyperesthesia) were reported by their owners to display more frequent and severe clinical signs (r = − 0.657; p = 0.022). Conclusion ST values were lower in SM-affected CKCS compared to control dogs, suggesting the presence of neuropathic pain. Dogs with lower ST pelvic limb values were perceived by their owners to have more severe clinical signs classically associated with SM. Our results suggest that VFA might offer quantitative assessment of neuropathic pain in SM-affected dogs and could be useful for monitoring response to therapy in future clinical studies.

Impulsivity and emotional dysregulation are two core features of borderline personality disorder (BPD), and the neural mechanisms recruited during mixed-strategy interactions overlap with frontolimbic networks that have been implicated in BPD. We investigated strategic choice patterns during the classic two-player game, Matching Pennies, where the most efficient strategy is to choose each option randomly from trial-to-trial to avoid exploitation by one’s opponent. Twenty-seven female adolescents with BPD (mean age: 16 years) and twenty-seven age-matched female controls (mean age: 16 years) participated in an experiment that explored the relationship between strategic choice behavior and impulsivity in both groups and emotional dysregulation in BPD. Relative to controls, BPD participants showed marginally fewer reinforcement learning biases, particularly decreased lose-shift biases, increased variability in reaction times (coefficient of variation; CV), and a greater percentage of anticipatory decisions. A subset of BPD participants with high levels of impulsivity showed higher overall reward rates, and greater modulation of reaction times by outcome, particularly following loss trials, relative to control and BPD participants with lower levels of impulsivity. Additionally, BPD participants with higher levels of emotional dysregulation showed marginally increased reward rate and increased entropy in choice patterns. Together, our preliminary results suggest that impulsivity and emotional dysregulation may contribute to variability in mixed-strategy decision-making in female adolescents with BPD.

Conserved IncI1 and IncHI1 plasmids carrying blaCTX-M-1 have been found circulating in chickens and horses from continental Europe, respectively. In Canada, blaCTX-M-1 is overwhelmingly the most common blaCTX-M variant found in Escherichia coli from chicken and horses and can be recovered at lower frequencies in swine, cattle, and dogs. Whole-genome sequencing has identified a large genetic diversity of isolates carrying this variant, warranting further investigations into the plasmids carrying this gene. Therefore, the objective of this study was to describe the genetic profiles of blaCTX-M-1 plasmids circulating in E. coli from Canadian domestic animals and compare them to those recovered in animals in Europe. Fifty-one blaCTX-M-1 positive E. coli isolates from chicken (n = 14), horses (racetrack horses n = 11; community horses n = 3), swine (n = 7), turkey (n = 6), dogs (n = 5), beef cattle (n = 3), and dairy cattle (n = 2) were selected for plasmid characterization. Sequences were obtained through both Illumina and Oxford Nanopore technologies. Genomes were assembled using either Unicycler hybrid assembly or Flye with polishing performed using Pilon. blaCTX-M-1 was found residing on a plasmid in 45 isolates and chromosomally located in six isolates. A conserved IncI1/ST3 plasmid was identified among chicken (n = 12), turkey (n = 4), swine (n = 6), dog (n = 2), and beef cattle (n = 2) isolates. When compared against publicly available data, these plasmids showed a high degree of similarity to those identified in isolates from poultry and swine in Europe. These results suggest that an epidemic IncI1/ST3 plasmid similar to the one found in Europe is contributing to the spread of blaCTX-M-1 in Canada. A conserved IncHI1/FIA(HI1)/ST2 plasmid was also recovered from nearly all racetrack horse isolates (n = 10). Although IncHI1/ST2 plasmids have been reported among European horse isolates, IncHI1/ST9 plasmids appear to be more widespread. Further studies are necessary to understand the factors contributing to these plasmids’ success in their respective populations.

Newcastle Disease (ND), caused by virulent forms of Avian orthoavulavirus serotype-1 (AOAV-1) is an economically important avian disease worldwide. The past two incursions of ND into the United Kingdom occurred in game bird populations during 2005 and 2006. The nature of the game bird semi-feral rearing system, which can bring these birds into close contact with both wild birds and commercial or backyard poultry, has been hypothesized to act as a bridge between these two environments. As such, the risk that AOAV-1-infected game birds may pose to the UK poultry industry was investigated. Pheasants, partridges and chickens were experimentally infected with the virulent strain APMV-1/Chicken/Bulgaria/112/13, a genotype VII.2 virus associated with ND outbreaks in Eastern Europe. The study demonstrated that both chickens and pheasants are susceptible to infection with APMV-1/Chicken/Bulgaria/112/13, which results in high mortality and onward transmission. Partridges by contrast are susceptible to infection, but mortality was reduced, as was onward transmission. However, the data indicated that both pheasants and partridges may serve as intermediate hosts of AOAV-1 and may bridge the wild bird–domestic poultry interface enabling transmission into an economically damaging environment where morbidity and mortality may be high.

Mutations in the human LMNA gene cause a collection of diseases called laminopathies, which includes muscular dystrophy and dilated cardiomyopathy. The LMNA gene encodes lamins, filamentous proteins that form a meshwork on the inner side of the nuclear envelope. How mutant lamins cause muscle disease is not well understood, and treatment options are currently limited. To understand the pathological functions of mutant lamins so that therapies can be developed, we generated new Drosophila models and human iPS cell-derived cardiomyocytes. In the Drosophila models, muscle-specific expression of the mutant lamins caused nuclear envelope defects, cytoplasmic protein aggregation, activation of the Nrf2/Keap1 redox pathway, and reductive stress. These defects reduced larval motility and caused death at the pupal stage. Patient-derived cardiomyocytes expressing mutant lamins showed nuclear envelope deformations. The Drosophila models allowed for genetic and pharmacological manipulations at the organismal level. Genetic interventions to increase autophagy, decrease Nrf2/Keap1 signaling, or lower reducing equivalents partially suppressed the lethality caused by mutant lamins. Moreover, treatment of flies with pamoic acid, a compound that inhibits the NADPH-producing malic enzyme, partially suppressed lethality. Taken together, these studies have identified multiple new factors as potential therapeutic targets for LMNA-associated muscular dystrophy.

Rabies is a neglected tropical disease. The prototype virus, the rabies virus, still causes tens of thousands of human fatalities annually. Rabies is one member of the genus Lyssavirus. The burden of other lyssaviruses is unclear. The continued emergence of novel lyssaviruses means that assessment of vaccine efficacy against these viruses is critical, as standard rabies vaccines are not efficacious against all lyssaviruses. Taiwan bat lyssavirus (TWBLV) was first reported in 2018 following isolation from Japanese house bats. Since the initial detection and genetic characterisation, no attempts have been made to antigenically define this virus. Due to the inaccessibility of the wildtype isolate, the successful generation of a live recombinant virus, cSN-TWBLV, is described, where the full-length genome clone of the RABV vaccine strain, SAD-B19, was constructed with the glycoprotein of TWBLV. In vitro and in vivo characterization of cSN-TWBLV was undertaken and demonstrated evidence for cross-neutralisation of cSN-TWBLV with phylogroup I -specific sera and rabies virus standard sera. For neutralisation equivalent to 0.5 IU/mL of WHO and World Organisation of Animal Health (WOAH) sera against CVS, 0.5 IU/mL of WOAH sera and 2.5 IU/mL of WHO sera were required to neutralise cSN-TWBLV. In addition, specific sera for ARAV and EBLV-1 exhibited the highest neutralising antibody titres against cSN-TWBLV, compared to other phylogroup I-specific sera.

Commercial elderberry production requires complete pruning in late fall to maintain productive canes. For integrated farms (livestock and crops), this biomass has potential as ensiled fodder for ruminant livestock. The objectives of this study were to determine the forage nutritive value of late-season (November) pruned elderberry (Sambucus canadensis L. “Rogersville”) fodder when ensiled. A 2 × 2 factorial laboratory silo experiment was conducted testing two packing densities with or without inoculation with lactic acid-producing bacteria silage inoculant to determine effects on silage nutritive values and fermentation parameters. Pre-ensiled elderberry fodder, composited from plants over 2000 m2, averaged 5.6% crude protein, 62.5% acid detergent fiber (ADF), 72.5% neutral detergent fiber, 11.4% non-fiber carbohydrates, 53% total digestive nutrients, and 52% relative feed value (RFV). The two packing densities were 160.2 kg dry matter/m3 and 240.3 kg dry matter/m3. Packing density did not affect any nutrient characteristics of the ensiled fodder. Acid detergent fiber was greater (p = 0.01) in un-inoculated silage, resulting in lower (p < 0.01) RFV for un-inoculated silage. Only lactic acid concentration was affected by packing density with greater concentrations (p = 0.04) in high-density silos. Inoculant affected several fermentation parameters with greater concentrations of (p < 0.01) propanediol, (p = 0.01) propanol, and (p < 0.01) acetic acid, while un-inoculated silages had greater concentrations of (p = 0.03) ammonia-nitrogen, (p < 0.01) lactic acid, (p = 0.02) succinic acid, and (p < 0.01) ethanol. Overall, late-season elderberry fodder was successfully ensiled, but nutritive value was low. Packing density did not affect nutritive value but did increase lactic acid concentration. Inoculation improved the RFV by reducing ADF, and though acetic acid production was greater in inoculated silage, total acid concentration was not affected.

TWIK-related acid-sensitive potassium (TASK) channels--members of the two pore domain potassium (K.sub.2P) channel family--are found in neurons.sup.1, cardiomyocytes.sup.2-4 and vascular smooth muscle cells.sup.5, where they are involved in the regulation of heart rate.sup.6, pulmonary artery tone.sup.5,7, sleep/wake cycles.sup.8 and responses to volatile anaesthetics.sup.8-11. K.sub.2P channels regulate the resting membrane potential, providing background K.sup.+ currents controlled by numerous physiological stimuli.sup.12-15. Unlike other K.sub.2P channels, TASK channels are able to bind inhibitors with high affinity, exceptional selectivity and very slow compound washout rates. As such, these channels are attractive drug targets, and TASK-1 inhibitors are currently in clinical trials for obstructive sleep apnoea and atrial fibrillation.sup.16. In general, potassium channels have an intramembrane vestibule with a selectivity filter situated above and a gate with four parallel helices located below; however, the K.sub.2P channels studied so far all lack a lower gate. Here we present the X-ray crystal structure of TASK-1, and show that it contains a lower gate--which we designate as an 'X-gate'--created by interaction of the two crossed C-terminal M4 transmembrane helices at the vestibule entrance. This structure is formed by six residues (.sup.243VLRFMT.sup.248) that are essential for responses to volatile anaesthetics.sup.10, neurotransmitters.sup.13 and G-protein-coupled receptors.sup.13. Mutations within the X-gate and the surrounding regions markedly affect both the channel-open probability and the activation of the channel by anaesthetics. Structures of TASK-1 bound to two high-affinity inhibitors show that both compounds bind below the selectivity filter and are trapped in the vestibule by the X-gate, which explains their exceptionally low washout rates. The presence of the X-gate in TASK channels explains many aspects of their physiological and pharmacological behaviour, which will be beneficial for the future development and optimization of TASK modulators for the treatment of heart, lung and sleep disorders. The X-ray crystal structure of the potassium channel TASK-1 reveals the presence of an X-gate, which traps small-molecule inhibitors in the intramembrane vestibule and explains their low washout rates from the channel., Author(s): Karin E. J. Rödström [sup.1] , Aytug K. Kiper [sup.2] , Wei Zhang [sup.1] [sup.5] , Susanne Rinné [sup.2] , Ashley C. W. Pike [sup.1] , Matthias Goldstein [sup.2] [...]

Neurodevelopment is characterized by rapid rates of neural cell proliferation and differentiation followed by massive cell death in which more than half of all recently generated brain cells are pruned back. Large amounts of DNA damage, cellular debris, and by-products of cellular stress are generated during these neurodevelopmental events, all of which can potentially activate immune signalling. How the immune response to this collateral damage influences brain maturation and function remains unknown. Here we show that the AIM2 inflammasome contributes to normal brain development and that disruption of this immune sensor of genotoxic stress leads to behavioural abnormalities. During infection, activation of the AIM2 inflammasome in response to double-stranded DNA damage triggers the production of cytokines as well as a gasdermin-D-mediated form of cell death known as pyroptosis.sup.1-4. We observe pronounced AIM2 inflammasome activation in neurodevelopment and find that defects in this sensor of DNA damage result in anxiety-related behaviours in mice. Furthermore, we show that the AIM2 inflammasome contributes to central nervous system (CNS) homeostasis specifically through its regulation of gasdermin-D, and not via its involvement in the production of the cytokines IL-1 and/or IL-18. Consistent with a role for this sensor of genomic stress in the purging of genetically compromised CNS cells, we find that defective AIM2 inflammasome signalling results in decreased neural cell death both in response to DNA damage-inducing agents and during neurodevelopment. Moreover, mutations in AIM2 lead to excessive accumulation of DNA damage in neurons as well as an increase in the number of neurons that incorporate into the adult brain. Our findings identify the inflammasome as a crucial player in establishing a properly formed CNS through its role in the removal of genetically compromised cells. The sensing of DNA damage by the AIM2 inflammasome promotes the death of central nervous system cells and is required for normal brain development., Author(s): Catherine R. Lammert [sup.1] [sup.2] , Elizabeth L. Frost [sup.1] , Calli E. Bellinger [sup.1] , Ashley C. Bolte [sup.1] [sup.3] [sup.4] , Celia A. McKee [sup.1] , Mariah [...]

Protein based polymers provide an exciting and complex landscape for tunable natural biomaterials through modulation of molecular level interactions. Here we demonstrate the ability to modify protein polymer structural and mechanical properties at multiple length scales by molecular 'interference' of fibrin's native polymerization mechanism. We have previously reported that engagement of fibrin's polymerization 'hole b', also known as 'b-pockets', through PEGylated complementary 'knob B' mimics can increase fibrin network porosity but also, somewhat paradoxically, increase network stiffness. Here, we explore the possible mechanistic underpinning of this phenomenon through characterization of the effects of knob B-fibrin interaction at multiple length scales from molecular to bulk polymer. Despite its weak monovalent binding affinity for fibrin, addition of both knob B and PEGylated knob B at concentrations near the binding coefficient, Kd, increased fibrin network porosity, consistent with the reported role of knob B-hole b interactions in promoting lateral growth of fibrin fibers. Addition of PEGylated knob B decreases the extensibility of single fibrin fibers at concentrations near its Kd but increases extensibility of fibers at concentrations above its Kd. The data suggest this bimodal behavior is due to the individual contributions knob B, which decreases fiber extensibility, and PEG, which increase fiber extensibility. Taken together with laser trap-based microrheological and bulk rheological analyses of fibrin polymers, our data strongly suggests that hole b engagement increases in single fiber stiffness that translates to higher storage moduli of fibrin polymers despite their increased porosity. These data point to possible strategies for tuning fibrin polymer mechanical properties through modulation of single fiber mechanics.

Following photoreceptors ablation by intense light exposure, adult zebrafish are capable of complete regeneration due to the ability of their Müller glia (MG) to re-enter the cell cycle, creating progenitors that differentiate into new photoreceptors. The majority of previous reports on retinal regeneration focused on the first few days of the regenerative response, which include MG cell-cycle re-entry and progenitor cell proliferation. With this study, we analyzed the full 28-day time-course of regeneration by pairing a detailed morphological/immunological analysis with RNA-seq transcriptional profiling at 8 key time points during retinal regeneration. We observed several novel findings. First, we provide evidence for two separate peaks of MG gliosis, with the secondary gliotic peak occurring after MG cell-cycle re-entry. Second, we highlight a distinct transcriptional shift between 5- and 10-days post lesion that highlights the transition from progenitor proliferation to differentiation into new photoreceptors. Third, we show distinctly different patterns of transcriptional recovery of the photoreceptor opsins at 28 days post lesion. Finally, using differential gene expression analysis, we revealed that the established functional recovery of the retina at 28 days post lesion does not, in fact, return to an undamaged transcriptional state, potentially redefining what the field considers complete regeneration. Together, to our knowledge, this work represents the first histological and transcriptomic map of a 28-day time-course of retinal regeneration in adult zebrafish.

Repetitive sensory motor behaviors are a direct target for clinical treatment and a potential treatment endpoint for individuals with intellectual or developmental disabilities. By removing the burden associated with video annotation or direct observation, automated detection of stereotypy would allow for longer term monitoring in ecologic settings. We report automated detection of common stereotypical motor movements using commercially available accelerometers affixed to the body and a generalizable detection algorithm. The method achieved a sensitivity of 80% for body rocking and 93% for hand flapping without individualized algorithm training or foreknowledge of subject's specific movements. This approach is well-suited for implementation in a continuous monitoring system outside of a clinical setting.

Our aim was to test the hypothesized relationships between trauma exposure and alcohol-related problems, mediated by PTS symptoms, moderated by prior trauma exposure and help-seeking. Participants were 244 members of a private university who were enrolled or employed at the school on the date of a campus shooting. Online measures were distributed via e-mail in October 2014, and included the AUDIT, BTQ, PCL-5, and self-report measures of trauma exposure and counseling services utilized. The overall moderated mediation model examining the indirect effect of exposure to trauma on alcohol-related problems through PTSD symptoms, moderated by prior trauma and help seeking was significant, ß(SE) = 0.310(0.3554), p = 0.0001. This study highlights the importance of crisis interventions following trauma exposure.