Type I interferon (IFN) inhibits virus replication by activating multiple antiviral mechanisms and pathways. It has long been recognized that type I IFNs can potently block HIV-1 replication in ...vitro; as such, HIV-1 has been used as a system to identify and characterize IFN-induced antiviral proteins responsible for this block. IFN-induced HERC5 contains an amino-terminal Regulator of Chromosome Condensation 1 (RCC1)-like domain and a carboxyl-terminal Homologous to the E6-AP Carboxyl Terminus (HECT) domain. HERC5 is the main cellular E3 ligase that conjugates the IFN-induced protein ISG15 to proteins. This E3 ligase activity was previously shown to inhibit the replication of evolutionarily diverse viruses, including HIV-1. The contribution of the RCC1-like domain to the antiviral activity of HERC5 was previously unknown.
In this study, we showed that HERC5 inhibits HIV-1 particle production by a second distinct mechanism that targets the nuclear export of Rev/RRE-dependent RNA. Unexpectedly, the E3 ligase activity of HERC5 was not required for this inhibition. Instead, this activity required the amino-terminal RCC1-like domain of HERC5. Inhibition correlated with a reduction in intracellular RanGTP protein levels and/or the ability of RanGTP to interact with RanBP1. Inhibition also correlated with altered subcellular localization of HIV-1 Rev. In addition, we demonstrated that positive evolutionary selection is operating on HERC5. We identified a region in the RCC1-like domain that exhibits an exceptionally high probability of having evolved under positive selection and showed that this region is required for HERC5-mediated inhibition of nuclear export.
We have identified a second distinct mechanism by which HERC5 inhibits HIV-1 replication and demonstrate that HERC5 is evolving under strong positive selection. Together, our findings contribute to a growing body of evidence suggesting that HERC5 is a novel host restriction factor.
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Allotment food gardens represent important sources of food security for urban residents. Since urban gardeners rarely receive formal agricultural education and have extremely limited space, they may ...be relying on readily available gardening advice (e.g., seed packet instructions), inventing cultural strategies that consider inter-specific competitive dynamics, or making poor planting decisions. Knowledge of garden crop diversity and planting arrangements can aid in designing strategies for productive urban gardens and food systems. We surveyed 96 individual plots in 10 allotment gardens in the Toronto region, assessed crop diversity within gardens and recorded planting practices used by urban gardeners by measuring the proximity of individual plants relative to similar or different crop species. We also compared planting densities used by urban gardeners with those recommended by major seed distributers. Collectively, Toronto urban agriculture contributes substantially to urban plant diversity (108 crops), but each plot tends to be relatively depauperate. Carrots and lettuce were three to five times more likely to be planted in clusters than intermingled with other crops (P < 0.05); whereas gardeners did not appear to use consistent planting arrangements for tomatoes or zucchini. Gardeners tended to plant tomatoes and zucchini 56–62.5% more densely than recommended by seed distributers (P < 0.001), whereas they planted 147 times fewer carrots in a given area than recommended (P < 0.05). Furthermore, neither crop planting density nor crop diversity changed with plot size. The planting arrangements we have documented suggest gardeners using allotment plots attempt plant densely in extremely limited space, and are employing cultural strategies that intensify competitive dynamics within gardens. Future research should assess the absolute and relative effect of altered cultural practices on yield, such that any modifications can be prioritized by their impact on yield.
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The blood–brain barrier controls the passage of molecules from the blood into the central nervous system (CNS) and is a major challenge for treatment of neurological diseases. Metachromatic ...leukodystrophy is a neurodegenerative lysosomal storage disease caused by loss of arylsulfatase A (ARSA) activity. Gene therapy via intraventricular injection of a lentiviral vector is a potential approach to rapidly and permanently deliver therapeutic levels of ARSA to the CNS. We present the distribution of integration sites of a lentiviral vector encoding human ARSA (LV-ARSA) in murine brain choroid plexus and ependymal cells, administered via a single intracranial injection into the CNS. LV-ARSA did not exhibit a strong preference for integration in or near actively transcribed genes, but exhibited a strong preference for integration in or near satellite DNA. We identified several genomic hotspots for LV-ARSA integration and identified a consensus target site sequence characterized by two G-quadruplex-forming motifs flanking the integration site. In addition, our analysis identified several other non-B DNA motifs as new factors that potentially influence lentivirus integration, including human immunodeficiency virus type-1 in human cells. Together, our data demonstrate a clinically favorable integration site profile in the murine brain and identify non-B DNA as a potential new host factor that influences lentiviral integration in murine and human cells.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Adult Still disease is an inflammatory arthritis classically associated with daily spiking fevers, evanescent rash, organomegaly, lymphadenopathy, and laboratory anomalies. The typical cutaneous ...lesions are thin pink papules in a morbilliform distribution, of short duration. Histologically, these lesions are characterized by a superficial perivascular and interstitial mixed dermatitis with lymphocytes and variable neutrophils. A variant clinical presentation is increasingly recognized, which demonstrates persistent hyperpigmented plaques, often with a rippled or linear appearance. The histologic findings consist of upper epidermal dyskeratotic keratinocytes, increased dermal mucin, and a superficial perivascular infiltrate of lymphocytes and possibly neutrophils or eosinophils. We encountered 2 patients who presented with the characteristic rash of adult Still disease, both of whom progressed to develop the pigmented cutaneous plaques. We propose that this variant clinical and histologic appearance is the outcome of persistent disease activity.
Recent studies have proposed that MART-1 may falsely stain clusters of intraepidermal nonmelanocytic cells in lichenoid dermatitides. This may become an issue especially in isolated lesions of lichen ...planus-like keratosis (LPLK), a condition also known as benign lichenoid keratosis, and one that is often mistaken clinically for a malignant cutaneous neoplasm. LPLKs are known to exhibit basal epidermal pseudonests, mimicking a regressing melanocytic lesion histologically, and often may prompt the pathologist to obtain a MART-1 stain. If MART-1 is falsely positive, it may seal an incorrect diagnosis. To determine whether or not pseudonests in LPLK decorated with MART-1, we reviewed 70 cases from our institution, stained them with MART-1 (Thermo Fisher-Lab Vision, Ab3 clone, 1:400 dilution, heat-induced epitope retrieval with 0.02M citrate buffer at pH 6.0), and evaluated them for the presence or absence of staining within pseudonests. Four cases demonstrated an occasional MART-1-positive junctional nest. In these cases, microphthalmia transcription factor was also positive, confirming a true melanocytic origin. None of the other cases showed a MART-1 pattern that would have been suspicious for a melanocytic lesion. We propose that this discrepancy between our study and prior ones may be explained by differences in staining protocols or by a very low incidence of non-specific staining. Our study suggests that MART-1 is a useful marker in differentiating melanocytic nests from pseudonests in LPLK.
Branching structures are ubiquitous in biological systems with organs such as mammary glands, mammalian lungs, kidneys and endocrine glands displaying highly branched structures. Spatial ...characterization of branching structures is vital for understanding how they evolve and develop. We propose the use of multifractal analysis, a technique which quantifies the spatial distribution and pattern scaling of datasets for the analysis of the mouse mammary gland. The theory of multifractal analysis is introduced and various methods for estimating multifractal spectra are detailed and compared for performance and practicality. In particular, we identify potential drawbacks in the use of a traditional rectangular partitioning scheme for the analysis of objects which do not fit a rectangular geometry. We propose a novel multifractal algorithm that builds on existing approaches by extending one-dimensional partitioning schemes on a circular support to two dimensional partitioning schemes on an elliptical support. These algorithms are then used to quantify the effect of tensional force on pubertal branching development of the mammary glands in mice. We analyzed mice glands that were exposed to exogenous tensional force and compared them to controls. In addition to analyzing the whole branching structure of the glands, we also apply the analysis to two specific structures in mouse mammary glands. First, we analyze the location/node of branches and second, the locations of side branches, small hair-like structures that bud orthogonally from the main branching structure. Our analysis finds that the application of mechanical stress causes a decrease in the intra-group variance of the multifractal scaling of the branching nodes in the mammary gland and also increases the homogeneity in the spatial distribution of the side branching nodes. These findings identify the role of exogenous mechanical force in the regulation of organ formation. And highlights the need for further characterization of the impact of exogenous mechanical force on organ development and long-term function.
To determine the effect a novel formulation of fluocinonide cream on skin barrier function in subjects with atopic dermatitis.
The authors performed an open-label, investigator-blinded, side-by-side, ...controlled trial examining skin barrier function before and after a two-week course of a class I, super-potent topical steroid.
Outpatient university-based dermatology clinic in Portland, OR.
Twenty-five subjects aged 12 or older with a diagnosis of moderate, severe, or very severe AD were recruited for this study.
Fluocinonide 0.1% cream, a novel formulation of a class I super-potent topical steroid was applied to all affected areas, except a control site, once daily for two weeks or until clear. The control target site was treated with the vehicle once daily.
The study's primary outcome was change in skin barrier function as measured by basal transepidermal water loss (TEWL) in acute lesional skin from baseline as measured at two weeks.
TEWL readings significantly decreased (reflecting improved barrier function) in both the active and control target sites. The active target site decreased 14.35+/-16 mg/cm2 per hour; 95 percent confidence interval, P<0.001. The control target site decreased 8.75+/-11.80 mg/cm2 per hour in 25 subjects; 95 percent confidence interval, P<0.001. Skin electrical capacitance also improved significantly, reflecting improved stratum corneum hydration with therapy. Pruritus, clinical severity, and quality of life scores all showed significant improvement by the end of the study.
The authors have shown that short-term treatment with a novel formulation of 0.1% fluocinonide led to significantly improved barrier function as measured by basal TEWL in subjects with active moderate to severe AD. These data suggest short-term treatment with AD with a super-potent corticosteroid improves skin barrier function.
Abstract
Severe convective storms (SCS) and their associated hazards present significant societal risk. Understanding of how these hazards, such as hailfall, may change due to anthropogenic climate ...change is in its infancy. Previous methods used to investigate possible changes in SCS and their hail used climate model output and were limited by their coarse spatiotemporal resolution and less detailed representations of hail. This study instead uses an event-level pseudo–global warming (PGW) approach to simulate seven different hailstorms in their historical environments, and again in five different end-of-century PGW environments obtained from the worst-case scenario increases in CO
2
of five different CMIP5 members. Changes in large-scale environmental parameters were generally found to be consistent with prior studies, showing mostly increases in CAPE, CIN, and precipitable water, with minor changes in vertical wind shear. Nearly all simulated events had moderately stronger updrafts in the PGW environments. Only cold-season events showed an increase in hail sizes both within the storms and at the surface, whereas warm-season events exhibited a decrease in hail sizes at the surface and aloft. Changes in the event-total hailfall area at the ground also showed a seasonal trend, with increases in cold-season events and decreases in warm-season events. Melting depths increased for all PGW environments, and these increases likely contributed to greater rainfall area for warm-season events, where an increase in smaller hail aloft would be more prone to melting. The differences in PGW simulation hail sizes in cold-season and warm-season events found here are likely related to differences in microphysical processes and warrant future study.
Significance Statement
It is uncertain how severe thunderstorm hazards (such as hail, tornadoes, and damaging winds) may change due to human-induced climate change. Given the significant societal risk these hazards pose, this study seeks to better understand how hailstorms may change in the future. Simulated end-of-century storms in winter months showed larger hail sizes and a larger area of event-total hailfall than in the historical simulations, whereas simulated future storms in spring and summer months showed smaller hail sizes and a reduction in the area where hail fell. An analysis of traditional environmental and storm-scale properties did not reveal a clear distinction between cold-season and warm-season hailstorms, suggesting that changes in small-scale precipitation processes may be responsible.
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