The proinflammatory cytokines interleukin (IL)-1β and IL-18 are products of activation of the inflammasome, an innate sensing system, and important in the pathogenesis of herpes simplex virus type 1 ...(HSV-1). The release of IL-18 and IL-1β from monocytes/macrophages is critical for protection from HSV-1 based on animal models of encephalitis and genital infection, yet if and how HSV-1 activates inflammasomes in human macrophages is unknown. To investigate this, we utilized both primary human monocyte derived macrophages and human monocytic cell lines (THP-1 cells) with various inflammasome components knocked-out. We found that HSV-1 activates inflammasome signaling in proinflammatory primary human macrophages, but not in resting macrophages. Additionally, HSV-1 inflammasome activation in THP-1 cells is dependent on nucleotide-binding domain and leucine-rich repeat-containing receptor 3 (NLRP3), apoptosis-associated speck-like molecule containing a caspase recruitment domain (ASC), and caspase-1, but not on absent in melanoma 2 (AIM2), or gamma interferon-inducible protein 16 (IFI16). In contrast, HSV-1 activates non-canonical inflammasome signaling in proinflammatory macrophages that results in IL-1β, but not IL-18, release that is independent of NLRP3, ASC, and caspase-1. Ultraviolet irradiation of HSV-1 enhanced inflammasome activation, demonstrating that viral replication suppresses inflammasome activation. These results confirm that HSV-1 is capable of activating the inflammasome in human macrophages through an NLRP3 dependent process and that the virus has evolved an NLRP3 specific mechanism to inhibit inflammasome activation in macrophages.
Since thoracic endovascular aortic repair (TEVAR) received U.S. Food and Drug Administration approval for the treatment of descending thoracic aneurysms in March 2005, excellent 30-day and midterm ...outcomes have been described. However, data on long-term outcomes are lacking with Medicare data suggesting that TEVAR has worse late survival compared with open descending repair. As such, the purpose of this study was to examine the long-term outcomes for on-label use of TEVAR for repair of descending thoracic aneurysms.
Of 579 patients undergoing TEVAR between March 2005 and April 2016 at a single referral center for aortic surgery, 192 (33.2%) were performed for a descending thoracic aneurysm indication in accordance with the device instructions for use, including 106 fusiform (55.2%), 80 saccular (41.7%), and 6 with both saccular and fusiform (3.1%) aneurysms. All aneurysms were located distal to the left subclavian artery and proximal to the celiac axis, and hybrid procedures including arch or visceral debranching were excluded with the exception of left carotid-subclavian artery bypass. Aortic dissection and intramural hematoma as indications for TEVAR were also excluded. Primary 30-day and in-hospital outcomes included mortality, stroke, need for new permanent dialysis, and permanent paraparesis or paraplegia. Primary long-term outcomes included survival and rate of reintervention secondary to endoleak. The Kaplan-Meier method was used to estimate long-term overall and aorta-specific survivals.
The mean age was 71.1 ± 10.4 years. All aneurysms in this series were degenerative in nature and no patients with a connective tissue disorder were included. The mean aortic diameter was 5.9 ± 1.5 cm at time of intervention. Rates of 30-day and in-hospital mortality, stroke, permanent dialysis, and permanent paraparesis and paraplegia were 4.7%, 2.1%, 0.5%, and 0.5%, respectively. At a mean follow-up of 69 ± 44 months (range, 3-141 months), there were 68 late deaths (35.4%), two of which were due to aortic rupture. Overall and aorta-specific survivals at 141 months (11.8 years) were 45.7% and 96.2%, respectively. Endovascular reintervention was required in 14 patients (7.3%) owing to type I (n = 10), type II (n = 2), and type III (n = 2) endoleak, all of which subsequently resolved. No patient required open reintervention for any cause.
Long-term (12-year) aorta-specific survival after on-label endovascular repair of degenerative descending thoracic aneurysms in nonsyndromic patients is excellent (96%) with sustained protection from rupture, and a low rate of reintervention owing to endoleak (7%). Endovascular repair should be considered the treatment of choice for this pathology.
Dendritic cells play a key role in processing and presenting antigens to naïve T cells to prime adaptive immunity. Circadian rhythms are known to regulate many aspects of immunity; however, the role ...of circadian rhythms in dendritic cell function is still unclear. Here, we show greater T cell responses when mice are immunised in the middle of their rest versus their active phase. We find a circadian rhythm in antigen processing that correlates with rhythms in both mitochondrial morphology and metabolism, dependent on the molecular clock gene, Bmal1. Using Mdivi-1, a compound that promotes mitochondrial fusion, we are able to rescue the circadian deficit in antigen processing and mechanistically link mitochondrial morphology and antigen processing. Furthermore, we find that circadian changes in mitochondrial Ca
are central to the circadian regulation of antigen processing. Our results indicate that rhythmic changes in mitochondrial calcium, which are associated with changes in mitochondrial morphology, regulate antigen processing.
Mediterranean-type ecosystems constitute one of the rarest terrestrial biomes and yet they are extraordinarily biodiverse. Home to over 250 million people, the five regions where these ecosystems are ...found have climate and coastal conditions that make them highly desirable human habitats. The current conservation landscape does not reflect the mediterranean biome's rarity and its importance for plant endemism. Habitat conversion will clearly outpace expansion of formal protected-area networks, and conservationists must augment this traditional strategy with new approaches to sustain the mediterranean biota. Using regional scale datasets, we determine the area of land in each of the five regions that is protected, converted (e.g., to urban or industrial), impacted (e.g., intensive, cultivated agriculture), or lands that we consider to have conservation potential. The latter are natural and semi-natural lands that are unprotected (e.g., private range lands) but sustain numerous native species and associated habitats. Chile has the greatest proportion of its land (75%) in this category and California-Mexico the least (48%). To illustrate the potential for achieving mediterranean biodiversity conservation on these lands, we use species-area curves generated from ecoregion scale data on native plant species richness and vertebrate species richness. For example, if biodiversity could be sustained on even 25% of existing unprotected, natural and semi-natural lands, we estimate that the habitat of more than 6,000 species could be represented. This analysis suggests that if unprotected natural and semi-natural lands are managed in a manner that allows for persistence of native species, we can realize significant additional biodiversity gains. Lasting biodiversity protection at the scale needed requires unprecedented collaboration among stakeholders to promote conservation both inside and outside of traditional protected areas, including on lands where people live and work.
Abstract For many years, pharmaceutical therapies for osteoarthritis (OA) were focused on cartilage. However, it has been theorized that bone changes such as increased bone volume fraction and ...decreased bone matrix mineralization may play an important role in the initiation and pathogenesis of OA as well. The mechanisms behind the bone changes are subject of debate, and a better understanding may help in the development of bone-targeting OA therapies. In the literature, the increase in bone volume fraction has been hypothesized to result from mechanoregulated bone adaptation in response to decreased mineralization. Furthermore, both changes in bone volume fraction and mineralization have been reported to be highest close to the cartilage, and bone volume fraction has been reported to be correlated with cartilage degeneration. These data indicate that cartilage degeneration, bone volume fraction, and bone matrix mineralization may be related in OA. In the current study, we aimed to investigate the relationships between cartilage degeneration, bone matrix mineralization and bone volume fraction at a local level. With microCT, we determined bone matrix mineralization and bone volume fraction as a function of distance from the cartilage in osteochondral plugs from human OA tibia plateaus with varying degrees of cartilage degeneration. In addition, we evaluated whether mechanoregulated bone adaptation in response to decreased bone matrix mineralization may be responsible for the increase in bone volume fraction observed in OA. For this purpose, we used the experimentally obtained mineralization data as input for bone adaptation simulations. We simulated the effect of mechanoregulated bone adaptation in response to different degrees of mineralization, and compared the simulation results to the experimental data. We found that local changes in subchondral bone mineralization and bone volume fraction only occurred underneath severely degenerated cartilage, indicating that bone mineralization and volume fraction are related to cartilage degeneration at a local level. In addition, both the experimental data and the simulations indicated that a depth-dependent increase in bone volume fraction could be caused by decreased bone matrix mineralization. However, a quantitative comparison showed that decreased mineralization can only explain part of the subchondral sclerosis observed in OA.
Innate immune sensing of viral infection results in type I interferon (IFN) production and inflammasome activation. Type I IFNs, primarily IFN-α and IFN-β, are produced by all cell types upon virus ...infection and promote an antiviral state in surrounding cells by inducing the expression of IFN-stimulated genes. Type I IFN production is mediated by Toll-like receptor (TLR) 3 in HCV infected hepatocytes. Type I IFNs are also produced by plasmacytoid dendritic cells (pDC) after sensing of HIV and HCV through TLR7 in the absence of productive pDC infection. Inflammasomes are multi-protein cytosolic complexes that integrate several pathogen-triggered signaling cascades ultimately leading to caspase-1 activation and generation pro-inflammatory cytokines including interleukin (IL)-18 and IL-1β. Here, we demonstrate that HIV and HCV activate the inflammasome, but not Type I IFN production, in monocytes and macrophages in an infection-independent process that requires clathrin-mediated endocytosis and recognition of the virus by distinct endosomal TLRs. Knockdown of each endosomal TLR in primary monocytes by RNA interference reveals that inflammasome activation in these cells results from HIV sensing by TLR8 and HCV recognition by TLR7. Despite its critical role in type I IFN production by pDCs stimulated with HIV, TLR7 is not required for inflammasome activation by HIV. Similarly, HCV activation of the inflammasome in monocytes does not require TLR3 or its downstream signaling adaptor TICAM-1, while this pathway leads to type I IFN in infected hepatocytes. Monocytes and macrophages do not produce type I IFN upon TLR8 or TLR7 sensing of HIV or HCV, respectively. These findings reveal a novel infection-independent mechanism for chronic viral induction of key anti-viral programs and demonstrate distinct TLR utilization by different cell types for activation of the type I IFN vs. inflammasome pathways of inflammation.
Trapped in a Vice explores the consequences of a juvenile justice system that is aimed at promoting change in the lives of young people, yet ultimately relies upon tools and strategies that enmesh ...them in a system that they struggle to move beyond. The system, rather than the crimes themselves, is the vice. Trapped in a Vice explores the lives of the young people and adults in the criminal justice system, revealing the ways that they struggle to manage the expectations of that system; these stories from the ground level of the justice system demonstrate the complex exchange of policy and practice.  
Aims. Information on the existence and properties of diffuse interstellar bands (DIBs) outside the optical domain is still limited. Additional infra-red (IR) measurements and IR-optical correlative ...studies are needed to constrain DIB carriers and locate various absorbers in 3D maps of the interstellar matter. Methods. We extended our study of H-band DIBs in Apache Point Observatory Galactic Evolution Experiment (APOGEE) Telluric Standard Star (TSS) spectra. We used the strong lambda 15273 band to select the most and least absorbed targets. We used individual spectra of the former subsample to extract weaker DIBs, and we searched the two stacked series for differences that could indicate additional bands. High-resolution NARVAL and SOPHIE optical spectra for a subsample of 55 TSS targets were additionally recorded for NIR/optical correlative studies. Results. From the TSS spectra we extract a catalog of measurements of the poorly studied lambdalambda 15617, 15653, and 15673 DIBs in =300 sightlines, we obtain a first accurate determination of their rest wavelength and constrained their intrinsic width and shape. In addition, we studied the relationship between these weak bands and the strong lambda 15273 DIB. We provide a first or second confirmation of several other weak DIBs that have been proposed based on different instruments, and we add new constraints on their widths and locations. We finally propose two new DIB candidates. Conclusions. We compared the strength of the lambda 15273 absorptions with their optical counterparts lambdalambda 5780, 5797, 6196, 6283, and 6614. Using the 5797-5780 ratio as a tracer of shielding against the radiation field, we showed that the lambda 15273 DIB carrier is significantly more abundant in unshielded (sigma-type) clouds, and it responds even more strongly than the lambda 5780 band carrier to the local ionizing field.
Phylogenetic comparative methods represent a major advance in integrative and comparative biology and have allowed researchers to rigorously test for adaptation in a macroevolutionary framework. ...However, phylogenetic comparative methods require trait data for many species, which is impractical for certain taxonomic groups and trait types. We propose that the philosophical principle of severity can be implemented in an integrative framework to generate strong inference of adaptation in studies that compare only a few populations or species. This approach requires (1) ensuring that the study system contains species that are relatively closely related; (2) formulating a specific, clear, overarching hypothesis that can be subjected to integrative testing across levels of biological organization (e.g., ecology, behavior, morphology, physiology, and genetics); (3) collecting data that avoid statistical underdetermination and thus allow severe tests of hypotheses; and (4) systematically refining and refuting alternative hypotheses. Although difficult to collect for more than a few species, detailed, integrative data can be used to differentiate among several potential agents of selection. In this way, integrative studies of small numbers of closely related species can complement and even improve on broadscale phylogenetic comparative studies by revealing the specific drivers of adaptation.
•Bacterial blight and Fusarium wilt of cotton are recurrent diseases in U.S. cotton.•SWEET sugar transporters function as a susceptibility factor of bacterial blight.•Cell surface and intracellular ...immune receptors mediate host Fusarium wilt response.•Environment–pathogen–cotton interactions underpin strategies for disease control.
Bacterial blight of cotton, caused by Xanthomonas citri subsp. malvacearum, and Fusarium wilt of cotton, caused by Fusarium oxysporum f. sp. vasinfectum, contribute cotton losses worldwide. Resurgences of these diseases in the United States were reported in recent years. There is a pressing need to understand pathogenicity and host responses to the pathogens and develop effective strategies for disease prevention and management. Here, we discuss the current status of bacterial blight and Fusarium wilt of cotton in the field as well as the knowledge of cotton resistance and susceptibility to these pathogens. In addition, we aim to provide insights into how these diseases are recurring and possible methods to use current technologies for biological control of these pathogens.
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