Aging promotes pro-fibrotic matrix production and increases fibrocyte recruitment during acute lung injury.

Fibrotic lung diseases increase with age. Previously we determined that senescence increases tissue expression of fibronectin EDA (Fn-EDA) and decreases fibroblast expression of Thy-1, and that fibrocytes contribute to fibrosis following bleomycin-induced lung injury in mice. In this study we hypothesized that fibroblasts lacking Thy-1 expression produce an extracellular matrix that promotes fibrocyte retention and myofibroblast transdifferentiation, thereby promoting fibrogenesis. Young and old mice were treated with bleomycin intratracheally; fibrocytes in the bone marrow, blood, and lungs were quantified, and lung fibroblast Thy-1 expression assessed. Bone marrow-derived fibrocytes were cultured on matrices derived from Thy-1(+) or Thy-1(-) fibroblasts ± the pro-fibrotic cytokine TGFβ1. Older mice had more fibrocytes in their bone marrows at baseline and more fibrocytes in their lungs following bleomycin treatment. In parallel, lung fibroblasts in older mice had lower expression of Thy-1 at baseline that increased transiently 7 days after bleomycin treatment but then rapidly waned such that 14 days after bleomycin treatment Thy-1 expression was again markedly lower. Fibrocytes cultured on matrices derived from Thy-1(-) fibroblasts + TGFβ1 had increased gene expression for collagen type 1, fibronectin, Fn-EDA, and α-smooth muscle actin. In parallel, whereas the matrices derived from Thy-1(-) fibroblasts stimulated phosphorylation of Akt in cultured fibrocytes, the matrices derived from Thy-1(+) fibroblasts induced apoptosis. These findings suggest that senescence increases fibrocyte recruitment to the lung following injury and that loss of Thy-1 expression by lung fibroblasts promotes fibrocyte retention and myofibroblast trans-differentiation that renders the "aging lung" susceptible to fibrosis

Disentangling the effects of plant species invasion and urban development on arthropod community composition

Urban development and species invasion are two major global threats to biodiversity. These threats often co-occur, as developed areas are more prone to species invasion. However, few empirical studies have tested if both factors affect biodiversity in similar ways. Here we study the individual and combined effects of urban development and plant invasion on the composition of arthropod communities. We assessed 36 paired invaded and non-invaded sample plots, invaded by the plant Antigonon leptopus, with half of these pairs located in natural and the other half in developed land-use types on the Caribbean island of St. Eustatius. We used several taxonomic and functional variables to describe community composition and diversity. Our results show that both urban development and A. leptopus invasion affected community composition, albeit in different ways. Development significantly increased species richness and exponential Shannon diversity, while invasion had no effect on these variables. However, invasion significantly increased arthropod abundance and caused biotic homogenization. Specifically, uninvaded arthropod communities were distinctly different in species composition between developed and natural sites, while they became undistinguishable after A. leptopus invasion. Moreover, functional variables were significantly affected by species invasion, but not by urban development. Invaded communities had higher community-weighted mean body size and the feeding guild composition of invaded arthropod communities was characterized by the exceptional numbers of nectarivores, herbivores, and detritivores. With the exception of species richness and exponential Shannon diversity, invasion influenced four out of six response variables to a greater degree than urban development did. Hence, we can conclude that species invasion is not just a passenger of urban development but also a driver of change

A common yardstick to measure the effects of different extreme climatic events on soil arthropod community composition using time-series data

Extreme climatic events can have profound effects on ecosystems. Climate change is causing an increase in the frequency and intensity of extreme events, which raises the probability that natural ecosystems will be exposed to subsequent or simultaneous extreme events. Exposure to multiple extreme events may involve very different abiotic stressors, which makes it hard to compare their consequences for more than a single or a few species, limiting our knowledge of community level effects. Here, we propose a novel approach to assess how different abiotic stressors influenced soil arthropod communities in a coastal ecosystem, using a species abundance time series of more than 2 years. We first correlated shifts in community composition with the climatic conditions preceding the sampling dates. Temperature was found to be the most important factor influencing community composition in both locations. Based on local meteorological data, we then defined five types of extreme events which occurred during our monitoring period: heat, cold, drought, heavy precipitation, and high sea water levels. To compare the effect of different types of extreme climatic events on community composition, we calculated the multidimensional Hellinger distance between two subsequent sampling dates, which is a measure for the compositional dissimilarity between communities. Extreme events were expected to result in a larger change in community composition between sampling dates and thus a larger Hellinger distance. However, no significant difference in Hellinger distance was found for intervals with or without extreme events in three out of the four location-vegetation combinations. In the saline location with an open vegetation type we found that Hellinger's distance was reduced when extreme events had occurred, which is discussed in the light of the buffering potential of different vegetation types. Our study illustrates the novel use of an established method from the community ecological toolbox to facilitate direct comparison of different types of extreme climatic events on community composition. We highly encourage other ecologists with long-term monitoring datasets to perform similar analyses and test the general applicability of this method

Thrombolytic removal of intraventricular haemorrhage in treatment of severe stroke: results of the randomised, multicentre, multiregion, placebo-controlled CLEAR III trial

Background: Intraventricular haemorrhage is a subtype of intracerebral haemorrhage, with 50% mortality and serious disability for survivors. We aimed to test whether attempting to remove intraventricular haemorrhage with alteplase versus saline irrigation improved functional outcome. Methods: In this randomised, double-blinded, placebo-controlled, multiregional trial (CLEAR III), participants with a routinely placed extraventricular drain, in the intensive care unit with stable, non-traumatic intracerebral haemorrhage volume less than 30 mL, intraventricular haemorrhage obstructing the 3rd or 4th ventricles, and no underlying pathology were adaptively randomly assigned (1:1), via a web-based system to receive up to 12 doses, 8 h apart of 1 mg of alteplase or 0·9% saline via the extraventricular drain. The treating physician, clinical research staff, and participants were masked to treatment assignment. CT scans were obtained every 24 h throughout dosing. The primary efficacy outcome was good functional outcome, defined as a modified Rankin Scale score (mRS) of 3 or less at 180 days per central adjudication by blinded evaluators. This study is registered with ClinicalTrials.gov, NCT00784134. Findings: Between Sept 18, 2009, and Jan 13, 2015, 500 patients were randomised: 249 to the alteplase group and 251 to the saline group. 180-day follow-up data were available for analysis from 246 of 249 participants in the alteplase group and 245 of 251 participants in the placebo group. The primary efficacy outcome was similar in each group (good outcome in alteplase group 48% vs saline 45%; risk ratio [RR] 1·06 [95% CI 0·88–1·28; p=0·554]). A difference of 3·5% (RR 1·08 [95% CI 0·90–1·29], p=0·420) was found after adjustment for intraventricular haemorrhage size and thalamic intracerebral haemorrhage. At 180 days, the treatment group had lower case fatality (46 [18%] vs saline 73 [29%], hazard ratio 0·60 [95% CI 0·41–0·86], p=0·006), but a greater proportion with mRS 5 (42 [17%] vs 21 [9%]; RR 1·99 [95% CI 1·22–3·26], p=0·007). Ventriculitis (17 [7%] alteplase vs 31 [12%] saline; RR 0·55 [95% CI 0·31–0·97], p=0·048) and serious adverse events (114 [46%] alteplase vs 151 [60%] saline; RR 0·76 [95% CI 0·64–0·90], p=0·002) were less frequent with alteplase treatment. Symptomatic bleeding (six [2%] in the alteplase group vs five [2%] in the saline group; RR 1·21 [95% CI 0·37–3·91], p=0·771) was similar. Interpretation: In patients with intraventricular haemorrhage and a routine extraventricular drain, irrigation with alteplase did not substantially improve functional outcomes at the mRS 3 cutoff compared with irrigation with saline. Protocol-based use of alteplase with extraventricular drain seems safe. Future investigation is needed to determine whether a greater frequency of complete intraventricular haemorrhage removal via alteplase produces gains in functional status

Deep coverage whole genome sequences and plasma lipoprotein(a) in individuals of European and African ancestries.

Lipoprotein(a), Lp(a), is a modified low-density lipoprotein particle that contains apolipoprotein(a), encoded by LPA, and is a highly heritable, causal risk factor for cardiovascular diseases that varies in concentrations across ancestries. Here, we use deep-coverage whole genome sequencing in 8392 individuals of European and African ancestry to discover and interpret both single-nucleotide variants and copy number (CN) variation associated with Lp(a). We observe that genetic determinants between Europeans and Africans have several unique determinants. The common variant rs12740374 associated with Lp(a) cholesterol is an eQTL for SORT1 and independent of LDL cholesterol. Observed associations of aggregates of rare non-coding variants are largely explained by LPA structural variation, namely the LPA kringle IV 2 (KIV2)-CN. Finally, we find that LPA risk genotypes confer greater relative risk for incident atherosclerotic cardiovascular diseases compared to directly measured Lp(a), and are significantly associated with measures of subclinical atherosclerosis in African Americans

Publisher Correction: Deep coverage whole genome sequences and plasma lipoprotein(a) in individuals of European and African ancestries.

The original version of this article contained an error in the name of the author Ramachandran S. Vasan, which was incorrectly given as Vasan S. Ramachandran. This has now been corrected in both the PDF and HTML versions of the article

A novel approach to analyze lysosomal dysfunctions through subcellular proteomics and lipidomics : the case of NPC1 deficiency

Superparamagnetic iron oxide nanoparticles (SPIONs) have mainly been used as cellular carriers for genes and therapeutic products, while their use in subcellular organelle isolation remains underexploited. We engineered SPIONs targeting distinct subcellular compartments. Dimercaptosuccinic acid-coated SPIONs are internalized and accumulate in late endosomes/lysosomes, while aminolipid-SPIONs reside at the plasma membrane. These features allowed us to establish standardized magnetic isolation procedures for these membrane compartments with a yield and purity permitting proteomic and lipidomic profiling. We validated our approach by comparing the biomolecular compositions of lysosomes and plasma membranes isolated from wild-type and Niemann-Pick disease type C1 (NPC1) deficient cells. While the accumulation of cholesterol and glycosphingolipids is seen as a primary hallmark of NPC1 deficiency, our lipidomics analysis revealed the buildup of several species of glycerophospholipids and other storage lipids in selectively late endosomes/lysosomes of NPC1-KO cells. While the plasma membrane proteome remained largely invariable, we observed pronounced alterations in several proteins linked to autophagy and lysosomal catabolism reflecting vesicular transport obstruction and defective lysosomal turnover resulting from NPC1 deficiency. Thus the use of SPIONs provides a major advancement in fingerprinting subcellular compartments, with an increased potential to identify disease-related alterations in their biomolecular compositions

Ultraviolet Signatures of Tidal Interaction in the Giant Spiral Galaxy, M101

We present new evidence for tidal interactions having occurred in the disk of M101 in the last 10^8 - 10^9 years. Recent imaging of the far-ultraviolet emission from M101 by the Shuttle-borne Ultraviolet Imaging Telescope (UIT) reveals with unprecedented clarity a disk-wide pattern of multiple linear arm segments (``crooked arms''). The deep FUV image also shows a faint outer spiral arm with a (``curly tail'') feature that appears to loop around the supergiant HII region NGC 5471 - linking this outlying starburst with the rest of the galaxy. These FUV-bright features most likely trace hot O & B-type stars along with scattered light from associated nebular dust. Counterparts of the outermost ``crooked arms'' are evident in maps at visible wavelengths and in the 21-cm line of HI. The inner-disk FUV arms are most closely associated with H$\alpha$ knots and the outer (downstream) sides of CO arms. Comparisons of the ``crooked arm'' and ``curly tail'' morphologies with dynamical simulations yield the greatest similitude, when the non- axisymmetric forcing comes from a combination of ``external interactions'' with one or more companion galaxies and ``internal perturbations'' from massive objects orbiting within the disk. We speculate that NGC 5471 represents one of these ``massive disturbers'' within the disk, whose formation followed from a tidal interaction between M101 and a smaller galaxy.Comment: Paper format (latex); length of paper (8); 4 gif figure files; uses aas2pp4.sty AASTeX macro file; to be published in Part I of the Astrophysical Journa

An evolutionary divergent pestivirus lacking the Npro gene systemically infects a whale species

Pestiviruses typically infect members of the order Artiodactyla, including ruminants and pigs, although putative rat and bat pestiviruses have also been described. In the present study, we identified and characterized an evolutionary divergent pestivirus in the toothed whale species, harbour porpoise (Phocoena phocoena). We tentatively named the virus Phocoena pestivirus (PhoPeV). PhoPeV displays a typical pestivirus genome organization except for the unique absence of Npro, an N-terminal autoprotease that targets the innate host immune response. Evolutionary evidence indicates that PhoPeV emerged following an interspecies transmission event from an ancestral pestivirus that expressed Npro. We show that 9% (n = 10) of stranded porpoises from the Dutch North Sea coast (n = 112) were positive for PhoPeV and they displayed a systemic infection reminiscent of non-cytopathogenic persistent pestivirus infection. The identification of PhoPeV extends the host range of pestiviruses to cetaceans (dolphins, whales, porpoises), which are considered to have evolved from artiodactyls (even-toed ungulates). Elucidation of the pathophysiology of PhoPeV infection and Npro unique absence will add to our understanding of molecular mechanisms governing pestivirus pathogenesis

Expedition 391 Preliminary Report : Walvis Ridge Hotspot: drilling Walvis Ridge, Southeast Atlantic Ocean, to test models of ridge hotspot interaction, isotopic zonation, and the hotspot reference frame

Hotspot tracks (quasilinear chains of seamounts, ridges, and other volcanic structures) provide important records of plate motions, as well as mantle geodynamics, magma flux, and mantle source compositions. The Tristan-Gough-Walvis Ridge (TGW) hotspot track, extending from the active volcanic islands of Tristan da Cunha and Gough through a province of guyots and then along Walvis Ridge to the Etendeka flood basalt province, forms one of the most prominent and complex global hotspot tracks. The TGW hotspot track displays a tight linear age progression in which ages increase from the islands to the flood basalts (covering ~135 My). Unlike Pacific tracks, which are simple chains of seamounts that are often compared to chains of pearls, the TGW track is alternately a steep-sided narrow ridge, an oceanic plateau, subparallel linear ridges and chains of seamounts, and areas of what appear to be randomly dispersed seamounts. The track displays isotopic zonation over the last ~70 My. The zonation appears near the middle of the track just before it splits into two to three chains of ridge- and guyot-type seamounts. The older ridge is also overprinted with age-progressive late-stage volcanism, which was emplaced ~30–40 My after the initial eruptions and has a distinct isotopic composition. The plan for Expedition 391 was to drill at six sites, three along Walvis Ridge and three in the seamount (guyot) province, to gather igneous rocks to better understand the formation of track edifices, the temporal and geochemical evolution of the hotspot, and the variation in paleolatitudes at which the volcanic edifices formed. After a delay of 18 days to address a shipboard outbreak of the coronavirus disease 2019 (COVID-19) virus, Expedition 391 proceeded to drill at four of the proposed sites: three sites on the eastern Walvis Ridge around Valdivia Bank, an ocean plateau within the ridge, and one site on the lower flank of a guyot in the Center track, a ridge located between the Tristan subtrack (which extends from the end of Walvis Ridge to the island of Tristan da Cunha) and the Gough subtrack (which extends from Walvis Ridge to the island of Gough). One hole was drilled at Site U1575, located on a low portion of the northeastern Walvis Ridge north of Valdivia Bank. At this location, 209.9 m of sediments and 122.4 m of igneous basement were cored. The latter comprised 10 submarine lava units consisting of pillow, lobate, sheet, and massive lava flows, the thickest of which was ~21 m. Most lavas are tholeiitic, but some alkalic basalts were recovered. A portion of the igneous succession consists of low-Ti basalts, which are unusual because they appear in the Etendeka flood basalts but have not been previously found on Walvis Ridge. Two holes were drilled at Site U1576 on the west flank of Valdivia Bank. The first hole was terminated because a bit jammed shortly after penetrating igneous basement. Hole U1576A recovered a remarkable ~380 m thick sedimentary section consisting mostly of chalk covering a nearly complete sequence from Paleocene to Late Cretaceous (Campanian). These sediments display short and long cyclic color changes that imply astronomically forced and longer term paleoenvironmental changes. The igneous basement yielded 11 submarine lava units ranging from pillows to massive flows, which have compositions varying from tholeiitic basalt to basaltic andesite, the first occurrence of this composition recovered from the TGW track. These units are separated by seven sedimentary chalk units that range in thickness from 0.1 to 11.6 m, implying a long-term interplay of sedimentation and lava eruptions. Coring at Site U1577, on the extreme eastern flank of Valdivia Bank, penetrated a 154 m thick sedimentary section, the bottom ~108 m of which is Maastrichtian–Campanian (possibly Santonian) chalk with vitric tephra layers. Igneous basement coring progressed only 39.1 m below the sediment-basalt contact, recovering three massive submarine tholeiite basalt lava flows that are 4.1, 15.5, and >19.1 m thick, respectively. Paleomagnetic data from Sites U1577 and U1576 indicate that their volcanic basements formed just before the end of the Cretaceous Normal Superchron and during Chron 33r, shortly afterward, respectively. Biostratigraphic and paleomagnetic data suggest an east–west age progression across Valdivia Bank, becoming younger westward. Site U1578, located on a Center track guyot, provided a long and varied igneous section. After coring through 184.3 m of pelagic carbonate sediments mainly consisting of Eocene and Paleocene chalk, Hole U1578A cored 302.1 m of igneous basement. Basement lavas are largely pillows but are interspersed with sheet and massive flows. Lava compositions are mostly alkalic basalts with some hawaiite. Several intervals contain abundant olivine, and some of the pillow stacks consist of basalt with remarkably high Ti content. The igneous sequence is interrupted by 10 sedimentary interbeds consisting of chalk and volcaniclastics and ranging in thickness from 0.46 to 10.19 m. Paleomagnetic data display a change in basement magnetic polarity ~100 m above the base of the hole. Combining magnetic stratigraphy with biostratigraphic data, the igneous section is inferred to span >1 My. Abundant glass from pillow lava margins was recovered at Sites U1575, U1576, and U1578. Although the igneous penetration was only two-thirds of the planned amount, drilling during Expedition 391 obtained samples that clearly will lead to a deeper understanding of the evolution of the Tristan-Gough hotspot and its track. Relatively fresh basalts with good recovery will provide ample samples for geochemical, geochronologic, and paleomagnetic studies. Good recovery of Late Cretaceous and early Cenozoic chalk successions provides samples for paleoenvironmental study