In Vivo T Cell Costimulation Blockade with Abatacept for Acute Graft-versus-Host Disease Prevention: A First-in-Disease Trial

AbstractWe performed a first-in-disease trial of in vivo CD28:CD80/86 costimulation blockade with abatacept for acute graft-versus-host disease (aGVHD) prevention during unrelated-donor hematopoietic cell transplantation (HCT). All patients received cyclosporine/methotrexate plus 4 doses of abatacept (10 mg/kg/dose) on days −1, +5, +14, +28 post-HCT. The feasibility of adding abatacept, its pharmacokinetics, pharmacodynamics, and its impact on aGVHD, infection, relapse, and transplantation-related mortality (TRM) were assessed. All patients received the planned abatacept doses, and no infusion reactions were noted. Compared with a cohort of patients not receiving abatacept (the StdRx cohort), patients enrolled in the study (the ABA cohort) demonstrated significant inhibition of early CD4+ T cell proliferation and activation, affecting predominantly the effector memory (Tem) subpopulation, with 7- and 10-fold fewer proliferating and activated CD4+ Tem cells, respectively, at day+28 in the ABA cohort compared with the StdRx cohort (P < .01). The ABA patients demonstrated a low rate of aGVHD, despite robust immune reconstitution, with 2 of 10 patients diagnosed with grade II-IV aGVHD before day +100, no deaths from infection, no day +100 TRM, and with 7 of 10 evaluable patients surviving (median follow-up, 16 months). These results suggest that costimulation blockade with abatacept can significantly affect CD4+ T cell proliferation and activation post-transplantation, and may be an important adjunct to standard immunoprophylaxis for aGVHD in patients undergoing unrelated-donor HCT

Using geographically weighted regression to explore the spatially heterogeneous spread of bovine tuberculosis in England and Wales

An understanding of the factors that affect the spread of endemic bovine tuberculosis (bTB) is critical for the development of measures to stop and reverse this spread. Analyses of spatial data need to account for the inherent spatial heterogeneity within the data, or else spatial autocorrelation can lead to an overestimate of the significance of variables. This study used three methods of analysis—least-squares linear regression with a spatial autocorrelation term, geographically weighted regression (GWR) and boosted regression tree (BRT) analysis—to identify the factors that influence the spread of endemic bTB at a local level in England and Wales. The linear regression and GWR methods demonstrated the importance of accounting for spatial differences in risk factors for bTB, and showed some consistency in the identification of certain factors related to flooding, disease history and the presence of multiple genotypes of bTB. This is the first attempt to explore the factors associated with the spread of endemic bTB in England and Wales using GWR. This technique improves on least-squares linear regression approaches by identifying regional differences in the factors associated with bTB spread. However, interpretation of these complex regional differences is difficult and the approach does not lend itself to predictive models which are likely to be of more value to policy makers. Methods such as BRT may be more suited to such a task. Here we have demonstrated that GWR and BRT can produce comparable outputs

CSAP localizes to polyglutamylated microtubules and promotes proper cilia function and zebrafish development

The diverse populations of microtubule polymers in cells are functionally distinguished by different posttranslational modifications, including polyglutamylation. Polyglutamylation is enriched on subsets of microtubules including those found in the centrioles, mitotic spindle, and cilia. However, whether this modification alters intrinsic microtubule dynamics or affects extrinsic associations with specific interacting partners remains to be determined. Here we identify the microtubule-binding protein centriole and spindle–associated protein (CSAP), which colocalizes with polyglutamylated tubulin to centrioles, spindle microtubules, and cilia in human tissue culture cells. Reducing tubulin polyglutamylation prevents CSAP localization to both spindle and cilia microtubules. In zebrafish, CSAP is required for normal brain development and proper left–right asymmetry, defects that are qualitatively similar to those reported previously for depletion of polyglutamylation-conjugating enzymes. We also find that CSAP is required for proper cilia beating. Our work supports a model in which polyglutamylation can target selected microtubule-associated proteins, such as CSAP, to microtubule subpopulations, providing specific functional capabilities to these populations.National Institutes of Health (U.S.) (Grant no. GM074746)American Cancer Society. Research Scholar Grant (121776)National Institute of General Medical Sciences (U.S.) (GM088313

Have whales returned to a historical hotspot of industrial whaling? The pattern of southern right whale Eubalaena australis recovery at South Georgia

Around 176500 whales were killed in the sub-Antarctic waters off South Georgia (South Atlantic) between 1904 and 1965. In recent decades, whales have once again become summer visitors, with the southern right whale (SRW) the most commonly reported species until 2011. Here, we assess the distribution, temporal pattern, health status and likely prey of SRWs in these waters, combining observations from a summertime vessel-based expedition to South Georgia, stable isotope data collected from SRWs and putative prey and sightings reports collated by the South Georgia Museum. The expedition used directional acoustics and visual surveys to localise whales and collected skin biopsies and photo-IDs. During 76 h of visual observation effort over 19 expedition days, SRWs were encountered 15 times (~31 individuals). Photo-IDs, combined with publicly contributed images from commercial vessels, were reconciled and quality-controlled to form a catalogue of 6 fully (i.e. both sides) identified SRWs and 26 SRWs identified by either left or right sides. No photo-ID matches were found with lower-latitude calving grounds, but 3 whales had gull lesions supporting a direct link with Península Valdés, Argentina. The isotopic position of SRWs in the South Georgia food web suggests feeding on a combination of copepod and krill species. Opportunistic reports of SRW sightings and associated group sizes remain steady over time, while humpback whales provide a strong contrast, with increased sighting rates and group sizes seen since 2013. These data suggest a plateau in SRWs and an increasing humpback whale presence in South Georgia waters following the cessation of whaling

Photo-identification and satellite telemetry connect southern right whales from South Georgia Island (Islas Georgias del Sur) with multiple feeding and calving grounds in the southwest Atlantic

The sub-Antarctic waters of South Georgia Island (Islas Georgias del Sur, SG/IG) are a regularly visited feeding ground for southern right whales (Eubalaena australis, SRW) in the southwest Atlantic. Satellite telemetry and photo-identification records were compared to better understand the role of SG/IG in the SRW migratory network. We present the first insights from SRW satellite-tracked from the SG/IG feeding ground, habitat use patterns in the Scotia Arc, and movements to Antarctic habitats. Photo-identification comparisons to calving and feeding areas across the South Atlantic and a review of sightings of cetaceans reported from Bird Island (west of SG/IG) since 1979 illuminate long-term habitat use patterns in SG/IG. We present the first recorded migratory movement between SG/IG and multiple countries: Argentina, Uruguay, and Brazil. Photo-identification (1) linked SG/IG to a female SRW with a long-term sighting history in Brazil, and (2) provided the first match between SG/IG and the western Antarctic Peninsula, suggesting the latter could extend the feeding area for southwest Atlantic SRW. Satellite tracking and opportunistic sightings suggest that shelf and coastal waters west of SG/IG represent an important multi-season SRW feeding habitat and add to our overall understanding of habitats and ranges occupied by recovering southwest Atlantic SRW

Drivers of genetic diversity in secondary metabolic gene clusters within a fungal species

Drivers of genetic diversity in secondary metabolic gene clusters within a fungal speciesFilamentous fungi produce a diverse array of secondary metabolites (SMs) critical for defense, virulence, and communication. The metabolic pathways that produce SMs are found in contiguous gene clusters in fungal genomes, an atypical arrangement for metabolic pathways in other eukaryotes. Comparative studies of filamentous fungal species have shown that SM gene clusters are often either highly divergent or uniquely present in one or a handful of species, hampering efforts to determine the genetic basis and evolutionary drivers of SM gene cluster divergence. Here, we examined SM variation in 66 cosmopolitan strains of a single species, the opportunistic human pathogen Aspergillus fumigatus. Investigation of genome-wide within-species variation revealed 5 general types of variation in SM gene clusters: nonfunctional gene polymorphisms; gene gain and loss polymorphisms; whole cluster gain and loss polymorphisms; allelic polymorphisms, in which different alleles corresponded to distinct, nonhomologous clusters; and location polymorphisms, in which a cluster was found to differ in its genomic location across strains. These polymorphisms affect the function of representative A. fumigatus SM gene clusters, such as those involved in the production of gliotoxin, fumigaclavine, and helvolic acid as well as the function of clusters with undefined products. In addition to enabling the identification of polymorphisms, the detection of which requires extensive genome-wide synteny conservation (e.g., mobile gene clusters and nonhomologous cluster alleles), our approach also implicated multiple underlying genetic drivers, including point mutations, recombination, and genomic deletion and insertion events as well as horizontal gene transfer from distant fungi. Finally, most of the variants that we uncover within A. fumigatus have been previously hypothesized to contribute to SM gene cluster diversity across entire fungal classes and phyla. We suggest that the drivers of genetic diversity operating within a fungal species shown here are sufficient to explain SM cluster macroevolutionary patterns.National Science Foundation (grant number DEB-1442113). Received by AR. U.S. National Library of Medicine training grant (grant number 2T15LM007450). Received by ALL. Conselho Nacional de Desenvolvimento Cientı´fico e 573 Tecnológico. Northern Portugal Regional Operational Programme (grant number NORTE-01- 0145-FEDER-000013). Received by FR. Fundação de Amparo à Pesquisa do 572 Estado de São Paulo. Received by GHG. National Institutes of Health (grant number R01 AI065728-01). Received by NPK. National Science Foundation (grant number IOS-1401682). Received by JHW. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.info:eu-repo/semantics/publishedVersio

Prehospital transdermal glyceryl trinitrate in patients with ultra-acute presumed stroke (RIGHT-2): an ambulance-based, randomised, sham-controlled, blinded, phase 3 trial

Background High blood pressure is common in acute stroke and is a predictor of poor outcome; however, large trials of lowering blood pressure have given variable results, and the management of high blood pressure in ultra-acute stroke remains unclear. We investigated whether transdermal glyceryl trinitrate (GTN; also known as nitroglycerin), a nitric oxide donor, might improve outcome when administered very early after stroke onset. Methods We did a multicentre, paramedic-delivered, ambulance-based, prospective, randomised, sham-controlled, blinded-endpoint, phase 3 trial in adults with presumed stroke within 4 h of onset, face-arm-speech-time score of 2 or 3, and systolic blood pressure 120 mm Hg or higher. Participants were randomly assigned (1:1) to receive transdermal GTN (5 mg once daily for 4 days; the GTN group) or a similar sham dressing (the sham group) in UK based ambulances by paramedics, with treatment continued in hospital. Paramedics were unmasked to treatment, whereas participants were masked. The primary outcome was the 7-level modified Rankin Scale (mRS; a measure of functional outcome) at 90 days, assessed by central telephone follow-up with masking to treatment. Analysis was hierarchical, first in participants with a confirmed stroke or transient ischaemic attack (cohort 1), and then in all participants who were randomly assigned (intention to treat, cohort 2) according to the statistical analysis plan. This trial is registered with ISRCTN, number ISRCTN26986053. Findings Between Oct 22, 2015, and May 23, 2018, 516 paramedics from eight UK ambulance services recruited 1149 participants (n=568 in the GTN group, n=581 in the sham group). The median time to randomisation was 71 min (IQR 45–116). 597 (52%) patients had ischaemic stroke, 145 (13%) had intracerebral haemorrhage, 109 (9%) had transient ischaemic attack, and 297 (26%) had a non-stroke mimic at the final diagnosis of the index event. In the GTN group, participants’ systolic blood pressure was lowered by 5·8 mm Hg compared with the sham group (p<0·0001), and diastolic blood pressure was lowered by 2·6 mm Hg (p=0·0026) at hospital admission. We found no difference in mRS between the groups in participants with a final diagnosis of stroke or transient ischaemic stroke (cohort 1): 3 (IQR 2–5; n=420) in the GTN group versus 3 (2–5; n=408) in the sham group, adjusted common odds ratio for poor outcome 1·25 (95% CI 0·97–1·60; p=0·083); we also found no difference in mRS between all patients (cohort 2: 3 [2–5]; n=544, in the GTN group vs 3 [2–5]; n=558, in the sham group; 1·04 [0·84–1·29]; p=0·69). We found no difference in secondary outcomes, death (treatment-related deaths: 36 in the GTN group vs 23 in the sham group [p=0·091]), or serious adverse events (188 in the GTN group vs 170 in the sham group [p=0·16]) between treatment groups. Interpretation Prehospital treatment with transdermal GTN does not seem to improve functional outcome in patients with presumed stroke. It is feasible for UK paramedics to obtain consent and treat patients with stroke in the ultraacute prehospital setting. Funding British Heart Foundation