CSF-resident CD4+ T-cells display a distinct gene expression profile with relevance to immune surveillance and multiple sclerosis

The CNS has traditionally been considered an immune privileged site, but is now understood to have a system of immune surveillance, predominantly involving CD4+ T-cells. Identifying functional differences between CNS and blood CD4+ T-cells, therefore, have relevance to CNS immune surveillance as well as to neurological conditions, such as multiple sclerosis, in which CD4+ T-cells play a central role. Here, CD4+ T-cells were purified from CSF and blood from 21 patients with newly diagnosed treatment-naïve multiple sclerosis and 20 individuals with non-inflammatory disorders using fluorescence-activated cell sorting, and their transcriptomes were profiled by RNA sequencing. Paired comparisons between CD4+ T-cells from CSF and blood identified 5156 differentially expressed genes in controls and 4263 differentially expressed in multiple sclerosis patients at false discovery rate <5%. Differential expression analysis of CD4+ T-cells collected from the CSF highlighted genes involved in migration, activation, cholesterol biosynthesis and signalling, including those with known relevance to multiple sclerosis pathogenesis and treatment. Expression of markers of CD4+ T-cell subtypes suggested an increased proportion of Th1 and Th17 cells in CSF. Gene ontology terms significant only in multiple sclerosis were predominantly those involved in cellular proliferation. A two-way comparison of CSF versus blood CD4+ T-cells in multiple sclerosis compared with non-inflammatory disorder controls identified four significant genes at false discovery rate <5% (CYP51A1, LRRD1, YES1 and PASK), further implicating cholesterol biosynthesis and migration mechanisms. Analysis of CSF CD4+ T-cells in an extended cohort of multiple sclerosis cases (total N = 41) compared with non-inflammatory disorder controls (total N = 38) identified 140 differentially expressed genes at false discovery rate < 5%, many of which have known relevance to multiple sclerosis, including XBP1, BHLHE40, CD40LG, DPP4 and ITGB1. This study provides the largest transcriptomic analysis of purified cell subpopulations in CSF to date and has relevance for the understanding of CNS immune surveillance, as well as multiple sclerosis pathogenesis and treatment discovery

Thermoregulatory traits combine with range shifts to alter the future of montane ant assemblages.

Predicting and understanding the biological response to future climate change is a pressing challenge for humanity. In the 21st century, many species will move into higher latitudes and higher elevations as the climate warms. In addition, the relative abundances of species within local assemblages is likely to change. Both effects have implications for how ecosystems function. Few biodiversity forecasts, however, take account of both shifting ranges and changing abundances. We provide a novel analysis predicting the potential changes to assemblage level relative abundances in the 21st century. We use an established relationship linking ant abundance and their colour and size traits to temperature and UV-B to predict future abundance changes. We also predict future temperature driven range shifts and use these to alter the available species pool for our trait-mediated abundance predictions. We do this across three continents under a low greenhouse gas emissions scenario (RCP2.6) and a business-as-usual scenario (RCP8.5). Under RCP2.6, predicted changes to ant assemblages by 2100 are moderate. On average, species richness will increase by 26%, while species composition and relative abundance structure will be 26% and 30% different, respectively, compared with modern assemblages. Under RCP8.5, however, highland assemblages face almost a tripling of species richness and compositional and relative abundance changes of 66% and 77%. Critically, we predict that future assemblages could be reorganised in terms of which species are common and which are rare: future highland assemblages will not simply comprise upslope shifts of modern lowland assemblages. These forecasts reveal the potential for radical change to montane ant assemblages by the end of the 21st century if temperature increases continue. Our results highlight the importance of incorporating trait-environment relationships into future biodiversity predictions. Looking forward, the major challenge is to understand how ecosystem processes will respond to compositional and relative abundance changes. This article is protected by copyright. All rights reserved

Thermoregulatory traits combine with range shifts to alter the future of montane ant assemblages.

Predicting and understanding the biological response to future climate change is a pressing challenge for humanity. In the 21st century, many species will move into higher latitudes and higher elevations as the climate warms. In addition, the relative abundances of species within local assemblages is likely to change. Both effects have implications for how ecosystems function. Few biodiversity forecasts, however, take account of both shifting ranges and changing abundances. We provide a novel analysis predicting the potential changes to assemblage level relative abundances in the 21st century. We use an established relationship linking ant abundance and their colour and size traits to temperature and UV-B to predict future abundance changes. We also predict future temperature driven range shifts and use these to alter the available species pool for our trait-mediated abundance predictions. We do this across three continents under a low greenhouse gas emissions scenario (RCP2.6) and a business-as-usual scenario (RCP8.5). Under RCP2.6, predicted changes to ant assemblages by 2100 are moderate. On average, species richness will increase by 26%, while species composition and relative abundance structure will be 26% and 30% different, respectively, compared with modern assemblages. Under RCP8.5, however, highland assemblages face almost a tripling of species richness and compositional and relative abundance changes of 66% and 77%. Critically, we predict that future assemblages could be reorganised in terms of which species are common and which are rare: future highland assemblages will not simply comprise upslope shifts of modern lowland assemblages. These forecasts reveal the potential for radical change to montane ant assemblages by the end of the 21st century if temperature increases continue. Our results highlight the importance of incorporating trait-environment relationships into future biodiversity predictions. Looking forward, the major challenge is to understand how ecosystem processes will respond to compositional and relative abundance changes. This article is protected by copyright. All rights reserved

Targeting patient recovery priorities in degenerative cervical myelopathy:design and rationale for the RECEDE-Myelopathy trial-study protocol

Introduction: Degenerative cervical myelopathy (DCM) is a common and disabling condition of symptomatic cervical spinal cord compression secondary to degenerative changes in spinal structures leading to a mechanical stress injury of the spinal cord. RECEDE-Myelopathy aims to test the disease-modulating activity of the phosphodiesterase 3/phosphodiesterase 4 inhibitor Ibudilast as an adjuvant to surgical decompression in DCM. Methods and analysis: RECEDE-Myelopathy is a multicentre, double-blind, randomised, placebo-controlled trial. Participants will be randomised to receive either 60-100 mg Ibudilast or placebo starting within 10 weeks prior to surgery and continuing for 24 weeks after surgery for a maximum of 34 weeks. Adults with DCM, who have a modified Japanese Orthopaedic Association (mJOA) score 8-14 inclusive and are scheduled for their first decompressive surgery are eligible for inclusion. The coprimary endpoints are pain measured on a visual analogue scale and physical function measured by the mJOA score at 6 months after surgery. Clinical assessments will be undertaken preoperatively, postoperatively and 3, 6 and 12 months after surgery. We hypothesise that adjuvant therapy with Ibudilast leads to a meaningful and additional improvement in either pain or function, as compared with standard routine care. Study design: Clinical trial protocol V.2.2 October 2020. Ethics and dissemination: Ethical approval has been obtained from HRA - Wales. The results will be presented at an international and national scientific conferences and in a peer-reviewed journals.Trial registration number: ISRCTN Number: ISRCTN16682024.</p

Thermoregulatory traits combine with range shifts to alter the future of montane ant assemblages

Predicting and understanding the biological response to future climate change is a pressing challenge for humanity. In the 21st century, many species will move into higher latitudes and higher elevations as the climate warms. In addition, the relative abundances of species within local assemblages are likely to change. Both effects have implications for how ecosystems function. Few biodiversity forecasts, however, take account of both shifting ranges and changing abundances. We provide a novel analysis predicting the potential changes to assemblage‐level relative abundances in the 21st century. We use an established relationship linking ant abundance and their colour and size traits to temperature and UV‐B to predict future abundance changes. We also predict future temperature driven range shifts and use these to alter the available species pool for our trait‐mediated abundance predictions. We do this across three continents under a low greenhouse gas emissions scenario (RCP2.6) and a business‐as‐usual scenario (RCP8.5). Under RCP2.6, predicted changes to ant assemblages by 2100 are moderate. On average, species richness will increase by 26%, while species composition and relative abundance structure will be 26% and 30% different, respectively, compared with modern assemblages. Under RCP8.5, however, highland assemblages face almost a tripling of species richness and compositional and relative abundance changes of 66% and 77%. Critically, we predict that future assemblages could be reorganized in terms of which species are common and which are rare: future highland assemblages will not simply comprise upslope shifts of modern lowland assemblages. These forecasts reveal the potential for radical change to montane ant assemblages by the end of the 21st century if temperature increases continue. Our results highlight the importance of incorporating trait–environment relationships into future biodiversity predictions. Looking forward, the major challenge is to understand how ecosystem processes will respond to compositional and relative abundance changes.Australian Research Council, Grant/Award Number: DP120100781; University of Pretoria; Leverhulme Trust; NERC; DST‐NRF CIB.http://wileyonlinelibrary.com/journal/gcb2020-06-01hj2019Zoology and Entomolog

Ant assemblages have darker and larger members in cold environments

Aim In ectotherms, the colour of an individual's cuticle may have important thermoregulatory and protective consequences. In cool environments, ectotherms should be darker, to maximize heat gain, and larger, to minimize heat loss. Dark colours should also predominate under high UV‐B conditions because melanin offers protection. We test these predictions in ants (Hymenoptera: Formicidae) across space and through time based on a new, spatially and temporally explicit, global‐scale combination of assemblage‐level and environmental data. Location Africa, Australia and South America. Methods We sampled ant assemblages (n = 274) along 14 elevational transects on three continents. Individual assemblages ranged from 250 to 3000 m a.s.l. (minimum to maximum range in summer temperature of 0.5–35 °C). We used mixed‐effects models to explain variation in assemblage cuticle lightness. Explanatory variables were average assemblage body size, temperature and UV‐B irradiation. Annual temporal changes in lightness were examined for a subset of the data. Results Assemblages with large average body sizes were darker in colour than those with small body sizes. Assemblages became lighter in colour with increasing temperature, but darkened again at the highest temperatures when there were high levels of UV‐B. Through time, temperature and body size explained variation in lightness. Both the spatial and temporal models explained c. 50% of the variation in lightness. Main conclusions Our results are consistent with the thermal melanism hypothesis, and demonstrate the importance of considering body size and UV‐B radiation exposure in explaining the colour of insect cuticle. Crucially, this finding is at the assemblage level. Consequently, the relative abundances and identities of ant species that are present in an assemblage can change in accordance with environmental conditions over elevation, latitude and relatively short time spans. These findings suggest that there are important constraints on how ectotherm assemblages may be able to respond to rapidly changing environmental conditions

GRIPS - Gamma-Ray Imaging, Polarimetry and Spectroscopy

We propose to perform a continuously scanning all-sky survey from 200 keV to 80 MeV achieving a sensitivity which is better by a factor of 40 or more compared to the previous missions in this energy range. The Gamma-Ray Imaging, Polarimetry and Spectroscopy (GRIPS) mission addresses fundamental questions in ESA's Cosmic Vision plan. Among the major themes of the strategic plan, GRIPS has its focus on the evolving, violent Universe, exploring a unique energy window. We propose to investigate $\gamma$-ray bursts and blazars, the mechanisms behind supernova explosions, nucleosynthesis and spallation, the enigmatic origin of positrons in our Galaxy, and the nature of radiation processes and particle acceleration in extreme cosmic sources including pulsars and magnetars. The natural energy scale for these non-thermal processes is of the order of MeV. Although they can be partially and indirectly studied using other methods, only the proposed GRIPS measurements will provide direct access to their primary photons. GRIPS will be a driver for the study of transient sources in the era of neutrino and gravitational wave observatories such as IceCUBE and LISA, establishing a new type of diagnostics in relativistic and nuclear astrophysics. This will support extrapolations to investigate star formation, galaxy evolution, and black hole formation at high redshifts.Comment: to appear in Exp. Astron., special vol. on M3-Call of ESA's Cosmic Vision 2010; 25 p., 25 figs; see also www.grips-mission.e

Old World Arenaviruses Enter the Host Cell via the Multivesicular Body and Depend on the Endosomal Sorting Complex Required for Transport

The highly pathogenic Old World arenavirus Lassa virus (LASV) and the prototypic arenavirus lymphocytic choriomeningitis virus (LCMV) use α-dystroglycan as a cellular receptor and enter the host cell by an unusual endocytotic pathway independent of clathrin, caveolin, dynamin, and actin. Upon internalization, the viruses are delivered to acidified endosomes in a Rab5-independent manner bypassing classical routes of incoming vesicular trafficking. Here we sought to identify cellular factors involved in the unusual and largely unknown entry pathway of LASV and LCMV. Cell entry of LASV and LCMV required microtubular transport to late endosomes, consistent with the low fusion pH of the viral envelope glycoproteins. Productive infection with recombinant LCMV expressing LASV envelope glycoprotein (rLCMV-LASVGP) and LCMV depended on phosphatidyl inositol 3-kinase (PI3K) as well as lysobisphosphatidic acid (LBPA), an unusual phospholipid that is involved in the formation of intraluminal vesicles (ILV) of the multivesicular body (MVB) of the late endosome. We provide evidence for a role of the endosomal sorting complex required for transport (ESCRT) in LASV and LCMV cell entry, in particular the ESCRT components Hrs, Tsg101, Vps22, and Vps24, as well as the ESCRT-associated ATPase Vps4 involved in fission of ILV. Productive infection with rLCMV-LASVGP and LCMV also critically depended on the ESCRT-associated protein Alix, which is implicated in membrane dynamics of the MVB/late endosomes. Our study identifies crucial cellular factors implicated in Old World arenavirus cell entry and indicates that LASV and LCMV invade the host cell passing via the MVB/late endosome. Our data further suggest that the virus-receptor complexes undergo sorting into ILV of the MVB mediated by the ESCRT, possibly using a pathway that may be linked to the cellular trafficking and degradation of the cellular receptor

New loci for body fat percentage reveal link between adiposity and cardiometabolic disease risk

To increase our understanding of the genetic basis of adiposity and its links to cardiometabolic disease risk, we conducted a genome-wide association meta-analysis of body fat percentage (BF%) in up to 100,716 individuals. Twelve loci reached genome-wide significance (P<5 × 10−8), of which eight were previously associated with increased overall adiposity (BMI, BF%) and four (in or near COBLL1/GRB14, IGF2BP1, PLA2G6, CRTC1) were novel associations with BF%. Seven loci showed a larger effect on BF% than on BMI, suggestive of a primary association with adiposity, while five loci showed larger effects on BMI than on BF%, suggesting association with both fat and lean mass. In particular, the loci more strongly associated with BF% showed distinct cross-phenotype association signatures with a range of cardiometabolic traits revealing new insights in the link between adiposity and disease risk

Multidifferential study of identified charged hadron distributions in ZZ-tagged jets in proton-proton collisions at s=\sqrt{s}=13 TeV

Jet fragmentation functions are measured for the first time in proton-proton collisions for charged pions, kaons, and protons within jets recoiling against a $Z$ boson. The charged-hadron distributions are studied longitudinally and transversely to the jet direction for jets with transverse momentum 20 $< p_{\textrm{T}} < 100$ GeV and in the pseudorapidity range $2.5 < \eta < 4$. The data sample was collected with the LHCb experiment at a center-of-mass energy of 13 TeV, corresponding to an integrated luminosity of 1.64 fb$^{-1}$. Triple differential distributions as a function of the hadron longitudinal momentum fraction, hadron transverse momentum, and jet transverse momentum are also measured for the first time. This helps constrain transverse-momentum-dependent fragmentation functions. Differences in the shapes and magnitudes of the measured distributions for the different hadron species provide insights into the hadronization process for jets predominantly initiated by light quarks.Comment: All figures and tables, along with machine-readable versions and any supplementary material and additional information, are available at https://cern.ch/lhcbproject/Publications/p/LHCb-PAPER-2022-013.html (LHCb public pages