A subset of patients with systemic lupus erythematosus fails to degrade DNA from multiple clinically relevant sources

Patients with systemic lupus erythematosus (SLE) have a decreased ability to clear cell remnants and multiple deficiencies in the ability to degrade cellular chromatin have been linked to the disease. Since the discovery of neutrophil extracellular traps (NETs), a renewed interest has been sparked in this field of research with multiple studies reporting a decreased ability of patients with SLE to degrade NETs. In this study we extend these findings by investigating the ability of patients with SLE to degrade chromatin from multiple clinically relevant sources

Constitutive IP₃ signaling underlies the sensitivity of B-cell cancers to the Bcl-2/IP₃ receptor disruptor BIRD-2

Anti-apoptotic Bcl-2 proteins are upregulated in different cancers, including diffuse large B-cell lymphoma (DLBCL) and chronic lymphocytic leukemia (CLL), enabling survival by inhibiting pro-apoptotic Bcl-2-family members and inositol 1,4,5-trisphosphate (IP3) receptor (IP3R)-mediated Ca2+-signaling. A peptide tool (Bcl-2/IP3R Disruptor-2; BIRD-2) was developed to abrogate the interaction of Bcl-2 with IP3Rs by targeting Bcl-2′s BH4 domain. BIRD-2 triggers cell death in primary CLL cells and in DLBCL cell lines. Particularly, DLBCL cells with high levels of IP3R2 were sensitive to BIRD-2. Here, we report that BIRD-2-induced cell death in DLBCL cells does not only depend on high IP3R2-expression levels, but also on constitutive IP3 signaling, downstream of the tonically active B-cell receptor. The basal Ca2+ level in SU-DHL-4 DLBCL cells was significantly elevated due to the constitutive IP3 production. This constitutive IP3 signaling fulfilled a pro-survival role, since inhibition of phospholipase C (PLC) using U73122 (2.5 µM) caused cell death in SU-DHL-4 cells. Milder inhibition of IP3 signaling using a lower U73122 concentration (1 µM) or expression of an IP3 sponge suppressed both BIRD-2-induced Ca2+ elevation and apoptosis in SU-DHL-4 cells. Basal PLC/IP3 signaling also fulfilled a pro-survival role in other DLBCL cell lines, including Karpas 422, RI-1 and SU-DHL-6 cells, whereas PLC inhibition protected these cells against BIRD-2-evoked apoptosis. Finally, U73122 treatment also suppressed BIRD-2-induced cell death in primary CLL, both in unsupported systems and in co-cultures with CD40L-expressing fibroblasts. Thus, constitutive IP3 signaling in lymphoma and leukemia cells is not only important for cancer cell survival, but also represents a vulnerability, rendering cancer cells dependent on Bcl-2 to limit IP3R activity. BIRD-2 seems to switch constitutive IP3 signaling from pro-survival into pro-death, presenting a plausible therapeutic strategy

Efficient generation of highly crystalline carbon quantum dots via electrooxidation of ethanol for rapid photodegradation of organic dyes

Achieving versatile routes to generate crystalline carbon-based nanostructures has become a fervent pursuit in photocatalysis-related fields. We demonstrate that the direct electrooxidation of ethanol, performed on Ni foam, yields ultra-small and highly crystalline graphene-like structures named carbon quantum dots (CQDs). We perform simulations of various sp2 and sp3 domains in order to understand the optical properties of CQDs by accounting their contribution as absorbance/luminescent centers in the overall optical response. Experiments and simulations reveal that absorbance bands for as-synthesized CQDs are dominated by small sp2 domains comprised of r7 aromatic-rings. After 48 h synthesis, the dispersion transition from yellow to red, exhibiting new and red shifted absorbance bands. Furthermore, fluorescence emission is governed by medium-sized sp 2 domains (with aromatic ring counts r12) and oxygen-containing groups. These oxygen-rich groups within the CQDs, confirmed by FT-IR and XPS, are responsible for the fast photodegradation of organic dyes, with B90% of methylene blue (MB) being degraded within the first 5 min of light exposure. Our work provides crucial insights about the electrochemical synthesis and overall optical properties of carbon nanostructures, while being effective and reliable toward the degradation of contaminants in water

First application of dynamic oxygen-17 magnetic resonance imaging at 7 Tesla in a patient with early subacute stroke.

Dynamic oxygen-17 (17O) magnetic resonance imaging (MRI) is an imaging method that enables a direct and non-invasive assessment of cerebral oxygen metabolism and thus potentially the distinction between viable and non-viable tissue employing a three-phase inhalation experiment. The purpose of this investigation was the first application of dynamic 17O MRI at 7 Tesla (T) in a patient with stroke. In this proof-of-concept experiment, dynamic 17O MRI was applied during 17O inhalation in a patient with early subacute stroke. The analysis of the relative 17O water (H217O) signal for the affected stroke region compared to the healthy contralateral side revealed no significant difference. However, the technical feasibility of 17O MRI has been demonstrated paving the way for future investigations in neurovascular diseases

Stimulation of the cuneiform nucleus enables training and boosts recovery after spinal cord injury

Severe spinal cord injuries result in permanent paraparesis in spite of the frequent sparing of small portions of white matter. Spared fibre tracts are often incapable of maintaining and modulating the activity of lower spinal motor centres. Effects of rehabilitative training thus remain limited. Here, we activated spared descending brainstem fibres by electrical deep brain stimulation of the cuneiform nucleus of the mesencephalic locomotor region, the main control centre for locomotion in the brainstem, in adult female Lewis rats. We show that deep brain stimulation of the cuneiform nucleus enhances the weak remaining motor drive in highly paraparetic rats with severe, incomplete spinal cord injuries and enables high-intensity locomotor training. Stimulation of the cuneiform nucleus during rehabilitative aquatraining after subchronic (n = 8 stimulated versus n = 7 unstimulated versus n = 7 untrained rats) and chronic (n = 14 stimulated versus n = 9 unstimulated versus n = 9 untrained rats) spinal cord injury re-established substantial locomotion and improved long-term recovery of motor function. We additionally identified a safety window of stimulation parameters ensuring context-specific locomotor control in intact rats (n = 18) and illustrate the importance of timing of treatment initiation after spinal cord injury (n = 14). This study highlights stimulation of the cuneiform nucleus as a highly promising therapeutic strategy to enhance motor recovery after subchronic and chronic incomplete spinal cord injury with direct clinical applicability

On the encounter between the GASP galaxy JO36 and the radio plume of GIN 049

We report on the serendipitous discovery of an unprecedented interaction between the radio lobe of a radio galaxy and a spiral galaxy. The discovery was made thanks to LOFAR observations at 144 MHz of the galaxy cluster Abell 160 ($z=0.04317$) provided by the LOFAR Two-metre Sky Survey. The new low-frequency observations revealed that one of the radio plumes of the central galaxy GIN 049 overlaps with the spiral galaxy JO36. Previous studies carried out with MUSE revealed that the warm ionized gas in the disk of JO36, traced by the H$\alpha$ emission, is severely truncated with respect to the stellar disk. We further explore this unique system by including new uGMRT observations at 675 MHz to map the spectral index. The emerging scenario is that JO36 has interacted with the radio plume in the past 200-500 Myr. The encounter resulted in a positive feedback event for JO36 in the form of a star formation rate burst of $\sim14$ $M_\odot$ yr$^{-1}$. In turn, the galaxy passage left a trace in the radio-old plasma by re-shaping the old relativistic plasma via magnetic draping.Comment: 20 pages, 11 figures. Accepted for publication on ApJ on September 4th, 202

Post-transplant cyclophosphamide after matched sibling, unrelated and haploidentical donor transplants in patients with acute myeloid leukemia: a comparative study of the ALWP EBMT

BACKGROUND: The use of post-transplant cyclophosphamide (PTCy) is highly effective in preventing graft-versus-host disease (GVHD) in the haploidentical (Haplo) transplant setting and is being increasingly used in matched sibling (MSD) and matched unrelated (MUD) transplants. There is no information on the impact of donor types using homogeneous prophylaxis with PTCy. METHODS: We retrospectively compared outcomes of adult patients with acute myeloid leukemia (AML) in first complete remission (CR1) who received a first allogeneic stem cell transplantation (SCT) with PTCy as GVHD prophylaxis from MSD (n = 215), MUD (n = 235), and Haplo (n = 789) donors registered in the EBMT database between 2010 and 2017. RESULTS: The median follow-up was 2 years. Haplo-SCT carried a significantly increased risk of acute grade II-IV GVHD (HR 1.6; 95% CI 1.1-2.4) and NRM (HR 2.6; 95% CI 1.5-4.5) but a lower risk of relapse (HR 0.7; 95% CI 0.5-0.9) that translated to no differences in LFS (HR 1.1; 95% CI 0.8-1.4) or GVHD/relapse-free survival (HR 1; 95% CI 0.8-1.3). Interestingly, the use of peripheral blood was associated with an increased risk of acute (HR 1.9; 95% CI 1.4-2.6) and chronic GVHD (HR 1.7; 95% CI 1.2-2.4) but a lower risk of relapse (HR 0.7; 95% CI 0.5-0.9). CONCLUSIONS: The use of PTCy in patients with AML in CR1 receiving SCT from MSD, MUD, and Haplo is safe and effective. Haplo-SCT had increased risk of acute GVHD and NRM and lower relapse incidence but no significant difference in survival

Large-scale genome-wide association studies and meta-analyses of longitudinal change in adult lung function.

BACKGROUND: Genome-wide association studies (GWAS) have identified numerous loci influencing cross-sectional lung function, but less is known about genes influencing longitudinal change in lung function. METHODS: We performed GWAS of the rate of change in forced expiratory volume in the first second (FEV1) in 14 longitudinal, population-based cohort studies comprising 27,249 adults of European ancestry using linear mixed effects model and combined cohort-specific results using fixed effect meta-analysis to identify novel genetic loci associated with longitudinal change in lung function. Gene expression analyses were subsequently performed for identified genetic loci. As a secondary aim, we estimated the mean rate of decline in FEV1 by smoking pattern, irrespective of genotypes, across these 14 studies using meta-analysis. RESULTS: The overall meta-analysis produced suggestive evidence for association at the novel IL16/STARD5/TMC3 locus on chromosome 15 (P  =  5.71 × 10(-7)). In addition, meta-analysis using the five cohorts with ≥3 FEV1 measurements per participant identified the novel ME3 locus on chromosome 11 (P  =  2.18 × 10(-8)) at genome-wide significance. Neither locus was associated with FEV1 decline in two additional cohort studies. We confirmed gene expression of IL16, STARD5, and ME3 in multiple lung tissues. Publicly available microarray data confirmed differential expression of all three genes in lung samples from COPD patients compared with controls. Irrespective of genotypes, the combined estimate for FEV1 decline was 26.9, 29.2 and 35.7 mL/year in never, former, and persistent smokers, respectively. CONCLUSIONS: In this large-scale GWAS, we identified two novel genetic loci in association with the rate of change in FEV1 that harbor candidate genes with biologically plausible functional links to lung function

Geographic Variation in Salt Marsh Structure and Function for Nekton: a Guide to Finding Commonality Across Multiple Scales

Coastal salt marshes are distributed widely across the globe and are considered essential habitat for many fish and crustacean species. Yet, the literature on fishery support by salt marshes has largely been based on a few geographically distinct model systems, and as a result, inadequately captures the hierarchical nature of salt marsh pattern, process, and variation across space and time. A better understanding of geographic variation and drivers of commonalities and differences across salt marsh systems is essential to informing future management practices. Here, we address the key drivers of geographic variation in salt marshes: hydroperiod, seascape configuration, geomorphology, climatic region, sediment supply and riverine input, salinity, vegetation composition, and human activities. Future efforts to manage, conserve, and restore these habitats will require consideration of how environmental drivers within marshes affect the overall structure and subsequent function for fisheries species. We propose a future research agenda that provides both the consistent collection and reporting of sources of variation in small-scale studies and collaborative networks running parallel studies across large scales and geographically distinct locations to provide analogous information for data poor locations. These comparisons are needed to identify and prioritize restoration or conservation efforts, identify sources of variation among regions, and best manage fisheries and food resources across the globe

Circulating Monocyte Chemoattractant Protein-1 and Risk of Stroke: A Meta-Analysis of Population-Based Studies Involving 17,180 Individuals.

RATIONALE: Pro-inflammatory cytokines have been identified as potential targets for lowering vascular risk. Experimental evidence and Mendelian randomization suggest a role of monocyte-chemoattractant protein-1 (MCP-1) in atherosclerosis and stroke. However, data from large-scale observational studies are lacking. OBJECTIVE: To determine whether circulating levels of MCP-1 are associated with risk of incident stroke in the general population. METHODS AND RESULTS: We used previously unpublished data on 17,180 stroke-free individuals (mean age 56.7{plus minus}8.1 years; 48.8% males) from six population-based prospective cohort studies and explored associations between baseline circulating MCP-1 levels and risk of any stroke, ischemic stroke, and hemorrhagic stroke over a mean follow-up interval of 16.3 years (280,522 person-years at risk; 1,435 incident stroke events). We applied Cox proportional hazard models and pooled hazard ratios (HR) using random-effects meta-analyses. Following adjustments for age, sex, race, and vascular risk factors, higher MCP-1 levels were associated with increased risk of any stroke (HR per 1 SD increment in ln-transformed MCP-1: 1.07, 95%CI: 1.01-1.14). Focusing on stroke subtypes, we found a significant association between baseline MCP-1 levels and higher risk of ischemic stroke (HR: 1.11, [1.02-1.21]), but not hemorrhagic stroke (HR: 1.02, [0.82-1.29]). The results followed a dose-response pattern with a higher risk of ischemic stroke among individuals in the upper quartiles of MCP-1 levels as compared to the 1st quartile (HRs: 2nd quartile: 1.19 [1.00-1.42]; 3rd quartile: 1.35, [1.14-1.59]; 4th quartile: 1.38, [1.07-1.77]). There was no indication for heterogeneity across studies and in a sub-sample of four studies (12,516 individuals) the risk estimates were stable after additional adjustments for circulating levels of interleukin-6 and high-sensitivity C-reactive protein. CONCLUSIONS: Higher circulating levels of MCP-1 are associated with increased long-term risk of stroke. Our findings along with genetic and experimental evidence suggest that MCP-1-signaling might represent a therapeutic target to lower stroke risk.M. Georgakis is funded by scholarships from the German Academic Exchange Service (DAAD) and Onassis Foundation. The ARIC study has been funded in whole or in part with Federal funds from the National Heart, Lung, and Blood Institute, National Institutes of Health, Department of Health and Human Services, under Contract nos. (HHSN268201700001I, HHSN268201700002I, HHSN268201700003I, HHSN268201700005I, HHSN268201700004I). The DHS study was funded by a grant from the Donald W. Reynolds Foundation. The EPIC-Norfolk study is funded by grants from the Medical Research Council UK (G9502233, G0401527) and Cancer Research UK (C864/A8257, C864/A2883). FHS is supported by the National Heart, Lung and Blood Institute’s Framingham Heart Study (Contract No. N01-HC-25195 and No. HHSN268201500001I and 75N92019D00031), received funding by grants from the National Institute of Aging (R01s AG054076, AG049607, AG059421, U01-AG049505, AG058589 and AG052409) and the National Institute of Neurological Disorders and Stroke (R01 NS017950, UH2 NS100605), as well as grants for the MCP-1 measurements by NIH (1RO1 HL64753, R01 HL076784, 1 R01 AG028321). The KORA study was initiated and financed by the Helmholtz Zentrum München – German Research Center for Environmental Health, which is funded by the German Federal Ministry of Education and Research (BMBF) and by the State of Bavaria. Furthermore, KORA research was supported within the Munich Center of Health Sciences (MC-Health), Ludwig-Maximilians-Universität, as part of LMUinnovativ. The MDCS-CV study has been supported with funding from the Swedish Research Council, Swedish Heart and Lung Foundations, and the Swedish Foundation for Strategic Research. This project has received funding from the European Union’s Horizon 2020 research and innovation programme (No 666881), SVDs@target (to M. Dichgans) and No 667375, CoSTREAM (to M. Dichgans); the DFG as part of the Munich Cluster for Systems Neurology (EXC 2145 SyNergy – ID 390857198) and the CRC 1123 (B3) (to M. Dichgans); the Corona Foundation (to M. Dichgans); the Fondation Leducq (Transatlantic Network of Excellence on the Pathogenesis of Small Vessel Disease of the Brain)(to M. Dichgans); the e:Med program (e:AtheroSysMed) (to M. Dichgans) and the FP7/2007-2103 European Union project CVgenes@target (grant agreement number Health-F2-2013-601456) (to M. Dichgans)