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A recent CLOUD (Cosmics Leaving OUtdoor Droplets) chamber study showed that sulfuric acid and dimethylamine produce new aerosols very efficiently, and yield particle formation rates that are compatible with boundary layer observations. These previously published new particle formation (NPF) rates are re-analyzed in the present study with an advanced method. The results show that the NPF rates at 1.7 nm are more than a factor of 10 faster than previously published due to earlier approximations in correcting particle measurements made at larger detection threshold. The revised NPF rates agree almost perfectly with calculated rates from a kinetic aerosol model at different sizes (1.7 nm and 4.3 nm mobility diameter). In addition, modeled and measured size distributions show good agreement over a wide range (up to ca. 30 nm). Furthermore, the aerosol model is modified such that evaporation rates for some clusters can be taken into account; these evaporation rates were previously published from a flow tube study. Using this model, the findings from the present study and the flow tube experiment can be brought into good agreement. This confirms that nucleation proceeds at rates that are compatible with collision-controlled (a.k.a. kinetically-controlled) new particle formation for the conditions during the CLOUD7 experiment (278 K, 38% RH, sulfuric acid concentration between 1×106 and 3×107 cm-3 and dimethylamine mixing ratio of ~40 pptv). Finally, the simulation of atmospheric new particle formation reveals that even tiny mixing ratios of dimethylamine (0.1 pptv) yield NPF rates that could explain significant boundary layer particle formation. This highlights the need for improved speciation and quantification techniques for atmospheric gas-phase amine measurements.
Although often depicted as rigid structures, proteins are highly dynamic systems, whose motions are essential to their functions. Despite this, it is difficult to investigate protein dynamics due to the rapid timescale at which they sample their conformational space, leading most NMR-determined structures to represent only an averaged snapshot of the dynamic picture. While NMR relaxation measurements can help to determine local dynamics, it is difficult to detect translational or concerted motion, and only recently have significant advances been made to make it possible to acquire a more holistic representation of the dynamics and structural landscapes of proteins. Here, we briefly revisit our most recent progress in the theory and use of exact nuclear Overhauser enhancements (eNOEs) for the calculation of structural ensembles that describe their conformational space. New developments are primarily targeted at increasing the number and improving the quality of extracted eNOE distance restraints, such that the multi-state structure calculation can be applied to proteins of higher molecular weights. We then review the implications of the exact NOE to the protein dynamics and function of cyclophilin A and the WW domain of Pin1, and finally discuss our current research and future directions.
Resonance assignments are challenging for membrane proteins due to the size of the lipid/detergent-protein complex and the presence of line-broadening from conformational exchange. As a consequence, many correlations are missing in the triple-resonance NMR experiments typically used for assignments. Herein, we present an approach in which correlations from these solution-state NMR experiments are supplemented by data from 13C unlabeling, single-amino acid type labeling, 4D NOESY data and proximity of moieties to lipids or water in combination with a structure of the protein. These additional data are used to edit the expected peaklists for the automated assignment protocol FLYA, a module of the program package CYANA. We demonstrate application of the protocol to the 262-residue proton pump from archaeal bacteriorhodopsin (bR) in lipid nanodiscs. The lipid-protein assembly is characterized by an overall correlation time of 44 ns. The protocol yielded assignments for 62% of all backbone (H, N, Cα, Cβ, C′) resonances of bR, corresponding to 74% of all observed backbone spin systems, and 60% of the Ala, Met, Ile (δ1), Leu and Val methyl groups, thus enabling to assign a large fraction of the protein without mutagenesis data. Most missing resonances stem from the extracellular half, likely due intermediate exchange line-broadening. Further analysis revealed that missing information of the amino acid type of the preceding residue is the largest problem, and that 4D NOESY experiments are particularly helpful to compensate for that information loss.
Background: Peritonitis is responsible for thousands of deaths annually in Germany alone. Even source control (SC) and antibiotic treatment often fail to prevent severe sepsis or septic shock, and this situation has hardly improved in the past two decades. Most experimental immunomodulatory therapeutics for sepsis have been aimed at blocking or dampening a specific pro-inflammatory immunological mediator. However, the patient collective is large and heterogeneous. There are therefore grounds for investigating the possibility of developing personalized therapies by classifying patients into groups according to biomarkers. This study aims to combine an assessment of the efficacy of treatment with a preparation of human immunoglobulins G, A, and M (IgGAM) with individual status of various biomarkers (immunoglobulin level, procalcitonin, interleukin 6, antigen D-related human leucocyte antigen (HLA-DR), transcription factor NF-κB1, adrenomedullin, and pathogen spectrum).
Methods/design: A total of 200 patients with sepsis or septic shock will receive standard-of-care treatment (SoC). Of these, 133 patients (selected by 1:2 randomization) will in addition receive infusions of IgGAM for 5 days. All patients will be followed for approximately 90 days and assessed by the multiple-organ failure (MOF) score, by the EQ QLQ 5D quality-of-life scale, and by measurement of vital signs, biomarkers (as above), and survival.
Discussion: This study is intended to provide further information on the efficacy and safety of treatment with IgGAM and to offer the possibility of correlating these with the biomarkers to be studied. Specifically, it will test (at a descriptive level) the hypothesis that patients receiving IgGAM who have higher inflammation status (IL-6) and poorer immune status (low HLA-DR, low immunoglobulin levels) have a better outcome than patients who do not receive IgGAM. It is expected to provide information that will help to close the knowledge gap concerning the association between the effect of IgGAM and the presence of various biomarkers, thus possibly opening the way to a personalized medicine.
Trial registration: EudraCT, 2016–001788-34; ClinicalTrials.gov, NCT03334006. Registered on 17 Nov 2017.
Trial sponsor: RWTH Aachen University, represented by the Center for Translational & Clinical Research Aachen (contact Dr. S. Isfort).
Droughts are anticipated to intensify in many parts of the world due to climate change. However, the issue of drought definition, namely the diversity of drought indices, makes it difficult to compare drought assessments. This issue is widely known, but its relative importance has never been quantitatively evaluated in comparison to other sources of uncertainty. Here, encompassing three drought categories (meteorological, agricultural, and hydrological droughts) with four temporal scales of interest, we evaluated changes in the drought frequency using multi-model and multi-scenario simulations to identify areas where the definition issue could result in pronounced uncertainties and to what extent. We investigated the disagreement in the signs of changes between drought definitions and decomposed the variance into four main factors: drought definitions, greenhouse gas concentration scenarios, global climate models, and global water models, as well as their interactions. The results show that models were the primary sources of variance over 82% of the global land area. On the other hand, the drought definition was the dominant source of variance in the remaining 17%, especially in parts of northern high-latitudes. Our results highlight specific regions where differences in drought definitions result in a large spread among projections, including areas showing opposite signs of significant changes. At a global scale, 7% of the variance resulted independently from the definition issue, and that value increased to 44% when 1st and 2nd order interactions were considered. The quantitative results suggest that by clarifying hydrological processes or sectors of interest, one could avoid these uncertainties in drought assessments to obtain a clearer picture of future drought change.
Introduction: Deep brain stimulation (DBS) has become a well-established treatment modality for a variety of conditions over the last decades. Multiple surgeries are an essential part in the postoperative course of DBS patients if nonrechargeable implanted pulse generators (IPGs) are applied. So far, the rate of subclinical infections in this field is unknown. In this prospective cohort study, we used sonication to evaluate possible microbial colonization of IPGs from replacement surgery. Methods: All consecutive patients undergoing IPG replacement between May 1, 2019 and November 15, 2020 were evaluated. The removed hardware was investigated using sonication to detect biofilm-associated bacteria. Demographic and clinical data were analyzed. Results: A total of 71 patients with a mean (±SD) of 64.5 ± 15.3 years were evaluated. In 23 of these (i.e., 32.4%) patients, a positive sonication culture was found. In total, 25 microorganisms were detected. The most common isolated microorganisms were Cutibacterium acnes (formerly known as Propionibacterium acnes) (68%) and coagulase-negative Staphylococci (28%). Within the follow-up period (5.2 ± 4.3 months), none of the patients developed a clinical manifest infection. Discussions/Conclusions: Bacterial colonization of IPGs without clinical signs of infection is common but does not lead to manifest infection. Further larger studies are warranted to clarify the impact of low-virulent pathogens in clinically asymptomatic patients.
Apheresis therapies for NMOSD attacks : a retrospective study of 207 therapeutic interventions
(2018)
Objective: To analyze whether 1 of the 2 apheresis techniques, therapeutic plasma exchange (PE) or immunoadsorption (IA), is superior in treating neuromyelitis optica spectrum disorder (NMOSD) attacks and to identify predictive factors for complete remission (CR).
Methods: This retrospective cohort study was based on the registry of the German Neuromyelitis Optica Study Group, a nationwide network established in 2008. It recruited patients with neuromyelitis optica diagnosed according to the 2006 Wingerchuk criteria or with aquaporin-4 (AQP4-ab)-antibody–seropositive NMOSD treated at 6 regional hospitals and 16 tertiary referral centers until March 2013. Besides descriptive data analysis of patient and attack characteristics, generalized estimation equation (GEE) analyses were applied to compare the effectiveness of the 2 apheresis techniques. A GEE model was generated to assess predictors of outcome.
Results: Two hundred and seven attacks in 105 patients (87% AQP4-ab-antibody seropositive) were treated with at least 1 apheresis therapy. Neither PE nor IA was proven superior in the therapy of NMOSD attacks. CR was only achieved with early apheresis therapy. Strong predictors for CR were the use of apheresis therapy as first-line therapy (OR 12.27, 95% CI: 1.04–144.91, p = 0.047), time from onset of attack to start of therapy in days (OR 0.94, 95% CI: 0.89–0.99, p = 0.014), the presence of AQP4-ab-antibodies (OR 33.34, 95% CI: 1.76–631.17, p = 0.019), and monofocal attack manifestation (OR 4.71, 95% CI: 1.03–21.62, p = 0.046).
Conclusions: Our findings suggest early use of an apheresis therapy in NMOSD attacks, particularly in AQP4-ab-seropositive patients. No superiority was shown for one of the 2 apheresis techniques.
Classification of evidence: This study provides Class IV evidence that for patients with NMOSD, neither PE nor IA is superior in the treatment of attacks.
Inflammatory diseases including psoriasis are associated with metabolic and cardiovascular comorbidities, including obesity and metabolic syndrome. Obesity is associated with greater psoriasis disease severity and reduced response to treatment. Therefore, targeting metabolic comorbidities could improve patients’ health status and psoriasis-specific outcomes. METABOLyx is a randomized controlled trial evaluating the combination of a lifestyle intervention program with secukinumab treatment in psoriasis. Here, the rationale, methodology and baseline patient characteristics of METABOLyx are presented. A total of 768 patients with concomitant moderate to severe plaque psoriasis and metabolic syndrome were randomized to secukinumab 300 mg, or secukinumab 300 mg plus a tailored lifestyle intervention program, over 24 weeks. A substudy of immunologic and metabolic biomarkers is ongoing. The primary endpoint of METABOLyx is PASI90 response at week 24. Other endpoints include patient-reported outcomes and safety. METABOLyx represents the first large scale clinical trial of an immunomodulatory biologic in combination with a standardized lifestyle intervention.
Abrasion-ablation models and the empirical EPAX parametrization of projectile fragmentation are described. Their cross section predictions are compared to recent data of the fragmentation of secondary beams of neutron-rich, unstable 19,20,21O isotopes at beam energies near 600 MeV/nucleon as well as data for stable 17,18O beams.
Development of fragmented low-Z ion beams for the NA61 fixed-target experiment at the CERN SPS
(2011)
The NA61 experiment, aims to study the properties of the onset of deconfinement at low SPS energies and to find signatures of the critical point of strongly interacting matter. A broad range in T-μB phase diagram will be covered by performing an energy (13A-158A GeV/c) and system size (p+p, Be+Be, Ar+Ca, Xe+La) scan. In a first phase, fragmented ion beams of 7Be or 11C produced as secondaries with the same momentum per nucleon when the incident primary Pb-ion beam hits a thin Be target will be used. The H2 beam line that transports the beam to the experiment acts as a double spectrometer which combined with a new thin target (degrader) where fragments loose energy proportional to the square of their charge allows the separation of the wanted A/Z fragments. Thin scintillators and TOF measurement for the low energy points are used as particle identification devices. In this paper results from the first test of the fragmented ion beam done in 2010 will be presented showing that a pure Be beam can be obtained satisfying the needs of the experiment.