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Die Synthese des Coenzymmodells Flavin-benzimidazol-dinucleotid * gelang durch Kondensation von Benzimidazolribotid-imidazolid 1 oder Benzimidazolribotid-guanidiniumamidat 2 mit Flavinmononucleotid. Das Coenzymmodell war enzymatisch nicht aktiv und bildete keinen Enzym-Coenzym-Komplex. Im Absorptionsspektrum konnte eine Extinktionszunahme nach der Spaltung der Pyrophosphatbrücke nur im Bereich von 260 mμ beobachtet werden. Das Molekül liegt daher vermutlich in einer gefalteten Form vor. Ein Komplex zwischen Flavin- und Benzimidazolteil konnte nicht nachgewiesen werden. Eine Fluoreszenzunterdrückung, die im FAD durch die Komplexbildung zwischen Flavin- und Adeninteil bedingt wird, wurde im FBD-Coenzymmodell nicht beobachtet.
Mechanisms by which subvisible cirrus clouds (SVCs) might contribute to dehydration close to the tropical tropopause are not well understood. Recently Ultrathin Tropical Tropopause Clouds (UTTCs) with optical depths around 10-4 have been detected in the western Indian ocean. These clouds cover thousands of square kilometers as 200-300 m thick distinct and homogeneous layer just below the tropical tropopause. In their condensed phase UTTCs contain only 1-5% of the total water, and essentially no nitric acid. A new cloud stabilization mechanism is required to explain this small fraction of the condensed water content in the clouds and their small vertical thickness. This work suggests a mechanism, which forces the particles into a thin layer, based on upwelling of the air of some mm/s to balance the ice particles, supersaturation with respect to ice above and subsaturation below the UTTC. In situ measurements suggest that these requirements are fulfilled. The basic physical properties of this mechanism are explored by means of a single particle model. Comprehensive 1-D cloud simulations demonstrate this stabilization mechanism to be robust against rapid temperature fluctuations of +/- 0.5 K. However, rapid warming (Delta T > 2 K) leads to evaporation of the UTTC, while rapid cooling (Delta T < -2 K) leads to destabilization of the particles with the potential for significant dehydration below the cloud
Background: The flavin in its FMN and FAD forms is a versatile cofactor that is involved in catalysis of most disparate types of biological reactions. These include redox reactions such as dehydrogenations, activation of dioxygen, electron transfer, bioluminescence, blue light reception, photobiochemistry (as in photolyases), redox signaling etc. Recently, hitherto unrecognized types of biological reactions have been uncovered that do not involve redox shuffles, and might involve the reduced form of the flavin as a catalyst. The present work addresses properties of reduced flavin relevant in this context. Results: N(5)-H exchange reactions of the flavin reduced form and its pH dependence were studied using the 15N-NMR-signals of 15N-enriched, reduced flavin in the pH range from 5 to 12. The chemical shifts of the N(3) and N(5) resonances are not affected to a relevant extent in this pH range. This contrasts with the multiplicity of the N(5)-resonance, which strongly depends on pH. It is a doublet between pH 8.45 and 10.25 that coalesces into a singlet at lower and higher pH values. From the line width of the 15N(5) signal the pH-dependent rate of hydrogen exchange was deduced. The multiplicity of the 15N(5) signal and the proton exchange rates are little dependent on the buffer system used. Conclusion: The exchange rates allow an estimation of the pKa value of N(5)-H deprotonation in reduced flavin to be ≥ 20. This value imposes specific constraints for mechanisms of flavoprotein catalysis based on this process. On the other hand the pK ≈ 4 for N(5)-H protonation (to form N(5)+-H2) would be consistent with a role of N(5)-H as a base.
The solution structure of the lantibiotic immunity protein NisI and its interactions with nisin
(2015)
Many Gram-positive bacteria produce lantibiotics, genetically encoded and posttranslationally modified peptide antibiotics, which inhibit the growth of other Gram-positive bacteria. To protect themselves against their own lantibiotics these bacteria express a variety of immunity proteins including the LanI lipoproteins. The structural and mechanistic basis for LanI-mediated lantibiotic immunity is not yet understood. Lactococcus lactis produces the lantibiotic nisin, which is widely used as a food preservative. Its LanI protein NisI provides immunity against nisin but not against structurally very similar lantibiotics from other species such as subtilin from Bacillus subtilis. To understand the structural basis for LanI-mediated immunity and their specificity we investigated the structure of NisI. We found that NisI is a two-domain protein. Surprisingly, each of the two NisI domains has the same structure as the LanI protein from B. subtilis, SpaI, despite the lack of significant sequence homology. The two NisI domains and SpaI differ strongly in their surface properties and function. Additionally, SpaI-mediated lantibiotic immunity depends on the presence of a basic unstructured N-terminal region that tethers SpaI to the membrane. Such a region is absent from NisI. Instead, the N-terminal domain of NisI interacts with membranes but not with nisin. In contrast, the C-terminal domain specifically binds nisin and modulates the membrane affinity of the N-terminal domain. Thus, our results reveal an unexpected structural relationship between NisI and SpaI and shed light on the structural basis for LanI mediated lantibiotic immunity.
Background: To investigate whether patients with critical emergency conditions are seeking or receiving the medical care that they require we characterized the reality of care for patients presenting with Neuro-emergencies during the first phase of the COVID-19 pandemic.
Methods: In this observational, longitudinal cohort study, all neurosurgical admissions that presented to our Department between February 1st and April 15th during the COVID-19 pandemic and during the same time-period in 2019 were identified and categorized according to the presence of a Neuro-emergency, the route of admission, management, and the category of disease. Further, the clinical course of patients with chronic subdural hematoma (cSDH) was investigated as a Neuro-emergency representative for a wide variety of semi-urgent symptoms.
Results: During the pandemic, the percentage of Neuro-emergencies among all neurosurgical admissions remained similar as in 2019 but a larger proportion presented through the emergency department than through the outpatient clinic or by referral (*p=0.009). The total number of Neuro-emergencies was significantly reduced (*p=0.0007) across all types of disease, particularly in severe vascular (*p=0.036) but also in spinal (*p=0.007) and hydrocephalus (*p=0.048) emergencies. Strikingly, elderly patients with cSDH and mild to moderate symptoms presented less frequently, with more severe symptoms (*p=0.046) and were less likely to reach favorable outcome (*p=0.003).
Conclusions: Despite pandemic-related restrictive measures and reallocation of resources, patients with Neuro-emergencies should be encouraged to present regardless of the severity of symptoms because deferred presentation may result in adverse outcome. Thus, conservation of critical healthcare resources remains essential in spite fighting COVID-19.
When a visual stimulus is repeated, average neuronal responses typically decrease, yet they might maintain or even increase their impact through increased synchronization. Previous work has found that many repetitions of a grating lead to increasing gamma-band synchronization. Here, we show in awake macaque area V1 that both repetition-related reductions in firing rate and increases in gamma are specific to the repeated stimulus. These effects show some persistence on the timescale of minutes. Gamma increases are specific to the presented stimulus location. Further, repetition effects on gamma and on firing rates generalize to images of natural objects. These findings support the notion that gamma-band synchronization subserves the adaptive processing of repeated stimulus encounters.
Poster presentation: Purpose of the study To compare the virological, immunological and clinical response to three boosted double protease inhibitor (PI) regimens of saquinavir and ritonavir in combination with lopinavir (LOPSAQ), atazanavir (ATSAQ) or fosamprenavir (FOSAQ) without reverse transcriptase inhibitors (RTI) in HIV-positive patients with limited RTI treatment options. ...
When a visual stimulus is repeated, average neuronal responses typically decrease, yet they might maintain or even increase their impact through increased synchronization. Previous work has found that many repetitions of a grating lead to increasing gamma-band synchronization. Here we show in awake macaque area V1 that both, repetition-related reductions in firing rate and increases in gamma are specific to the repeated stimulus. These effects showed some persistence on the timescale of minutes. Further, gamma increases were specific to the presented stimulus location. Importantly, repetition effects on gamma and on firing rates generalized to natural images. These findings suggest that gamma-band synchronization subserves the adaptive processing of repeated stimulus encounters, both for generating efficient stimulus responses and possibly for memory formation.
The production of Σ0 baryons in the nuclear reaction p (3.5 GeV) + Nb (corresponding to sNN=3.18 GeV) is studied with the detector set-up HADES at GSI, Darmstadt. Σ0s were identified via the decay Σ0→Λγ with subsequent decays Λ→pπ− in coincidence with a e+e− pair from either external (γ→e+e−) or internal (Dalitz decay γ⁎→e+e−) gamma conversions. The differential Σ0 cross section integrated over the detector acceptance, i.e. the rapidity interval 0.5<y<1.1, has been extracted as ΔσΣ0=2.3±(0.2)stat±(−0.6+0.6)sys±(0.2)norm mb, yielding the inclusive production cross section in full phase space σΣ0total=5.8±(0.5)stat±(−1.4+1.4)sys±(0.6)norm±(1.7)extrapol mb by averaging over different extrapolation methods. The Λall/Σ0 ratio within the HADES acceptance is equal to 2.3±(0.2)stat±(−0.6+0.6)sys. The obtained rapidity and momentum distributions are compared to transport model calculations. The Σ0 yield agrees with the statistical model of particle production in nuclear reactions. Keywords: Hyperons, Strangeness, Proton, Nucleus.
The new heavy ion superconducting continuous wave HElmholtz LInear ACcelerator (HELIAC) is under construction at GSI. A normal conducting injector, comprising an ECR ion source, an RFQ and a DTL, is recently in development. The new Interdigital H-mode DTL, presented in this paper, accelerates the heavy ion beam from 300 to 1400 keV/u, applying an Alternating Phase Focusing (APF) beam dynamics scheme. This APF section, consisting of two separately controlled tanks, has to provide for stable routine operation with assistance of dedicated beam diagnostics devices in the Intertank section. The installed quadrupole lenses and beam steerers installed there ensure full transmission in a wide range of input beam parameters.
New neutron cross section measurements of minor actinides have been performed recently in order to reduce the uncertainties in the evaluated data, which is important for the design of advanced nuclear reactors and, in particular, for determining their performance in the transmutation of nuclear waste. We have measured the 241Am(n,γ) cross section at the n_TOF facility between 0.2 eV and 10 keV with a BaF2 Total Absorption Calorimeter, and the analysis of the measurement has been recently concluded. Our results are in reasonable agreement below 20 eV with the ones published by C. Lampoudis et al. in 2013, who reported a 22% larger capture cross section up to 110 eV compared to experimental and evaluated data published before. Our results also indicate that the 241Am(n,γ) cross section is underestimated in the present evaluated libraries between 20 eV and 2 keV by 25%, on average, and up to 35% for certain evaluations and energy ranges.
The accuracy on neutron capture cross section of fissile isotopes must be improved for the design of future nuclear systems such as Gen-IV reactors and Accelerator Driven Systems. The High Priority Request List of the Nuclear Energy Agency, which lists the most important nuclear data requirements, includes also the neutron capture cross sections of fissile isotopes such as 233,235U and 239,241Pu. A specific experimental setup has been used at the CERN n_TOF facility for the measurement of the neutron capture cross section of 235U by a set of micromegas fission detectors placed inside a segmented BaF2 Total Absorption Calorimeter.
A new technique developed for measuring nuclear reactions at low momentum transfer with stored beams in inverse kinematics was successfully used to study isoscalar giant resonances. The experiment was carried out at the experimental heavy-ion storage ring (ESR) at the GSI facility using a stored 58Ni beam at 100 MeV/u and an internal helium gas-jet target. In these measurements, inelastically scattered α-recoils at very forward center-of-mass angles (θcm ≤ 1.5°) were detected with a dedicated setup, including ultra-high vacuum compatible detectors. Experimental results indicate a dominant contribution of the isoscalar giant monopole resonance at this very forward angular range. It was found that the monopole contribution exhausts 79+12−11% of the energy-weighted sum rule (EWSR), which agrees with measurements performed in normal kinematics. This opens up the opportunity to investigate the giant resonances in a large domain of unstable and exotic nuclei in the near future. It is a fundamental milestone towards new nuclear reaction studies with stored ion beams.
A wide variety of enzymatic pathways that produce specialized metabolites in bacteria, fungi and plants are known to be encoded in biosynthetic gene clusters. Information about these clusters, pathways and metabolites is currently dispersed throughout the literature, making it difficult to exploit. To facilitate consistent and systematic deposition and retrieval of data on biosynthetic gene clusters, we propose the Minimum Information about a Biosynthetic Gene cluster (MIBiG) data standard.
Background: SNPs near the interferon lambda (IFNL) 3 gene are predictors for sustained virological response (SVR) in patients with chronic hepatitis C genotype (GT) 1. In addition, a dinucleotide frame shift in ss469415590 was described, which generates IFNL4. In this study, we compared the role of IFNL4 variants with IFNL3-(rs12979860) and IFNL3-(rs8099917) on response to pegylated (PEG)-IFN and Ribavirin (RBV) in patients with chronic hepatitis C GT2/3.
Methods: We recruited 1006 patients with chronic hepatitis C and GT2/3 in a large German registry. A treatment with PEG-IFN and Ribavirin was started by 959 patients. We performed genotyping of IFNL3 (rs12979860, n = 726; rs8099917, n = 687) and of IFNL4 (ss469415590; n = 631).
Results: Both preferable IFNL3 genotypes were associated with RVR (both p<0.0001) rather than with SVR (rs12979860: p = 0.251; rs8099917: p = 0.447). Only RVR was linked to SVR in univariate and multivariate analyzes (both p<0.001). Concordance of genotyping in patients with available serum samples and EDTA blood samples (n = 259) was more than 96% for both IFNL3 SNPs. IFNL3-(rs12979860) correlated with IFNL4: 99.2% of patients with IFNL3-(rs12979860)-CC were IFNL4-(ss469415590)-TT/TT. IFNL3-(rs12979860)-CT was linked with IFNL4-(ss469415590)-TT/ΔG (98.0%) and IFNL3-(rs12979860)-TT was associated with IFNL4-(ss469415590)-ΔG/ΔG (97.6%).
Conclusion: IFNL3 genotyping from serum was highly efficient and can be used as an alternative if EDTA whole blood is not available. In Caucasian GT2/3 patients genotyping for INFL4-(ss469415590) does not lead to additional information for the decision-making process. Importantly, IFNL3 SNPs were not associated with SVR but with RVR. Even in the era of new direct acting antiviral (DAA) therapies, IFNL3 testing may therefore still be considered for naïve GT2/3 patients to decide if dual Peg-IFN/RBV therapy is an option in resource limited regions.
Simple Summary: Renal insufficiency is frequently seen in newly diagnosed multiple myeloma and can be due to the disease itself but also caused by medical interventions or infections. Patients with severe renal insufficiency are known to have an adverse prognosis, but recently, it was shown that even moderately impaired kidney function can have long-term sequelae. Achieving quick disease control by effective antimyeloma therapy can lead to the recovery of renal function. We investigated the kidney-specific variables in a large cohort of 770 myeloma patients receiving three different three-drug regimens for initial myeloma treatment to learn more about the differential effects on kidney function in an early disease phase. All regimens had a positive impact on kidney function without a difference in the proportion of patients who reached normal renal function after three cycles. Interestingly, patients who received bortezomib, lenalidomide, and dexamethasone tended to have higher risk for a worse renal function following induction when compared to the initial values.
Abstract: Background: Preservation of kidney function in newly diagnosed (ND) multiple myeloma (MM) helps to prevent excess toxicity. Patients (pts) from two prospective trials were analyzed, provided postinduction (PInd) restaging was performed. Pts received three cycles with bortezomib (btz), cyclophosphamide, and dexamethasone (dex; VCD) or btz, lenalidomide (len), and dex (VRd) or len, adriamycin, and dex (RAD). The minimum required estimated glomerular filtration rate (eGFR) was >30 mL/min. We analyzed the percent change of the renal function using the International Myeloma Working Group (IMWG) criteria and Kidney Disease: Improving Global Outcomes (KDIGO)-defined categories. Results: Seven hundred and seventy-two patients were eligible. Three hundred and fifty-six received VCD, 214 VRd, and 202 RAD. VCD patients had the best baseline eGFR. The proportion of pts with eGFR <45 mL/min decreased from 7.3% at baseline to 1.9% PInd (p < 0.0001). Thirty-seven point one percent of VCD versus 49% of VRd patients had a decrease of GFR (p = 0.0872). IMWG-defined “renal complete response (CRrenal)” was achieved in 17/25 (68%) pts after VCD, 12/19 (63%) after RAD, and 14/27 (52%) after VRd (p = 0.4747). Conclusions: Analyzing a large and representative newly diagnosed myeloma (NDMM) group, we found no difference in CRrenal that occurred independently from the myeloma response across the three regimens. A trend towards deterioration of the renal function with VRd versus VCD may be explained by a better pretreatment “renal fitness” in the latter group.
Background: Different parameters have been determined for prediction of treatment outcome in hepatitis c virus genotype 1 infected patients undergoing pegylated interferon, ribavirin combination therapy. Results on the importance of vitamin D levels are conflicting. In the present study, a comprehensive analysis of vitamin D levels before and during therapy together with single nucleotide polymorphisms involved in vitamin D metabolism in the context of other known treatment predictors has been performed.
Methods: In a well characterized prospective cohort of 398 genotype 1 infected patients treated with pegylated interferon-α and ribavirin for 24–72 weeks (INDIV-2 study) 25-OH-vitamin D levels and different single nucleotide polymorphisms were analyzed together with known biochemical parameters for a correlation with virologic treatment outcome.
Results: Fluctuations of more than 5 (10) ng/ml in 25-OH-vitamin D-levels have been observed in 66 (39) % of patients during the course of antiviral therapy and neither pretreatment nor under treatment 25-OH-vitamin D-levels were associated with treatment outcome. The DHCR7-TT-polymorphism within the 7-dehydrocholesterol-reductase showed a significant association (P = 0.031) to sustained viral response in univariate analysis. Among numerous further parameters analyzed we found that age (OR = 1.028, CI = 1.002–1.056, P = 0.035), cholesterol (OR = 0.983, CI = 0.975–0.991, P<0.001), ferritin (OR = 1.002, CI = 1.000–1.004, P = 0.033), gGT (OR = 1.467, CI = 1.073–2.006, P = 0.016) and IL28B-genotype (OR = 2.442, CI = 1.271–4.695, P = 0.007) constituted the strongest predictors of treatment response.
Conclusions: While 25-OH-vitamin D-levels levels show considerable variations during the long-lasting course of antiviral therapy they do not show any significant association to treatment outcome in genotype 1 infected patients.
Background and Aims: In patients with advanced liver cirrhosis due to chronic hepatitis C virus (HCV) infection antiviral therapy with peginterferon and ribavirin is feasible in selected cases only due to potentially life-threatening side effects. However, predictive factors associated with hepatic decompensation during antiviral therapy are poorly defined.
Methods: In a retrospective cohort study, 68 patients with HCV-associated liver cirrhosis (mean MELD score 9.18±2.72) were treated with peginterferon and ribavirin. Clinical events indicating hepatic decompensation (onset of ascites, hepatic encephalopathy, upper gastrointestinal bleeding, hospitalization) as well as laboratory data were recorded at baseline and during a follow up period of 72 weeks after initiation of antiviral therapy. To monitor long term sequelae of end stage liver disease an extended follow up for HCC development, transplantation and death was applied (240weeks, ±SD 136weeks).
Results: Eighteen patients (26.5%) achieved a sustained virologic response. During the observational period a hepatic decompensation was observed in 36.8%. Patients with hepatic decompensation had higher MELD scores (10.84 vs. 8.23, p<0.001) and higher mean bilirubin levels (26.74 vs. 14.63 µmol/l, p<0.001), as well as lower serum albumin levels (38.2 vs. 41.1 g/l, p = 0.015), mean platelets (102.64 vs. 138.95/nl, p = 0.014) and mean leukocytes (4.02 vs. 5.68/nl, p = 0.002) at baseline as compared to those without decompensation. In the multivariate analysis the MELD score remained independently associated with hepatic decompensation (OR 1.56, 1.18–2.07; p = 0.002). When the patients were grouped according to their baseline MELD scores, hepatic decompensation occurred in 22%, 59%, and 83% of patients with MELD scores of 6–9, 10–13, and >14, respectively. Baseline MELD score was significantly associated with the risk for transplantation/death (p<0.001).
Conclusions: Our data suggest that the baseline MELD score predicts the risk of hepatic decompensation during antiviral therapy and thus contributes to decision making when antiviral therapy is discussed in HCV patients with advanced liver cirrhosis.
Androgen receptor deregulation drives bromodomain-mediated chromatin alterations in prostate cancer
(2017)
Global changes in chromatin accessibility may drive cancer progression by reprogramming transcription factor (TF) binding. In addition, histone acetylation readers such as bromodomain-containing protein 4 (BRD4) have been shown to associate with these TFs and contribute to aggressive cancers including prostate cancer (PC). Here, we show that chromatin accessibility defines castration-resistant prostate cancer (CRPC). We show that the deregulation of androgen receptor (AR) expression is a driver of chromatin relaxation and that AR/androgen-regulated bromodomain-containing proteins (BRDs) mediate this effect. We also report that BRDs are overexpressed in CRPCs and that ATAD2 and BRD2 have prognostic value. Finally, we developed gene stratification signature (BROMO-10) for bromodomain response and PC prognostication, to inform current and future trials with drugs targeting these processes. Our findings provide a compelling rational for combination therapy targeting bromodomains in selected patients in which BRD-mediated TF binding is enhanced or modified as cancer progresses.
Preclinical studies point to a pivotal role of the orexin 1 (OX1) receptor in arousal and fear learning and therefore suggest the HCRTR1 gene as a prime candidate in panic disorder (PD) with/without agoraphobia (AG), PD/AG treatment response, and PD/AG-related intermediate phenotypes. Here, a multilevel approach was applied to test the non-synonymous HCRTR1 C/T Ile408Val gene variant (rs2271933) for association with PD/AG in two independent case-control samples (total n = 613 cases, 1839 healthy subjects), as an outcome predictor of a six-weeks exposure-based cognitive behavioral therapy (CBT) in PD/AG patients (n = 189), as well as with respect to agoraphobic cognitions (ACQ) (n = 483 patients, n = 2382 healthy subjects), fMRI alerting network activation in healthy subjects (n = 94), and a behavioral avoidance task in PD/AG pre- and post-CBT (n = 271). The HCRTR1 rs2271933 T allele was associated with PD/AG in both samples independently, and in their meta-analysis (p = 4.2 × 10−7), particularly in the female subsample (p = 9.8 × 10−9). T allele carriers displayed a significantly poorer CBT outcome (e.g., Hamilton anxiety rating scale: p = 7.5 × 10−4). The T allele count was linked to higher ACQ sores in PD/AG and healthy subjects, decreased inferior frontal gyrus and increased locus coeruleus activation in the alerting network. Finally, the T allele count was associated with increased pre-CBT exposure avoidance and autonomic arousal as well as decreased post-CBT improvement. In sum, the present results provide converging evidence for an involvement of HCRTR1 gene variation in the etiology of PD/AG and PD/AG-related traits as well as treatment response to CBT, supporting future therapeutic approaches targeting the orexin-related arousal system.