Background
Recent efficacy studies of asthma biologics have included highly enriched patient populations. Using a similar approach, we examined factors that predict response to omalizumab to ...facilitate selection of patients most likely to derive the greatest clinical benefit from therapy.
Methods
Data from two phase III clinical trials of omalizumab in patients with allergic asthma were examined. Differences in rates of asthma exacerbations between omalizumab and placebo groups during the 16‐week inhaled corticosteroid (ICS) dose‐stable phase were evaluated with respect to baseline blood eosinophil counts (eosinophils <300/μL low vs ≥300/μL high) and baseline markers of asthma severity (emergency asthma treatment in prior year, asthma hospitalization in prior year, forced expiratory volume in 1 second FEV1; FEV1 <65% vs ≥65% predicted, inhaled beclomethasone dipropionate dose <600 vs ≥600 μg/day, and long‐acting beta‐agonist LABA use yes/no).
Results
Adults/adolescents (N = 1071) were randomized to receive either omalizumab (n = 542) or placebo (n = 529). In the 16‐week ICS dose‐stable phase, rates of exacerbations requiring ≥3 days of systemic corticosteroid treatment were 0.066 and 0.147 with omalizumab and placebo, respectively, representing a relative rate reduction in omalizumab‐treated patients of 55% (95% CI, 32%‐70%; P = .002). For patients with eosinophils ≥300/μL or with more severe asthma, this rate reduction was significantly more pronounced.
Conclusion
In patients with allergic asthma, baseline blood eosinophil levels and/or clinical markers of asthma severity predict response to omalizumab.
Radiocaesium (
137Cs) was widely deposited over large areas of forest in Sweden as a result of the Chernobyl accident in 1986 and many people in Sweden eat wild fungi and game obtained from these ...contaminated forests. In terms of radioisotope accumulation in the food chain, it is well known that fungal sporocarps efficiently accumulate radiocaesium (
137Cs), as well as the alkali metals potassium (K), rubidium (Rb) and caesium (Cs). The fungi then enhance uptake of these elements into host plants. This study compared the accumulation of these three alkali metals in bulk soil, rhizosphere, soil–root interface, fungal mycelium and sporocarps of mycorrhizal fungi in a Swedish forest. The soil–root interface was found to be distinctly enriched in K and Rb compared with the bulk soil. Potassium concentrations increased in the order: bulk soil
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rhizosphere
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fungal mycelium
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soil–root interface
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fungal sporocarps; and Rb concentration in the order: bulk soil
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rhizosphere
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soil–root interface
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fungal mycelium
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fungal sporocarps. Caesium was more or less evenly distributed within the bulk soil, rhizosphere and soil–root interface fractions, but was actively accumulated by fungi. Fungi showed a greater preference for Rb and K than Cs, so the uptake of
137Cs could be prevented by providing additional Rb or K at contaminated sites. The levels of K, Rb, and Cs found in sporocarps were at least one order of magnitude higher than those in fungal mycelium. These results provide new insights into the use of transfer factors or concentration ratios. The final step, the transfer of alkali metals from fungal mycelium to sporocarps, raised some specific questions about possible mechanisms.
The impact of foliar fertilization with zinc (ZnSO4) and manganese (MnSO4 on 137Cs uptake by spring wheat and potato was studied. The experiments were conducted during 3 years (2014–2016) in ...a137Cs-contaminated area, Zhytomyr region of Ukraine. The fertilization was carried out on podzolic loamy sand soil, poor in most of the microelements. Both crops were fertilized at four successive stages of growth. Foliar application of fertilizers caused higher yield of wheat grain/straw and potato tubers yield in 2014–2015 years but had no effect in 2016. Thus, the overall effect of fertilization between 2014 and 2016 was less pronounced and generally insignificant. Application of Zn, Mn and EDTA reduced 137Cs uptake by wheat grain and potato tubers, when fertilized at earlier stages of growth and development in years 2014 and 2015 by factor 1.5–2.0, while in 2016 the effect was generally statistically insignificant. It is suggested, that reduction of 137Cs uptake by spring wheat and potato, at least partly, was caused by an effect of radionuclide dilution due to the higher biomass of the plants. A foliar spray of EDTA at earlier stages of plant growth and development may be considered as a potential countermeasure aiming reducing 137Cs uptake from soil to plants, even if such effect appeared to be conditional.
•Fertilization with Zn and Mn increases conditionally the yield of wheat and potatoes.•Fertilization on early stage growth is more effective than on later stages of growth.•Fertilization with Zn decreases 137Cs uptake for wheat grain.•Fertilization with Mn does not decrease 137Cs uptake for wheat grain.
The dry and wet deposition of radionuclides released into the atmosphere can be intercepted by vegetation in terrestrial ecosystems. The aim of this study was to quantify the interception of wet ...deposited 134Cs and 85Sr by spring oilseed rape (Brassíca napus L.) and spring wheat (Tríticum aestívum L.). The dependency of the intercepted fraction (f) on total above ground plant biomass, growing stage and the Leaf Area Index (LAI) was quantified. A trial was established in Uppsala (east central Sweden), with land management in accordance to common agricultural practices. The field trial was a randomised block design of 1 × 1 m2 parcels with three replicates. During the growing season of 2010, a rainfall simulator deposited 134Cs and 85Sr during six different growth stages. Two to 3 h after deposition, the biomass of the centre 25 × 25 cm2 area of each parcel was sampled and above ground biomass and LAI were measured. The radioactivity concentration and radioactivity of samples were measured by High Purity Germanium (HPGe)-detectors.
For 134Cs, there was a correlation between f and LAI (r2 = 0.55, p < 0.05) for spring wheat, but not for spring oilseed rape (r2 = 0.28, p > 0.05). For 85Sr, there was a correlation between f and LAI for both crops (r2 = 0.41, p < 0.05 for spring oilseed rape and r2 = 0.48 p, <0.05 for spring wheat). There was no correlation between f and above ground plant biomass in spring oilseed rape for either 134Cs (r2 = 0.01, p > 0.05) or for 85Sr (r2 = 0.11, p > 0.05). For spring wheat, there was a correlation for both 134Cs (r2 = 0.36, p < 0.05) and 85Sr (r2 = 0.32, p < 0.05). For spring oilseed rape, f was highest at growth stage ‘stem elongation’ for 134Cs (0.32 ± 0.22) and 85Sr (0.41 ± 0.29). For spring wheat, f was highest at growth stage ‘ripening’ for both radionuclides (134Cs was 0.36 ± 0.14 and 85Sr was 0.48 ± 0.18). Thus, LAI can be used to quantify interception of both radionuclides for both crops, whereas, above ground plant biomass is a weak measure of interception of wet deposited radiocaesium and radiostrontium.
► Deposition of radionuclides by artificial rain. ► Interception was more related to Leaf Area Index than to growth stage. ► Interception was highest at ripening for both crops. ► Interception was related to above ground biomass for spring wheat.
The saltatory pattern, characterized by wide and rapid oscillations of the fetal heart rate (FHR), remains a controversial entity. The authors sought to evaluate whether it could be associated with ...an adverse fetal outcome.
The authors report a case series of four saltatory patterns occurring in the last 30 minutes before birth in association with cord artery metabolic acidosis, obtained from three large databases of internally acquired FHR tracings. The distinctive characteristics of this pattern were evaluated with the aid of a computer system.
All cases were recorded in uneventful pregnancies, with normal birthweight singletons, born vaginally at term. The saltatory pattern lasted between 23 and 44 minutes, exhibited a mean oscillatory amplitude of 45.9 to 80.0 beats per minute (bpm) and a frequency between four and eight cycles per minute.
A saltatory pattern exceeding 20 minutes can be associated with the occurrence of fetal metabolic acidosis.
Biomolecular condensates concentrate macromolecules into discrete cellular foci without an encapsulating membrane. Condensates are often presumed to increase enzymatic reaction rates through ...increased concentrations of enzymes and substrates (mass action), although this idea has not been widely tested and other mechanisms of modulation are possible. Here we describe a synthetic system where the SUMOylation enzyme cascade is recruited into engineered condensates generated by liquid-liquid phase separation of multidomain scaffolding proteins. SUMOylation rates can be increased up to 36-fold in these droplets compared to the surrounding bulk, depending on substrate K
. This dependency produces substantial specificity among different substrates. Analyses of reactions above and below the phase-separation threshold lead to a quantitative model in which reactions in condensates are accelerated by mass action and changes in substrate K
, probaby due to scaffold-induced molecular organization. Thus, condensates can modulate reaction rates both by concentrating molecules and physically organizing them.
Fertilization of soils contaminated by radionuclides with potassium (K) and its effect on (137)Cs transfer from soil to crops is well studied in field conditions; however experiments over many years ...are few. The effects of potassium fertilization on cesium-137 ((137)Cs) transfer to hay, pasture grass, and barley growing on organic rich soils and mineral sand and loam soils in a number of field experimental sites situated in different environments in Sweden are summarized and discussed. The basic experimental treatments were control (no K fertilizers were applied), 50, 100, and 200 kg K ha(-1). In the experiment, which lasted over 3-6 years, (137)Cs transfer factors in control treatments ranged between 0.0004 m(2) kg(-1) (barley grain on sand soil) and 0.07 m(2) kg(-1) (pasture grass on organic rich soil). Potassium application on soils with low clay content i.e. mineral sand and organic rich soils was effective at the 50-100 kg ha(-1) level. Application of 200 kg K ha(-1) resulted in a five-fold reduction in (137)Cs transfer for hay and up to four-fold for barley grain. The effects of potassium application were generally greater on sand than organic rich soil and were observed already in the first cut. After K application, the reduction in (137)Cs transfer to crops was correlated with (137)Cs:K ratios in plant material. Additional application of zeolite caused a 1.4 reduction of (137)Cs transfer to hay on sand and 1.8-fold reduction on organic rich soil; whereas, application of potash-magnesia and CaO had no effect.
Contamination levels on potato foliage and tubers were investigated by repeated sampling after multiple foliar contaminations of wet-deposited (134)Cs at five different growth stages in a micro-plot ...field experiment in three successive years. Application of the radionuclide early in the growing season (deposition date 19-27 June, growth stage II = plant establishment) resulted in low (134)Cs activity concentration in potato tubers across sampling occasions (mean 60, 25 and 115 Bq kg(-1) dry weight (D.W.) for years 1, 2 and 3, respectively). Following radionuclide deposition in the middle of the growing season (15-24 July, growth stage III = tuber initiation), (134)Cs activity concentration in tubers across sampling occasions was found to be highest (mean 150, 850 and 660 Bq kg(-1) D.W. for years 1, 2 and 3, respectively). When the radionuclide was sprayed on at later stages (5-7 August, growth stage IV = tuber bulking), (134)Cs activity concentrations in tubers across sampling dates decreased (mean 75, 310 and 395 Bq kg(-1) D.W. for years 1, 2 and 3, respectively). Deposition in the second half of August (15-28 August, late growth stage IV and beginning of growth stage V = tuber maturation) resulted in yet lower (134)Cs activity concentration in tubers. Potato tubers may concentrate as much as up to 2 times more (134)Cs than foliage depending on deposition date of radionuclide.
Eukaryotic cells possess numerous dynamic membrane-less organelles, RNP granules, enriched in RNA and RNA-binding proteins containing disordered regions. We demonstrate that the disordered regions of ...key RNP granule components and the full-length granule protein hnRNPA1 can phase separate in vitro, producing dynamic liquid droplets. Phase separation is promoted by low salt concentrations or RNA. Over time, the droplets mature to more stable states, as assessed by slowed fluorescence recovery after photobleaching and resistance to salt. Maturation often coincides with formation of fibrous structures. Different disordered domains can co-assemble into phase-separated droplets. These biophysical properties demonstrate a plausible mechanism by which interactions between disordered regions, coupled with RNA binding, could contribute to RNP granule assembly in vivo through promoting phase separation. Progression from dynamic liquids to stable fibers may be regulated to produce cellular structures with diverse physiochemical properties and functions. Misregulation could contribute to diseases involving aberrant RNA granules.
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•Intrinsically disordered regions (IDRs) of RNA-binding proteins can phase separate•RNA, crowding agents, and low salt promote IDR phase separation•Phase-separated droplets stabilize over time by formation of amyloid-like fibers•Multiple IDRs can be recruited to phase-separated droplets
Lin et al. show that numerous intrinsically disordered regions of RNA-binding proteins can phase separate to form liquid droplets, which become less dynamic over time through formation of amyloid-like fibers. This defines a process by which cells could establish and maintain RNP granules with different physical properties.
Biomolecular condensates are found throughout eukaryotic cells, including in the nucleus, in the cytoplasm and on membranes. They are also implicated in a wide range of cellular functions, organizing ...molecules that act in processes ranging from RNA metabolism to signalling to gene regulation. Early work in the field focused on identifying condensates and understanding how their physical properties and regulation arise from molecular constituents. Recent years have brought a focus on understanding condensate functions. Studies have revealed functions that span different length scales: from molecular (modulating the rates of chemical reactions) to mesoscale (organizing large structures within cells) to cellular (facilitating localization of cellular materials and homeostatic responses). In this Roadmap, we discuss representative examples of biochemical and cellular functions of biomolecular condensates from the recent literature and organize these functions into a series of non-exclusive classes across the different length scales. We conclude with a discussion of areas of current interest and challenges in the field, and thoughts about how progress may be made to further our understanding of the widespread roles of condensates in cell biology.
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