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Purpose Immune-checkpoint inhibitors (ICI) present a new treatment for malignancies by boosting the immune system. This has led to a variety of immune-related adverse events, including ICI-associated pneumonitis (ICIaP). Diagnosis thereof is often challenging, and its pathogenesis has not yet been fully understood. The aim of this cross-sectional case–control study was to investigate cytokines in serum and bronchoalveolar lavage fluid (BALF) expressed in patients with ICIaP compared to controls consisting of healthy individuals, patients with lung cancer and patients with interstitial lung diseases (ILD) other than ICIaP. Methods From January 2018 until June 2019, 401 adult patients with various lung diseases were prospectively enrolled in a BALF- and serum biobank, called BALOTHEK. Of these, 12 patients were diagnosed with ICIaP (Pembrolizumab, Ipilimumab, or both, and Durvalumab) serving as case group. Subjects with one of three diagnosis groups from BALOTHEK, including lung cancer, ILD other than ICIaP, and healthy individuals, served as matched controls. The following 11 cytokines were simultaneously analyzed in BALF and serum of each study participant: interferon gamma, tumor necrosis factor alpha, interleukin (IL) 1b, IL-2, IL-4, IL-5, IL-6, IL-8, IL-12p70, IL-13 and IL-17A. This study was approved by the local ethic review committee (BASEC-ID 2017-02,307 and 2018-01,724). Results Absolute number and percentage of lymphocytes in BALF of patients with ICIaP were significantly higher compared to control groups. For the investigated cytokines in BALF, a significant increase of IL-6 level was shown for patients with ICIaP compared to control groups (p = 0.031, adjusted for multiple comparisons). Conclusion Cytokine profile assessed in BALF shows promising potential for facilitating diagnosis and understanding of pathophysiology of ICIaP. IL-6 may not only contribute to better understanding of pathophysiology but also herald therapeutic implications for Tocilizumab.

Quinolinic acid (QUIN) is an agonist of the neurotransmitter glutamate (Glu) capable of binding to N-methyl-D-aspartate receptors (NMDAR) increasing glutamatergic signaling. QUIN is known for being an endogenous neurotoxin, able to induce neurodegeneration. In Caenorhabditis elegans, the mechanism by which QUIN induces behavioral and metabolic toxicity has not been fully elucidated. The effects of QUIN on behavioral and metabolic parameters in nmr-1 and nmr-2 NMDA receptors in transgenic and wild-type (WT) worms were performed to decipher the pathway by which QUIN exerts its toxicity. QUIN increased locomotion parameters such as wavelength and movement amplitude medium, as well as speed and displacement, without modifying the number of body bends in an NMDAR-dependent-manner. QUIN increased the response time to the chemical stimulant 1-octanol, which is modulated by glutamatergic neurotransmission in the ASH neuron. Brood size increased after exposure to QUIN, dependent upon nmr-2/NMDA-receptor, with no change in lifespan. Oxygen consumption, mitochondrial membrane potential, and the flow of coupled and unbound electrons to ATP production were reduced by QUIN in wild-type animals, but did not alter citrate synthase activity, altering the functionality but the mitochondrial viability. Notably, QUIN modified fine locomotor and chemosensory behavioral parameters, as well as metabolic parameters, analogous to previously reported effects in mammals. Our results indicate that QUIN can be used as a neurotoxin to elicit glutamatergic dysfunction in C. elegans in a way analogous to other animal models.

Huntington's disease (HD) is an autosomal dominant, progressive neurodegenerative disease. It occurs due to a mutated huntingtin gene that contains an abnormal expansion of cytosine-adenine-guanine repeats, leading to a variable-length N-terminal polyglutamine (polyQ) chain. The mutation confers toxic functions to mutant huntingtin protein, causing neurodegeneration. Rutin is a flavonoid found in various plants, such as buckwheat, some teas, and apples. Our previous studies have indicated that rutin has protective effects in HD models, but more studies are needed to unravel its effects on protein homeostasis, and to discern the underlying mechanisms. In the present study, we investigated the effects of rutin in a Caenorhabditis elegans model of HD, focusing on ASH neurons and antioxidant defense. We tested behavioral changes (touch response, movement, and octanol response), measured neuronal polyQ aggregates, and assessed degeneration using a dye-filling assay. In addition, we analyzed expression levels of heat-shock protein-16.2 and superoxide dismutase-3. Overall, our data demonstrate that chronic rutin treatment maintains the function of ASH neurons, and decreases the degeneration of their sensory terminations. We propose that rutin does so in a mechanism that involves antioxidant activity by controlling the expression of antioxidant enzymes and other chaperones regulating proteostasis. Our findings provide new evidence of rutin's potential neuroprotective role in the C. elegans model and should inform treatment strategies for neurodegenerative diseases and other diseases caused by age-related protein aggregation.

As multifunctional catalytic hemoglobins, dehaloperoxidase isoenzymes A and B (DHP A and B) are among the most versatile hemoproteins in terms of activities displayed. The ability of DHP to bind over twenty different substrates in the distal pocket might appear to resemble the promiscuousness of monooxygenase enzymes, yet there are identifiable substrate-specific interactions that can steer the type of oxidation (O-atom vs. electron transfer) that occurs inside the DHP distal pocket. Here, we have investigated the DHP A(V59W) mutant in order to probe the limits of conformational flexibility in the distal pocket as it relates to the genesis of this substrate-dependent activity differentiation. The X-ray crystal structure of the metaquo DHP A(V59W) mutant (PDB 3K3U) and the V59W mutant in complex with fluoride [denoted as DHP A(V59W-F)] (PDB 7MNH) show significant mobility of the tryptophan in the distal pocket, with two parallel conformations having W59-N[Formula: see text] H-bonded to a heme-bound ligand (H2O or F[Formula: see text], and another conformation [observed only in DHP A(V59W-F)] that brings W59 sufficiently close to the heme as to preclude axial ligand binding. UV-vis and resonance Raman spectroscopic studies show that DHP A(V59W) is 5-coordinate high spin (5cHS) at pH 5 and 6-coordinate high spin (6cHS) at pH 7, whereas DHP A(V59W-F) is 6cHS from pH 5 to 7. Enzyme assays confirm robust peroxidase activity at pH 5, but complete loss of activity at pH 7. We find no evidence that tryptophan plays a role in the oxidation mechanism ([Formula: see text]. radical formation). Instead, the data reveal a new mechanism of DHP inhibition, namely a shift towards a non-reactive form by OH[Formula: see text] ligation to the heme-Fe that is strongly stabilized (presumably through H-bonding interactions) by the presence of W59 in the distal cavity.

The HV1 voltage‐gated proton (HV1) channel is a key component of the cellular proton extrusion machinery and is pivotal for charge compensation during the respiratory burst of phagocytes. The best‐described physiological inhibitor of HV1 is Zn2+. Externally applied ZnCl2 drastically reduces proton currents reportedly recorded in Homo sapiens, Rattus norvegicus, Mus musculus, Oryctolagus cuniculus, Rana esculenta, Helix aspersa, Ciona intestinalis, Coccolithus pelagicus, Emiliania huxleyi, Danio rerio, Helisoma trivolvis, and Lingulodinium polyedrum, but with considerable species variability. Here, we report the effects of Zn2+ and Cd2+ on HV1 from Nicoletia phytophila, NpHV1. We introduced mutations at potential Zn2+ coordination sites and measured Zn2+ inhibition in different extracellular pH, with Zn2+ concentrations up to 1000 μm. Zn2+ inhibition in NpHV1 was quantified by the slowing of the activation time constant and a positive shift of the conductance–voltage curve. Replacing aspartate in the S3‐S4 loop with histidine (D145H) enhanced both the slowing of activation kinetics and the shift in the voltage–conductance curve, such that Zn2+ inhibition closely resembled that of the human channel. Histidine is much more effective than aspartate in coordinating Zn2+ in the S3‐S4 linker. A simple Hodgkin Huxley model of NpHV1 suggests a decrease in the opening rate if it is inhibited by zinc or cadmium. Limiting slope measurements and high‐resolution clear native gel electrophoresis (hrCNE) confirmed that NpHV1 functions as a dimer. The data support the hypothesis that zinc is coordinated in between the dimer instead of the monomer. Zinc coordination sites may be potential targets for drug development., Zinc is bound or coordinated by numerous enzymes. However, the amino acids, involved in zinc coordination, differ between the proteins. Zinc inhibition of the insect voltage‐gated proton channel (NpHV1) suggests binding at the dimer interface. Zinc competes with protons and is interlocking both monomers in a nonconductive state. The mechanism of inhibition is a nonelectrostatic binding and not a block of the proton permeation pathway through the channel.

International journal of metalcasting : IJMC (2020). doi:10.1007/s40962-020-00412-7, Published by AFS, Schaumburg, Ill.

The development of sensory circuits is partially guided by sensory experience. In the medial superior olive (MSO), these refinements generate precise coincidence detection to localize sounds in the azimuthal plane. Glycinergic inhibitory inputs to the MSO, which tune the sensitivity to interaural time differences, undergo substantial structural and functional refinements after hearing onset. Whether excitation and calcium signaling in the MSO are similarly affected by the onset of acoustic experience is unresolved. To assess the time window and mechanism of excitatory and calcium-dependent refinements during late postnatal development, we quantified EPSCs and calcium entry in MSO neurons of Mongolian gerbils of either sex raised in a normal and in an activity altered, omnidirectional white noise environment. Global dendritic calcium transients elicited by action potentials disappeared rapidly after hearing onset. Local synaptic calcium transients decreased, leaving a GluR2 lacking AMPAR-mediated influx as the only activity-dependent source in adulthood. Exposure to omnidirectional white noise accelerated the decrease in calcium entry, leaving membrane properties unaffected. Thus, sound-driven activity accelerates the excitatory refinement and shortens the period of activity-dependent calcium signaling around hearing onset. Together with earlier reports, our findings highlight that excitation, inhibition, and biophysical properties are differentially sensitive to distinct features of sensory experience.SIGNIFICANCE STATEMENTNeurons in the medial superior olive, an ultra-fast coincidence detector for sound source localization, acquire their specialized function through refinements during late postnatal development. The refinement of inhibitory inputs that convey sensitivity to relevant interaural time differences is instructed by the experience of sound localization cues. Which cues instruct the refinement of excitatory inputs, calcium signaling, and biophysical properties is unknown. Here we demonstrate a time window for activity- and calcium-dependent refinements limited to shortly after hearing onset. Exposure to omnidirectional white noise, which suppresses sound localization cues but increases overall activity, accelerates the refinement of calcium signaling and excitatory inputs without affecting biophysical membrane properties. Thus, the refinement of excitation, inhibition, and intrinsic properties is instructed by distinct cues.

International journal of molecular sciences 22(17), 9306 (2021). doi:10.3390/ijms22179306 special issue: "Special Issue "Hematopoietic Stem Cells, Metabolic Regulations, and Aging" / Special Issue Editors: Prof. Dr. Anthony Dick Ho, Guest Editor; Prof. Dr. Toshio Suda, Guest Editor", Published by Molecular Diversity Preservation International, Basel

Kaltofen and colleagues criticize our use of the rate of production of epoxides per unit lung volume as the dose metric when we used a PBPK model of chloroprene to provide risk assessments for lung...

Ilex paraguariensis is a plant from South America, used to prepare a tea-like beverage rich in caffeine and polyphenols with antioxidant proprieties. Caffeine consumption is associated with a lower risk of age-associated neuropathologies, besides several extracts that have antioxidant proprieties are known to be neuroprotective, and oxidative stress strongly correlates with Aβ-toxicity. This study aims to investigate the neuroprotective effects of the Ilex paraguariensis hydroalcoholic extract (IPHE) and to evaluate if caffeine agent present in IPHE exerts neuroprotective effects in an amyloid beta-peptide (Aβ)-induced toxicity in Caenorhabditis elegans. The wild-type and CL2006 worms were treated with IPHE (2 and 4 mg/mL) or caffeine (200 and 400 μM) since larval stage 1 (L1) until they achieved the required age for each assay. IPHE and caffeine increased the lifespan and appeared to act directly by reactive oxygen species (ROS) scavenger in both wild-type and CL2006 worms, also conferred resistance against oxidative stress in wild-type animals. Furthermore, both treatments delayed Aβ-induced paralysis and decreased AChE activity in CL2006. The protective effect of IPHE against Aβ-induced paralysis was found to be dependent on heat shock factor hsf-1 and FOXO-family transcription factor daf-16, which are respectively involved in aging-related processes and chaperone synthesis, while that of caffeine was dependent only on daf-16. Mechanistically, IPHE and caffeine decreased the levels of Aβ mRNA in the CL2006 worms; however, only IPHE induced expression of the heat shock chaperonin hsp-16.2, involved in protein homeostasis. The results were overall better when treated with IPHE than with caffeine.

The present study investigates possible use of Layered Double Hydroxides (LDH) for Tc(VII) remediation. Mg/Al– and Mg/Fe–LDH were obtained by a hydrothermal route and thermally activated at 450 °C, which was shown to significantly improve the Tc(VII) removal efficiency. Based on XRD investigation of Tc–LDH phases, the uptake Tc(VII) from the solution follows the restoring of a LDH structure. X-ray absorption spectroscopy demonstrates that Tc ions interact solely via the Tc O bond, leaving no evidences of farther atomic interactions with, e.g., layers of LDH. The presence of competing anions, like NO3−, or CO32– in the solution decreases Tc(VII) uptake by LDH. Maximum uptake capacity of thermally activated Mg0.67/Al0.33-LDH and Mg0.75/Fe0.25–LDH were derived from fitting the experimental data into the modified Langmuir equation and correspondingly comprise 0.227 mol/kg and 0.213 mol/kg. In agreement with these findings, theoretical simulations predicted incorporation energies for Mg0.67/Al0.33–LDH and Mg0.75/Fe0.25–LDH of −128 kJ/mol and − 110 kJ/mol, respectively. Investigation of stability of Tc–LDH in different aqueous solutions demonstrated a rather low release Tc(VII) in contact with diluted solutions containing Cl− and OH−, however, in a high saline solution, like Q-brine a rather fast release of TcO4− occurs due to anion exchange with Cl−.

Glutamatergic neurotransmission is present in most mammalian excitatory synapses and plays a key role in central nervous system homeostasis. When over-activated, it can induce excitotoxicity, which is present in several neuropathologies. The nucleoside guanosine (GUO) is a guanine-based purine known to have neuroprotective effects by modulating glutamatergic system during glutamate excitotoxicity in mammals. However, GUO action in Caenorhabditis elegans, as well as on C. elegans glutamatergic excitotoxicity model, is not known. The GUO effects on behavioral parameters in Wild Type (WT) and knockouts worms for glutamate transporters (GLT-3, GLT-1), glutamate vesicular transporter (EAT-4), and NMDA and non-NMDA receptors were used to evaluate the GUO modulatory effects. The GUO tested concentrations did not alter the animals' development, but GUO reduced pharyngeal pumps in WT animals in a dose-dependent manner. The same effect was observed in pharyngeal pumps, when the animals were treated with 4 mM of GUO in glr-1, nmr-1 and eat-4, but not in glt-3 and glt-3;glt-1 knockouts. The double mutant glt-3; glt-1 for GluTs had decreased body bends and an increased number of reversions. This effect was reverted after treatment with GUO. Furthermore, GUO did not alter the sensory response in worms with altered glutamatergic signaling. Thus, GUO seems to modulate the worm's glutamatergic system in situations of exacerbated glutamatergic signaling, which are represented by knockout strains to glutamate transporters. However, in WT animals, GUO appears to reinforce glutamatergic signaling in specific neurons. Our findings indicate that C. elegans strains are useful models to study new compounds that could be used in glutamate-associated neurodegenerative diseases.

A series of N-rate experiments was previously conducted in spring wheat, corn and sunflower in North Dakota indicated that less N was required when fields were in 6-years or more continuous no-till compared to conventional till. The objective of this study was to determine whether part of the reason for the decreased requirement for N was the greater activity of asymbiotic N-fixing organisms. Twelve paired-samplings were conducted in 2018. A surface 0-5cm deep sample was obtained in a long-term no-till field directly across the fence/road from a similar soil in conventional till. Samples were incubated in an acetylene-reduction procedure to estimate N fixation rate. Ten of twelve paired samplings had greater asymbiotic N fixation compared to the conventional till counterpart. This indicates that long-term no-till soils support greater N production from soil microorganisms than conventional till soils, which would result in lower input costs to no-till farmers.

Nitrogen provided to crops through mineralization is an important factor in N management guidelines. Understanding of the interactive effects of soil and weather conditions on N mineralization needs to be improved. Relationships between anaerobic potentially mineralizable N (PMNₐₙ) and soil and weather conditions were evaluated under the contrasting climates of eight US Midwestern states. Soil was sampled (0–30 cm) for PMNₐₙ analysis before pre-plant N application (PP₀N) and at the V5 development stage from the pre-plant 0 (V5₀N) and 180 kg N ha⁻¹ (V5₁₈₀N) rates and incubated for 7, 14, and 28 d. Even distribution of precipitation and warmer temperatures before soil sampling and greater soil organic matter (SOM) increased PMNₐₙ. Soil properties, including total C, SOM, and total N, had the strongest relationships with PMNₐₙ (R² ≤ 0.40), followed by temperature (R² ≤ 0.20) and precipitation (R² ≤ 0.18) variables. The strength of the relationships between soil properties and PMNₐₙ from PP₀N, V5₀N, and V5₁₈₀N varied by ≤10%. Including soil and weather in the model greatly increased PMNₐₙ predictability (R² ≤ 0.69), demonstrating the interactive effect of soil and weather on N mineralization at different times during the growing season regardless of N fertilization. Delayed soil sampling (V5₀N) and sampling after fertilization (V5₁₈₀N) reduced PMNₐₙ predictability. However, longer PMNₐₙ incubations improved PMNₐₙ predictability from both V5 soil samplings closer to the PMNₐₙ predictability from PP₀N, indicating the potential of PMNₐₙ from longer incubations to provide improved estimates of N mineralization when N fertilizer is applied.

Electrocatalytically active materials on the industrial as well as on the laboratory scale may suffer from chemical instability during operation, air exposure, or storage in the electrolyte. A strategy to recover the loss of electrocatalytic activity is presented. Oxygen-depolarized cathodes (ODC), analogous to those that are utilized in industrial brine electrolysis, are analyzed: the catalytic activity of the electrodes upon storage (4 weeks) under industrial process conditions (30 wt % NaOH, without operation) diminishes. This phenomenon occurs as a consequence of surface oxidation and pore blockage, as revealed by scanning electron microscopy, focused ion beam milling, X-ray photoelectron spectroscopy, and Raman spectroscopy. Potentiodynamic cycling of the oxidized electrodes to highly reductive potentials and the formation of "nascent" hydrogen re-reduces the electrode material, ultimately recovering the former catalytic activity.

Bologna-type sausages were made with 25, 50, 75 and 100% replacement of pork back fat by oleogel made with pork skin, water, and high oleic sunflower oil (HOSO) (1.5, 1.5: 1). The technological, nutritional, oxidative, and sensory properties were evaluated. Emulsion stability increased and cooking loss decreased with increasing the pork back fat replacement by oleogel. The reformulation increased the proportion of oleic acid within the lipid fraction by up to 20% and decreased the proportion of linoleic acid by up to 10%, with no changes in the oxidative stability. The acceptance and the sensory profile of the samples were not affected by the substitution of up to 50% of pork back fat by oleogel. Thus, the results showed that it is possible to produce Bologna-type sausages with reduced fat (~16% fat, ~29% reduction), cholesterol (40 mg, ~10% reduction), and energy value (~210 kcal/100 g, ~21% reduction) and with healthier lipid profile using oleogel from HOSO.

Due to initially high soil test K values, K soil test correlation and calibration for corn in North Dakota has previously not been intensely investigated. Potassium fertilizer rate experiments were conducted on 25 sites from 2014 to 2016. The previously published soil test K critical value of 150 mg kg⁻¹ predicted crop response correctly at 16 of the sites. Alternative soil test methods, including a resin-based extraction at two timings, sodium tetraphenylboron extractions at two timings, and 1 mol L⁻¹ NH₄OAc extraction using moist soil were conducted; however, the currently used 1 mol L⁻¹ ammonium acetate extraction using dry soil was most predictive. Mineral analysis of soil from all sites was determined for potassium feldspar content of whole soil, and clay species, particularly smectite, illite, and kaolinite, were determined on the clay fraction. Cluster analysis revealed that a smectite/illite ratio of 3.5 separated the sites into two unique K response data sets. Sites with a smectite/illite ratio >3.5 had a K critical level of ∼200 mg kg⁻¹, whereas sites with a smectite/illite ratio

The excellent static mechanical properties of solid solution strengthened grades of ferritic ductile iron (SSFDI) are adjusted by elevated silicon contents and undergo a rapid loss above a critical...

Schweinfurter Grün ist ein künstlich hergestelltes, als Grünpigment verwendetes Kupferarsenitacetat. Gegen Ende des 18. Jahrhunderts wurden mehrere arsenhaltige Farbmittel entwickelt, die zu Beginn des 19. Jahrhunderts industriell produziert und im Handel unter vielen verschiedenen Bezeichnungen vertrieben wurden. Die Farben entwickelten sich zur Modeerscheinung und so fanden die Pigmente großflächige Verwendung. Trotz gesetzlichen Verbotes im Deutschen Reich in den 1880er-Jahren wurden Restbestände wissentlich oder unwissentlich bis weit in das 20. Jahrhundert hinein als Farbmittel verarbeitet oder als Pflanzenschutzmittel einer neuen Verwendung zugeführt. Heute können Beschäftigte u. a. bei der Restaurierung historischer Wandgestaltungen, Anstriche, Raumausstattungen, Möbel, Textilien, Bildwerke oder bei Sanierungsarbeiten in älteren Gebäuden gegenüber Stäuben exponiert sein, die solche Farbpigmente enthalten. Der Artikel macht über die Darstellung der Geschichte die Relevanz des Themas für Deutschland deutlich, beschreibt die analytische Identifikation und gibt Hinweise zum zeitgemäßen, denkmalgerechten und sicheren Umgang mit arsenhaltigen Farbfassungen.

Chimia, 75 (5), ISSN:0009-4293

Formaldehyde is one of the most comprehensively studied chemicals, with over 30 years of research focused on understanding the development of cancer following inhalation. The causal conclusions regarding the potential for leukemia are largely based on the epidemiological literature, with little consideration of cancer bioassays, dosimetry studies, and mechanistic research, which challenge the biological plausibility of the disease. Recent reanalyzes of the epidemiological literature have also raised significant questions related to the purported associations between formaldehyde and leukemia. Because of this, considerable scientific debate and uncertainty remain on whether there is a causal association between formaldehyde inhalation exposure and leukemia. Further complexity in evaluating this association is related to the endogenous production of formaldehyde. Multiple modes of action (MOA) have been postulated for the development of leukemia following formaldehyde inhalation that includes unsupported hypotheses of direct or indirect toxicity to the target cell population. Herein, the available evidence relevant to evaluating the postulated MOAs for leukemia following formaldehyde inhalation exposure is organized in the IPCS MOA Framework. The integration of all the available evidence clearly highlights the limited amount of data that support any of the postulated MOAs and demonstrates a significant amount of research supporting the null hypothesis that there is no causal association between formaldehyde inhalation exposure and leukemia. These analyses result in a lack of confidence in any of the postulated MOAs, increasing confidence in the conclusion that there is a lack of biological plausibility for a causal association between formaldehyde inhalation exposure and leukemia.

Central airway obstruction is a life-threatening disorder causing a high physical and psychological burden to patients. Standard-of-care airway stents are silicone tubes, which provide immediate relief but are prone to migration. Thus, they require additional surgeries to be removed, which may cause tissue damage. Customized bioresorbable airway stents produced by 3D printing would be highly needed in the management of this disorder. However, biocompatible and biodegradable materials for 3D printing of elastic medical implants are still lacking. Here, we report dual-polymer photoinks for digital light 3D printing of customized and bioresorbable airway stents. These stents exhibit tunable elastomeric properties with suitable biodegradability. In vivo study in healthy rabbits confirmed biocompatibility and showed that the stents stayed in place for 7 weeks after which they became radiographically invisible. This work opens promising perspectives for the rapid manufacturing of the customized medical devices for which high precision, elasticity, and degradability are sought., Science Advances, 7 (6), ISSN:2375-2548

Ibrutinib inhibits Bruton tyrosine kinase while venetoclax is a specific inhibitor of the anti-apoptotic protein BCL2. Both drugs are highly effective as monotherapy against chronic lymphocytic leukemia (CLL), and clinical trials using the combination therapy have produced remarkable results in terms of rate of complete remission and frequency of undetectable minimal residual disease. However, the laboratory rationale behind the success of the drug combination is still lacking. A better understanding of how these two drugs synergize would eventually help develop other rational combination strategies. Using an ex vivo model that promotes CLL proliferation, we show that modeled ibrutinib proliferative responses, but not viability responses, correlate well with patients’ actual clinical responses. Importantly, we demonstrate for the first time that ibrutinib and venetoclax act on distinct CLL subpopulations that have different proliferative capacities. While the dividing subpopulation of CLL responds to ibrutinib, the resting subpopulation preferentially responds to venetoclax. The combination of these targeted therapies effectively reduced both the resting and dividing subpopulations in most cases. Our laboratory findings help explain several clinical observations and contribute to the understanding of tumor dynamics. Additionally, our proliferation model may be used to identify novel drug combinations with the potential of eradicating residual disease.

Elevated plasma cholesterol and type 2 diabetes (T2D) are associated with coronary artery disease (CAD). Individuals treated with cholesterol-lowering statins have increased T2D risk, while individuals with hypercholesterolemia have reduced T2D risk. We explore the relationship between lipid and glucose control by constructing network models from the STARNET study with sequencing data from seven cardiometabolic tissues obtained from CAD patients during coronary artery by-pass grafting surgery. By integrating gene expression, genotype, metabolomic, and clinical data, we identify a glucose and lipid determining (GLD) regulatory network showing inverse relationships with lipid and glucose traits. Master regulators of the GLD network also impact lipid and glucose levels in inverse directions. Experimental inhibition of one of the GLD network master regulators, lanosterol synthase (LSS), in mice confirms the inverse relationships to glucose and lipid levels as predicted by our model and provides mechanistic insights., Some cholesterol-lowering drugs can increase the risk of type 2 diabetes, but the mechanism behind this is not fully understood. Here the authors show that there is a single genetic regulatory module that influences both cholesterol levels and glucose levels, providing a link between cholesterol levels and diabetes.

The most common formsof S fertilizers in the northern Great Plains are ammonium sulfate (AS), ammonium thiosulfate (ATS), and elemental S (ES). Among these, AS is preferred over the others because of its readily available SO42– form, and it can be blended with other dry fertilizer granules, but SO42– is prone to leaching. Recently, fertilizer industries introduced micronized (

International journal of metalcasting t.b.d., t.b.d. (2020). doi:10.1007/s40962-020-00533-z, Published by Springer International Publishing, [Cham, Switzerland]

The exchangeable fraction of soil potassium (K) has been viewed as the most important source of plant-available K, with other sources playing smaller roles that do not influence the predictive value of a soil test. Thus, as K mass balance changes, the soil test should change correspondingly to be associated with greater or reduced plant availability. However, soil test changes and the availability of K to plants are influenced by many other factors. This chapter reviews research on soil test K changes and the relation to crop uptake and yield. A mass-balance relationship is rarely achieved from the measurement of exchangeable K because of the potential for buffering of K removal from structural K in feldspars and from interlayer K in primary and secondary layer silicates. Similarly, surplus K additions can be fixed in interlayer positions in secondary layer silicates, or potentially sequestered in sparingly soluble neoformed secondary minerals, neither of which is measured as exchangeable K. In addition, soil moisture, temporal differences in exchangeable K with K uptake by crops, K leaching from residues, clay type, organic matter contribution to the soil CEC, and type of K amendment confound attempts to relate K additions and losses with an exchangeable K soil test. Research is needed to create regionally specific K soil test procedures that can predict crop response for a subset of clays and K-bearing minerals within specific cropping systems.