Concomitant Release Research Articles

Adjuvant hemoadsorption therapy in patients with severe COVID-19 and related organ failure requiring CRRT or ECMO therapy: A case series.

Severe cases of the COVID-19 are often associated with the development of a fulminant sepsis-like state with a concomitant cytokine release syndrome. Recently, immunomodulating approaches to treat such a hyperinflammation have come into focus, including the use of new extracorporeal organ support therapies such as CytoSorb hemoadsorption designed to remove cytokines and other circulating mediators from blood. Thirteen critically ill COVID-19 patients with ARDS who received either ECMO therapy and/or CRRT with concomitant multiple organ failure were included. Hemoadsorption therapy was initiated once the patient had established-or was at high risk of developing-a hyperinflammatory state with marked hemodynamic instability or progressive lung failure. Levels of inflammatory markers, vasopressor requirements, oxygenation, and ventilation parameters were measured, as well as clinically relevant outcome measures. Combined therapy was associated with a significant reduction in inflammatory mediators, hemodynamic stabilization with a concomitant decrease in requirements for vasoactive substances, and a pronounced improvement in lung function and the need for ventilatory support. Treatment appeared safe and well-tolerated. In this case series of SARS-CoV-2 infected patients admitted to the intensive care unit with ARDS, we report effective interleukin (IL)-6 removal, reduced norepinephrine requirement, and improved lung function while receiving adjuvant, extracorporeal hemoadsorption therapy in the context of a multimodal treatment approach. The presented protocol for CytoSorb initiation may be a good foundation for the development of further prospective studies in the field and may eventually also be applied to other forms of hyperinflammatory ARDS.

Nucleophilic Ring‐Opening of 1,6‐Anhydrosugars: Recent Advances and Applications in Organic Synthesis

Abstract1,6‐Anhydrosugars provide a valuable source of building blocks for the synthesis of a wide range of compounds of interest, from natural products to medicines. The unique reactivity of these functionalized, homochiral synthons is controlled by the 1,6‐anhydro bridge which locks the conformation of the pyranose ring, provides a dual protection of two hydroxyl groups, and either protects or activates the anomeric position. The concomitant release of the primary hydroxyl group at C‐6 during the ring‐opening step limits protecting group manipulations and enables the design of highly convergent synthetic strategies. In recent years, many examples of stereocontrolled ring‐opening of 1,6‐anhydrosugars by a diversity of nucleophiles, including hetero‐ and C‐nucleophiles, have been reported. The purpose of this review is to present an overview of the recent advances, applications and challenges associated with this process.

A Pair of Cobalt(III/IV) Terminal Imido Complexes

AbstractThe reaction of the cobalt(I) complex [(TIMMNmes)CoI](BPh4) (2) (TIMMNmes=tris‐[2‐(3‐mesitylimidazolin‐2‐ylidene)methyl]amine) with 1‐adamantylazide yields the cobalt(III) imido complex [(TIMMNmes)CoIII(NAd)](BPh4) (3) with concomitant release of dinitrogen. The N‐anchor in diamagnetic 3 features an unusual, planar tertiary amine, which results from repulsive electrostatic interaction with the filled d(z2)‐orbital of the cobalt ion and negative hyperconjugation with the neighboring methylene groups. One‐electron oxidation of 3 with [FeCp2](OTf) provides access to the rare, high‐valent cobalt(IV) imido complex [(TIMMNmes)CoIV(NAd)](OTf)2 (4). Despite a half‐life of less than 1 h at room temperature, 4 could be isolated at low temperatures in analytically pure form. Single‐crystal X‐ray diffractometry and EPR spectroscopy corroborate the molecular structure and the d5 low‐spin, S= , electron configuration. A computational analysis of 4 suggests high covalency within the CoIV=NAd bond with non‐negligible spin density located at the imido moiety, which translates into substantial triplet nitrene character.

Self-delivery oxidative stress amplifier for chemotherapy sensitized immunotherapy

Amplifying oxidative stress to break intracellular redox homeostasis could accelerate tumor cell death. In this work, a self-delivery oxidative stress amplifier is developed for chemotherapy sensitized immunotherapy. By virtue of the π-π stacking and coordination effect, copper ions (Cu2+), doxorubicin (DOX) and NLG919 are able to self-assembly into the nanosized oxidative stress amplifier (designated as Cu-DON) with a favorable stability and a biocompatibility. Intravenously administrated Cu-DON could effectively accumulate and penetrate into tumor tissues for cellular uptake. Subsequently, the GSH-responsive DOX release will initiate the immunogenic chemotherapy (IC) for primary tumor inhibition. Moreover, Cu2+-mediated GSH consumption and DOX-triggered oxidative stress could cause the intracellular redox imbalance, contributing to immunogenic cell death (ICD) response. Further, the concomitant release of NLG919 would inhibit indoleamine 2,3-dioxygenase 1 (IDO-1) to reverse immunosuppressive tumor microenvironment (ITM) for enhanced immunotherapy. Consequently, this self-delivery oxidative stress amplifier greatly restrains the growth of primary, distant as well as rechallenged tumors by chemotherapy sensitized immunotherapy, which would shed light on the development of combination therapy to block tumor growth and metastasis in clinic.

Characterization of toxicological effects of complex nano-sized metal particles using in vitro human cell and whole blood model systems.

Metal oxide fumes form at high temperatures, for instance, during welding or firing ammunition. Inhalation exposure to high levels of airborne metal oxide particles can cause metal fume fever, cardiovascular effects, and lung damage in humans, but the associated underlying pathological mechanisms are still not fully understood. Using human alveolar epithelial cells, vascular endothelial cells, and whole blood model systems, we aimed to elucidate the short-term effects of well-characterized metal particles emitted while firing pistol ammunition. Human lung epithelial cells exposed to gunshot smoke particles (0.1-50 μg/ml) produced reactive oxygen species (ROS) and pro-inflammatory cytokines (interleukin 8 (IL-8), granulocyte-macrophage colony-stimulating factor (GM-CSF)) that activate and recruit immune cells. Particles comprising high copper (Cu) and zinc (Zn) content activated human endothelial cells via a non-ROS-mediated mechanism that triggered immune activation (IL-8, GM-CSF), leukocyte adhesion to the endothelium (soluble intercellular adhesion molecule 1 (sICAM-1)), and secretion of regulators of the acute-phase protein synthesis (interleukin 6 (IL-6)). In human whole blood, metal oxides in gunshot smoke demonstrated intrinsic properties that activated platelets (release of soluble cluster of differentiation 40 ligand (sCD40L), platelet-derived growth factor B-chain homodimer(PDGF-BB), and vascular endothelial growth factor A (VEGF-A)) and blood coagulation and induced concomitant release of pro-inflammatory cytokines from blood leukocytes that further orchestrate thrombogenesis. The model systems applied provide useful tools for health risk assessment of particle exposures, but more studies are needed to further elucidate the mechanisms of metal fume fever and to evaluate the potential risk of long-term cardiovascular diseases.

Marine microbial L-glutaminase: from pharmaceutical to food industry.

Deamination of L-glutamine to glutamic acid with the concomitant release of ammonia by the activity of L-glutaminase (L-glutamine amidohydrolase EC 3.5.1.2) is a unique reaction that also finds potential applications in different sectors ranging from therapeutics to food industry. Owing to its cost-effectiveness, rapidity, and compatibility with downstream processes, microbial production of L-glutaminase is preferred over the production by other sources. Marine microorganisms including bacteria, yeasts, and moulds have manifested remarkable capacity to produce L-glutaminase and, therefore, are considered as prospective candidates for large-scale production of this enzyme. The main focus of this article is to provide an overview of L-glutaminase producing marine microorganisms, to discuss strategies used for the lab- and large-scale production of these enzyme and to review the application of L-glutaminase from marine sources so that the future prospects can be understood. KEY POINTS: • L-glutaminase has potential applications in different sectors ranging from therapeutics to food industry • Marine microorganisms are considered as prospective candidates for large-scale production of L-glutaminase • Marine microbial L-glutaminase havegreat potential in therapeutics and in the food industry.

Modulating Mechanical and Shape-Memory Properties while Mitigating Degradation-Induced Inflammation of Polylactides by Pendant Aspirin Incorporation.

Synergistically modulating mechanical properties and improving shape-memory performance while mitigating degradation-induced chronic inflammation of polylactide (PLA)-based implants for biomedical applications remain elusive. We test the hypothesis that copolymerizing aspirin-functionalized glycolide with d,l-lactide could enhance the thermal processing, toughness, and shape-memory efficiency of the copolymer while mitigating local inflammatory responses upon its degradation. The content of pendant aspirin was readily modulated by monomer feeds during ring-opening polymerization, and the copolymers with ∼10% or less aspirin pendants exhibited gigapascal-tensile moduli at body temperature and significantly improved fracture toughness and energy dissipation that positively correlated with the aspirin pendant content. The copolymers also exhibited excellent thermal-healing and shape-memory efficacy, achieving a >97% temporary shape fixing ratio at room temperature and facile shape recovery at 50-65 °C. These drastic improvements were attributed to the dynamic hydrophobic aggregations among aspirin pendants that strengthen glassy-state physical entanglement of PLA while readily dissociating under stress/thermal activation. When subcutaneously implanted, the copolymers mitigated degradation-induced inflammation due to concomitant hydrolytic release of aspirin without suppressing early acute inflammatory responses. The incorporation of aspirin pendants in PLA represents a straightforward and innovative strategy to enhance the toughness, shape-memory performance, and in vivo safety of this important class of thermoplastics for biomedical applications.

Unexpected degradation and deiodination of diatrizoate by the Cu(II)/S(IV) system under anaerobic conditions

Transition metal catalyzed sulfite auto-oxidation is a promising technology used in water and wastewater treatment for the elimination of contaminants. In the literature, this process has been reported to be efficient only in the presence of oxygen. However, in this study, we unexpectedly found that the degradation of diatrizoate (DTZ) by a system based on the combination of copper ion and sulfite (Cu(II)/S(IV)) reached over 95% under anaerobic conditions, but was considerably retarded under aerobic conditions at pH 7. Furthermore, it was found that Cu(I), generated from the cleavage of the CuSO3 complex, was the main reactive species responsible for the degradation of DTZ by the Cu(II)/S(IV) system under anaerobic conditions. In fact, the absence of oxygen promoted the accumulation of Cu(I). The concomitant release of the iodide ion with the degradation of DTZ indicated that the anaerobic degradation of DTZ by the Cu(II)/S(IV) system mainly proceeded through the deiodination pathway, which was also confirmed by the detection of deiodinated products. The anaerobic degradation of DTZ was favored at higher initial concentrations of Cu(II) or sulfite in this system. Since the CuSO3 complex, the precursor of Cu(I), was formed mainly at pH 7, the highest anaerobic degradation of DTZ was achieved at pH 7. An increase in reaction temperature considerably enhanced the degradation of DTZ by the Cu(II)/S(IV) system with an apparent activation energy of 119.4 kJ/mol. The presence of chloride, bicarbonate and humic acid slightly influenced the anaerobic degradation of DTZ. The experiments with real water samples also demonstrated the effectiveness of the degradation of DTZ by the Cu(II)/S(IV) system under anaerobic conditions.

A ghrelin receptor antagonist reduces the ability of ghrelin, alcohol or amphetamine to induce a dopamine release in the ventral tegmental area and in nucleus accumbens shell in rats

The orexigenic peptide ghrelin increases the release of dopamine in the nucleus accumbens (NAc) shell via central ghrelin receptors, especially those located in the ventral tegmental area (VTA). The activity of the VTA dopamine neurons projecting to NAc shell, involves somatodendritic dopamine release within the VTA. However, the effects of ghrelin on the concomitant dopamine release in the VTA and NAc shell is unknown. It is further unknown whether addictive drugs, such as alcohol and amphetamine, enhance the dopamine levels in both these areas via ghrelin receptor dependent mechanisms. Thus, the effects of a ghrelin receptor antagonist, JMV2959, on the ability of i) central ghrelin ii) systemic alcohol or iii) systemic amphetamine to increase the dopamine release in the VTA and in the NAc shell in rats by using in vivo microdialysis was explored. We showed that systemic administration of JMV2959 blocks the ability of central ghrelin to increases dopamine release in the VTA and the NAc shell, and reduces the alcohol- and amphetamine-induced dopamine release in both these areas. Locomotor activity studies was then conducted in an attempt to correlate the ghrelin-induced dopamine release in the VTA to a behavioural outcome. These revealed that local infusion of a dopamine D1 receptor antagonist into the VTA blocks the ability of central ghrelin to cause a locomotor stimulation in mice. Collectively, this study adds to the growing body of evidence indicating that ghrelin signalling modulates the ability of ghrelin, and addictive drugs, to activate the mesoaccumbal dopamine pathway.

Litter decomposes slowly on shaded steep slope and sunny gentle slope in a typical steppe ecoregion.

Plant litter decomposition is mainly affected by litter properties and environmental factors, but the influence of terrain on litter decomposition is not well understood. We studied the effects of terrain on litter decomposition over a period of 12 months at six locations in a typical steppe ecoregion and measured the concomitant release of carbon (C), nitrogen (N), and phosphorus (P). The study site has two aspects, shaded and sunny, each aspect having three slopes: 15°, 30°, and 45°. The same mixed litter was used at each location to exclude the influence of litter quality variation. Results showed that soil temperature and moisture, solar radiation, and plant species diversity varied by terrain, which in turn, affected the k‐value (standardized total effects, 0.78, 0.12, 0.92, 0.23, respectively) and the release of C (0.72, –0.25, 0.83, 0.24, respectively), N (0.89, –0.45, 0.76, 0.40, respectively) and P (0.88, 0.77, 0.58, 0.57, respectively). K‐value and C release decreased with increasing slope on shaded aspect, while increased with increasing slope on sunny aspect. The release of N and P decreased with increasing slope on the shaded aspect. K‐value and C, N, and P release were significantly higher on shaded than that on sunny aspect at 15° and 30°, while at 45°, it was higher on sunny than on shaded aspect. The litter mass loss was slower on shaded 45° and sunny 15°. So moderate grazing or mowing could be used to reduce litter accumulation and accelerate litter decomposition on these terrains. Structural equation modeling indicated that soil temperature and solar radiation had the greatest influence on k‐value and C, N, and P release, and these two factors were directly related to soil moisture and plant species diversity. Overall, our results emphasize the need to consider terrain for litter decomposition in typical steppe ecoregions.

Effect of organic compounds on the retention of radionuclides in clay rocks: Mechanisms and specificities of Eu(III), Th(IV), and U(VI)

The use of geological barriers is widely studied in the context of hazardous waste management and pollution events. In the near field of pollution sources, geological barriers endure disturbances with the concomitant release of hazardous chemicals and organic or saline plumes. In this study, we investigate the effect of organic compounds on the retention of radionuclides in contact with a sedimentary rock, namely Callovo-Oxfordian clay rock (East of Paris Basin). The retention of Eu(III), Th(IV), U(VI), was quantified at near-neutral pH, in presence of model organic compounds released from wastes and engineered barriers, e.g. ortho-phthalate, α-isosaccharinate (α-ISA), succinate, as well as high complexing compounds (oxalate, citrate, EDTA). The studied concentrations of organic compounds, eventually higher than disposal conditions, aimed at quantifying concentration ranges above which the retention of radionuclides decreases, and the underlying mechanisms occurring.A simplified surface complexation model, assuming illite as the main sorbing phase, was used for predictive modelling. The comparison with experimental results allowed the evaluation of the robustness of the surface complexation constants and of the thermodynamic database “ThermoChimie” of the Andra-RWM-Ondraf/Niras consortium, to account for speciation in solution (ThermoChimie V10a, https://www.thermochimie-tdb.com). Specific mechanisms are discussed, such as complexation of Eu(III) by α-ISA, or retention of Th(IV)/citrate complexes. U(VI) displayed a unique behaviour because of uranyl complexation by natural species under geological conditions. The low solid to liquid distribution ratio, Rd(U(VI)/COx) ~ 7.5 ± 1.6 L kg−1 decreases in presence of organic compounds, but without direct complexation by organic molecules. Indeed, the organic plume induces a disturbance of chemical equilibria in pore water of the clay rock, leading to additional complexation of uranyl by calcium and carbonates. Such effect highlights the crucial role of clay surfaces and carbonate minerals. More generally, these results provide insights on the geochemical buffers and key parameters involved during near-field disturbance of environmental media.

The Study of Soil Quality Indicators in Ibiono Ibom Area, Akwa Ibom State of Nigeria

Soil assessment of Ibiono Ibom area of Akwa Ibom State was carried out using morphological, physical and chemical properties. Undisturbed samples were collected using core cylinder samplers at different depths and disturbed samples were also collected from the genetic horizon of the soil profiles in Ikot User and Ibiaku Osuk areas. Soil profiles were described using the standard soil description in the USDA 1978/1999 system. Physical and chemical parameters were analyzed using standard laboratory procedures. Data obtained from the study were analyzed and results showed that saturated hydraulic conductivity ranged from 0.00 – 89.10 cm/hr. Bulk density, particle density and total porosity ranged from 1.20 – 1.66g/cm3, 1.50 – 3.07 g/cm3 and 19.8 – 56.7% respectively. Textures were generally sand to loamy sand. The impact of texture with bulk density and porosity enhances the performances of plants in the area and are indicative of moderate to high inherent soil quality. Most of the profiles have rapid permeability (mean of 17.03cm/hr and 48.88 cm/hr) and have relatively greater potential to support roots. pH rating varied from extremely acid (pH 4.3) to moderately acid (pH 5.7). Organic carbon content and total nitrogen were low having ranges of 0.0390 – 1.7356% and 0.01 – 0.14% respectively. The available phosphorus content ranged from 9.54 – 27.79 mg/kg and C:N ranged from 2 to 29. The implications of the narrow C: N ratios in some of the soils reflect high levels of microbial activity and rapid decomposition of organic matter with concomitant release of nutrient elements into soil solution for plant uptake.

Alcohol Oxidase from the Methylotrophic Yeast Ogataea polymorpha: Isolation, Purification, and Bioanalytical Application.

Alcohol oxidase (EC 1.1.3.13; AOX) is a flavoprotein that catalyzes the oxidation of primary short-chain alcohols to corresponding carbonyl compounds with a concomitant release of hydrogen peroxide. It is a key enzyme of methanol metabolism in methylotrophic yeasts, catalyzing the first step of methanol oxidation to formaldehyde.Here we describe the isolation and purification of AOX from the thermotolerant methylotrophic yeast Ogataea (Hansenula) polymorpha, and using this enzyme in enzymatic assay of ethanol, simultaneous analysis of methanol and formaldehyde, and in construction of amperometric biosensors selective to primary alcohols and formaldehyde.

Electron Redistribution within the Nitrogenase Active Site FeMo-Cofactor During Reductive Elimination of H2 to Achieve N≡N Triple-Bond Activation.

Nitrogen fixation by nitrogenase begins with the accumulation of four reducing equivalents at the active-site FeMo-cofactor (FeMo-co), generating a state (denoted E4(4H)) with two [Fe-H-Fe] bridging hydrides. Recently, photolytic reductive elimination (re) of the E4(4H) hydrides showed that enzymatic re of E4(4H) hydride yields an H2-bound complex (E4(H2,2H)), in a process corresponding to a formal 2-electron reduction of the metal-ion core of FeMo-co. The resulting electron-density redistribution from Fe-H bonds to the metal ions themselves enables N2 to bind with concomitant H2 release, a process illuminated here by QM/MM molecular dynamics simulations. What is the nature of this redistribution? Although E4(H2,2H) has not been trapped, cryogenic photolysis of E4(4H) provides a means to address this question. Photolysis of E4(4H) causes hydride-re with release of H2, generating doubly reduced FeMo-co (denoted E4(2H)*), the extreme limit of the electron-density redistribution upon formation of E4(H2,2H). Here we examine the doubly reduced FeMo-co core of the E4(2H)* limiting-state by 1H, 57Fe, and 95Mo ENDOR to illuminate the partial electron-density redistribution upon E4(H2,2H) formation during catalysis, complementing these results with corresponding DFT computations. Inferences from the E4(2H)* ENDOR results as extended by DFT computations include (i) the Mo-site participates negligibly, and overall it is unlikely that Mo changes valency throughout the catalytic cycle; and (ii) two distinctive E4(4H) 57Fe signals are suggested as associated with structurally identified "anchors" of one bridging hydride, two others with identified anchors of the second, with NBO-analysis further identifying one anchor of each hydride as a major recipient of electrons released upon breaking Fe-H bonds.

Unexpected varus deformity and concomitant metal ion release and MRI findings of modular-neck hip stems: descriptive RSA study in 75 hips with 8 years’ follow-up

Background and purpose — Modular-neck hip stems have been identified with corrosion-related problems from the neck–stem junction. We report an ongoing varus deformity of modular-neck hip stems with simultaneous metal ion release observed during a study comparing the migration of modular vs. standard hip stems. Patients and methods — We followed 50 patients with modular and 25 with standard neck stems using radiostereometry (RSA). At 5-year follow-up, we noted a compromised integrity of the modular stem with varus deformity in the neck–stem interface. Changes in head–tip distance as well as whole-blood ion concentration and MRI findings were analyzed. The modular stems were followed further up to 8 years. Results — The head–tip distance decreased continuously by 0.15 mm per year resulting in 1.2 (95% CI 1.0–1.4) mm at 8 years for modular stems, while for the standard stems at 5 years, the decrease was 0.09 (CI 0.0–0.2) mm or 0.02 mm/year. For the modular stems, the reduction in head–tip distance correlated to the increase in whole-blood cobalt concentration at 8 years but not to the MRI grading of tissue reactions. At 5 years, cobalt levels were 4.9 µg/L for modular stems and at 8 years 4.8 µg/L, whereas for standard stems this was 1.0 µg/L. After 8 years, 9 of 72 stems had been revised for different reasons, but only 1 with obvious adverse local tissue reaction (ALTR). Interpretation — We present a surprisingly large progressive deformation at the modular neck–stem junction, but so far without a definite clinical problem. Even the femoral head seems to show slight compression onto the taper over time. A high rate of revisions for the modular type of this stem has raised general concerns, and it has been recalled from the market.

Early prediction of macrocrack location in concrete, rocks and other granular composite materials

Heterogeneous quasibrittle composites like concrete, ceramics and rocks comprise grains held together by bonds. The question on whether or not the path of the crack that leads to failure can be predicted from known microstructural features, viz. bond connectivity, size, fracture surface energy and strength, remains open. Many fracture criteria exist. The most widely used are based on a postulated stress and/or energy extremal. Since force and energy share common transmission paths, their flow bottleneck may be the precursory failure mechanism to reconcile these optimality criteria in one unified framework. We explore this in the framework of network flow theory, using microstructural data from 3D discrete element models of concrete under uniaxial tension. We find the force and energy bottlenecks emerge in the same path and provide an early and accurate prediction of the ultimate macrocrack path {mathcal {C}}. Relative to all feasible crack paths, the Griffith’s fracture surface energy and the Francfort–Marigo energy functional are minimum in {mathcal {C}}; likewise for the critical strain energy density if bonds are uniformly sized. Redundancies in transmission paths govern prefailure dynamics, and predispose {mathcal {C}} to cascading failure during which the concomitant energy release rate and normal (Rankine) stress become maximum along {mathcal {C}}.

Purinergic Receptors Crosstalk with CCR5 to Amplify Ca2+ Signaling

Many G protein-coupled receptors (GPCRs) signal through more than one subtype of heterotrimeric G proteins. For example, the C–C chemokine receptor type 5 (CCR5), which serves as a co-receptor to facilitate cellular entry of human immunodeficiency virus 1 (HIV-1), normally signals through the heterotrimeric G protein, Gi. However, CCR5 also exhibits G protein signaling bias and certain chemokine analogs can cause a switch to Gq pathways to induce Ca2+ signaling. We want to understand how much of the Ca2+ signaling from Gi-coupled receptors is due to G protein promiscuity and how much is due to transactivation and crosstalk with other receptors. We propose a possible mechanism underlying the apparent switching between different G protein signaling pathways. We show that chemokine-mediated Ca2+ flux in HEK293T cells expressing CCR5 can be primed and enhanced by ATP pretreatment. In addition, agonist-dependent lysosomal exocytosis results in the release of ATP to the extracellular milieu, which amplifies cellular signaling networks. ATP is quickly degraded via ADP and AMP to adenosine. ATP, ADP and adenosine activate different cell surface purinergic receptors. Endogenous Gq-coupled purinergic P2Y receptors amplify Ca2+ signaling and allow for Gi- and Gq-coupled receptor signaling pathways to converge. Associated secretory release of GPCR ligands, such as chemokines, opioids, and monoamines, should also lead to concomitant release of ATP with a synergistic effect on Ca2+ signaling. Our results suggest that crosstalk between ATP-activated purinergic receptors and other Gi-coupled GPCRs is an important cooperative mechanism to amplify the intracellular Ca2+ signaling response.

Type 1 interferon-dependent repression of NLRC4 and iPLA2 licenses down-regulation of Salmonella flagellin inside macrophages

Inflammasomes have been implicated in the detection and clearance of a variety of bacterial pathogens, but little is known about whether this innate sensing mechanism has any regulatory effect on the expression of stimulatory ligands by the pathogen. During infection with Salmonella and many other pathogens, flagellin is a major activator of NLRC4 inflammasome-mediated macrophage pyroptosis and pathogen eradication. Salmonella switches to a flagellin-low phenotype as infection progresses to avoid this mechanism of clearance by the host. However, the host cues that Salmonella perceives to undergo this switch remain unclear. Here, we report an unexpected role of the NLRC4 inflammasome in promoting expression of its microbial ligand, flagellin, and identify a role for type 1 IFN signaling in switching of Salmonella to a flagellin-low phenotype. Early in infection, activation of NLRC4 by flagellin initiates pyroptosis and concomitant release of lysophospholipids which in turn enhance expression of flagellin by Salmonella thereby amplifying its ability to elicit cell death. TRIF-dependent production of type 1 IFN, however, later represses NLRC4 and the lysophospholipid biosynthetic enzyme iPLA2, causing a decline in intracellular lysophospholipids that results in down-regulation of flagellin expression by Salmonella These findings reveal a previously unrecognized immune-modulating regulatory cross-talk between endosomal TLR signaling and cytosolic NLR activation with significant implications for the establishment of infection with Salmonella.

The role of soil in defining planetary boundaries and the safe operating space for humanity

We use soils to provide 98.8% of our food, but we must ensure that the pressure we place on soils to provide this food in the short-term does not inadvertently push the Earth into a less hospitable state in the long-term. Using the planetary boundaries framework, we show that soils are a master variable for regulating critical Earth-system processes. Indeed, of the seven Earth-systems that have been quantified, soils play a critical and substantial role in changing the Earth-systems in at least two, either directly or indirectly, as well as smaller contributions for a further three. For the biogeochemical flows Earth-system process, soils contribute 66% of the total anthropogenic change for nitrogen and 38% for phosphorus, whilst for the land-system change Earth-system process, soils indirectly contribute 80% of global anthropogenic change. Furthermore, perturbations of soils contribute directly to 21% of climate change, 25% to ocean acidification, and 25% to stratospheric ozone depletion. We argue that urgent interventions are required to greatly improve soil management, especially for those Earth-system processes where the planetary boundary has already been exceeded and where soils make an important contribution, with this being for biogeochemical flows (both nitrogen and phosphorus), for climate change, and for land-system change. Of particular importance, it is noted that the highly inefficient use of N fertilizers results in release of excess N into the broader environment, contributes to climate change, and results in release of ozone-depleting substances. Furthermore, the use of soils for agricultural production results not only in land-system change, but also in the loss (mineralization) of organic matter with a concomitant release of CO2 contributing to both climate change and ocean acidification. Thus, there is a need to markedly improve the efficiency of fertilizer applications and to intensify usage of our most fertile soils in order to allow the restoration of degraded soils and limit further areal expansion of agriculture. Understanding, and acting upon, the role of soils is critical in ensuring that planetary boundaries are not transgressed, with no other single variable playing such a strategic role across all of the planetary boundaries.

Accuracy of Percutaneous Lateral Release for Hallux Valgus: An Anatomic Study

Category:Bunion; OtherIntroduction/Purpose:Minimally Invasive Chevron and Akin (MICA) surgery is growing in popularity. There are now multiple studies comparing minimally invasive bunion correction to traditional open techniques. Many of these studies include percutaneous lateral soft tissue release using a specific blade, while others use an open technique. To our knowledge, there is no prior study confirming the accuracy of soft tissue release via percutaneous technique. Our objective was to evaluate the precision of the percutaneous release, both the structures released and percent release. Additionally, we identified adjacent nerves potentially at risk with a lateral soft tissue release, measuring their proximity to the incision and if they were damaged.Methods:Sixteen fresh frozen cadaveric foot specimens (8 paired limbs) underwent percutaneous lateral release utilizing a beaver blade under fluoroscopic guidance by two Foot and Ankle Fellowship Faculty who regularly perform the procedure. As described in early MICA technique papers by Redfern and Vernois, the blade was inserted into the plantar plate between the lateral sesamoid and the proximal phalanx. Then the blade was rotated laterally while the hallux was directed into varus. The goal was to release the lateral head of the Flexor Hallucis Brevis (FHB) without violating the Lateral Collateral Ligament (LCL). During our experiment the sesamoids were able to be successfully reduced after each release. The specimens were then dissected to reveal the extent of release of the FHB and LCL. Distance was measured between the blade path and the dorsal digital branch of the deep peroneal nerve, as well as the plantar digital nerve.Results:The FHB was at least partially released in 15/16 specimens. It was completely released in two specimens. 5/16 specimens had greater than 50% but less than 100% release and 8/16 specimens had <50% release. The LCL was completely intact in 8/16 specimens. It was partially released in 8/16 specimens (5 less than 50% released and 3 greater than 50% released). There was no correlation between percent of FHB release and the likelihood of LCL release. The dorsal cutaneous nerve was consistently near the path of the beaver blade, with a median distance of 2mm (range 1-8mm). However, the nerve was never found to be incised or transected. Likewise, the plantar nerve was never injured.Conclusion:This study sought to verify the effectiveness of percutaneous lateral release. We found the FHB to be at least partially released in all but one case, resulting in adequate clinical correction of sesamoid position. Full FHB release may not be necessary to achieve the clinical objective of sesamoid reduction. There was no correlation between percent of FHB release and concomitant release of the LCL, which demonstrates the challenge of an isolated FHB release. The dorsal cutaneous nerve was consistently near the blade path but was never injured, suggesting patients should be counseled regarding the risk.