Reduction In Concentration Research Articles

Salmonella re-engineers the intestinal environment to break colonization resistance in the presence of a compositionally intact microbiota

The gut microbiota prevents harmful microbes from entering the body, a function known as colonization resistance. The enteric pathogen Salmonella enterica serovar (S.) Typhimurium uses its virulence factors to break colonization resistance through unknown mechanisms. Using metabolite profiling and genetic analysis, we show that the initial rise in luminal pathogen abundance was powered by a combination of aerobic respiration and mixed acid fermentation of simple sugars, such as glucose, which resulted in their depletion from the metabolome. The initial rise in the abundance of the pathogen in the feces coincided with a reduction in the cecal concentrations of acetate and butyrate and an increase in epithelial oxygenation. Notably, these changes in the host environment preceded changes in the microbiota composition. We conclude that changes in the host environment can weaken colonization resistance even in the absence of overt compositional changes in the gut microbiota.

Ensuring Operational Performance and Environmental Sustainability of Marine Diesel Engines through the Use of Biodiesel Fuel

This article considers the issues of ensuring operational performance and environmental sustainability of marine diesel engines by using biodiesel fuel. This research was conducted on 5S60ME-C8 MAN-B&W Diesel Group and 6DL-16 Daihatsu Diesel marine diesel engines, which are operated using RMG380 petroleum fuel and B10 and B30 biodiesel fuels. The efficiency of biofuel usage was assessed based on environmental (reduced nitrogen oxide concentration in exhaust gases) and economic (increased specific effective fuel consumption) criteria. It was found that the use of B10 and B30 biofuels provides a reduction in nitrogen oxide concentration in exhaust gases by 14.71–25.13% but at the same time increases specific effective fuel consumption by 1.55–6.01%. Optimum fuel injection advance angles were determined that ensure the best thermal energy, economic and environmental performance of diesel engines. The optimum angle of biofuel supply advance is determined experimentally and should correspond to the limits recommended by the diesel engine operating instructions. It has been proven experimentally that the use of biofuel increases the environmental sustainability of marine diesel engines by 13.75–29.42%. It increases the diesel engines environmental safety in case of emergency situations as well as accidental and short-term emissions of exhaust gases with an increased content of nitrogen oxides into the atmosphere phenomena that are possible in starting modes of diesel engine operation as well as in modes of sudden load changes. It is the increase in the environmental friendliness of marine diesel engines in the case of using biofuel that is the most positive criterion and contributes to the intensity of biofuel use in power plants of sea vessels.

Proteomic analysis of carbapenem-resistant Klebsiella pneumoniae outer membrane vesicles under the action of phages combined with tigecycline

BackgroundKlebsiella pneumoniae is the most commonly encountered pathogen in clinical practice. Widespread use of broad-spectrum antibiotics has led to the current global dissemination of carbapenem-resistant K. pneumoniae, which poses a significant threat to antibacterial treatment efficacy and public health. Outer membrane vesicles (OMVs) have been identified as carriers capable of facilitating the transfer of virulence and resistance genes. However, the role of OMVs in carbapenem-resistant K. pneumoniae under external pressures such as antibiotic and phage treatments remains unclear.MethodsTo isolate and purify OMVs under the pressure of phages and tigecycline, we subjected K. pneumoniae 0692 harboring plasmid-mediated blaNDM-1 and blaKPC-2 genes to density gradient separation. The double-layer plate method was used to isolate MJ1, which efficiently lysed K. pneumoniae 0692 cells. Transmission electron microscopy (TEM) was used to characterize the isolated phages and extract OMV groups for relevant morphological identification. Determination of protein content of each OMV group was conducted through bicinchoninic acid assay (BCA) and proteomic analysis.ResultsK. pneumoniae 0692 released OMVs in response to different environmental stimuli, which were characterized through TEM as having the typical structure and particle size of OMVs. Phage or tigecycline treatment alone resulted in a slight increase in the mean protein concentration of OMVs secreted by K. pneumoniae 0692 compared to that in the untreated group. However, when phage treatment was combined with tigecycline, there was a significant reduction in the average protein concentration of OMVs compared to tigecycline treatment alone. Proteomics showed that OMVs encapsulated numerous functional proteins and that under different external stresses of phages and tigecycline, the proteins carried by K. pneumoniae 0692-derived OMVs were significantly upregulated or downregulated compared with those in the untreated group.ConclusionsThis study confirmed the ability of OMVs to carry abundant proteins and highlighted the important role of OMV-associated proteins in bacterial responses to phages and tigecycline, representing an important advancement in microbial resistance research.

Free radical mechanisms of ammonium sulfate as intensively used industrial materials on suppressing organic pollutants

Organic free radicals are critical intermediates for the generation and inhibition of organic pollutants during industrial processes. Clarifying the free radical mechanism of pollutant inhibition is significant for their efficient control. Ammonium sulfate is intensively used in industrial materials to suppress organic pollutants. In this study, organic free radical intermediate species in metal-catalyzed reactions inhibited by ammonium sulfate were identified using continuous-wave electron paramagnetic resonance (EPR) spectroscopy, providing direct evidence for the free radical mechanisms of organic pollutants inhibition. The transverse (T2) and longitudinal (T1) relaxation time variations catalyzed by different metal catalysts in the presence of ammonium sulfate were compared using pulsed-wave EPR. Consequently, after the addition of ammonium sulfate, the observed increase in T2 suggests that ammonium sulfate leads to radical concentration reduction. A decrease in the T1 relaxation time suggests the enhanced interaction between organic radicals and metals, which is an obstacle to subsequent radical reactions. Therefore, ammonium sulfate dominantly changed the free radical intermediates species, concentrations, and their reactivity, and then inhibited the organic pollutants formations. The inhibition mechanisms of ammonium sulfate on metal-catalyzed pollutants were then proposed combining EPR analysis, X-ray characterization, and high-resolution mass spectrometry screening. As a result, (1) occupying the active sites of metal catalysis and (2) inhibiting free radical intermediates are the two main intrinsic inhibition mechanisms of ammonium sulfate. The findings provide new perspectives on the efficient inhibition of organic pollutants in industrial processes involving various metal catalysts.

Built-In Environmental Construction Mechanism and Sustainable Renewal Strategies of Traditional Qiang Dwellings in Western China

Indoor air quality (IAQ) has a significant impact on human health, as people spend 90% of their time in various indoor environments. Therefore, research on IAQ is extremely necessary. However, current research on traditional Qiang residences in western Sichuan mainly focuses on the indoor thermal environment and heritage protection, with relatively little attention paid to IAQ. This study investigates the IAQ of traditional Qiang residences in western Sichuan, which have open fire pits as the core of daily life, exploring the impact of passive renovation strategies on the indoor air quality. Using simulation methods, this study employs passive strategies, such as increasing the size of windward windows, changing ventilation methods, relocating the fire pit, and enlarging interior partition openings, to improve and optimize the IAQ through natural ventilation. The results show that when the windward window sizes are 0.8 m × 1.9 m and 0.7 m × 1.55 m, the reduction in the indoor CO2 concentration is the greatest, with a maximum decrease of 0.024% at the 1.5 m plane. This paper proposes passive renovation strategies to improve the indoor air quality of Qiang residences in western Sichuan. These strategies effectively enhance the indoor air quality of Qiang residences and address the research gap on indoor air quality in regional Qiang residences in western Sichuan. The insights and methods presented contribute to the improvement of the indoor air quality in traditional buildings and support the sustainable development of traditional architecture.

The Effect of Renaltec on Serum Uremic Toxins in Cats with Experimentally Induced Chronic Kidney Disease.

Serum uremic toxins markedly increase in cats with chronic kidney disease (CKD) and have deleterious consequences. Renaltec is an oral adsorbent that binds uremic toxin precursors in the gut. In this prospective cohort study utilizing 13 purpose-bred cats with remnant kidney model-induced CKD (12 IRIS Stage 2, 1 IRIS Stage 3) eating a standardized renal diet, we aimed to assess the effect of Renaltec administration on serum indoxyl sulfate (IDS) and p-cresol sulfate (pCS) concentrations. Cats were sequentially treated with standard of care for 56 days, 500 mg Renaltec orally once daily for 56 days, and then three months later, 500 mg Renaltec orally twice daily for 56 days. Serum IDS and pCS concentrations were measured 28 and 56 days after the administration of Renaltec. Blood pressure and kidney function were measured before and 56 days after the administration of Renaltec. Significant decreases in serum IDS and pCS concentrations were observed for both once- and twice-daily dosing, particularly during the first 28 days of administration. More cats with BID dosing had clinically significant reductions in serum IDS and pCS concentrations than with SID dosing. Renaltec can reduce the serum concentrations of deleterious gut-derived uremic toxins in cats with CKD.

Numerical analysis of the geometrical modifications effects on the tensile strength of bonded single-lap joints

Nowadays, bonded joints have increasingly become the most used joining process in many industrial fields and even in civil engineering due to their simple geometry and structural efficiency and especially with the development of structural adhesives. Several solutions have been proposed in order to improve the mechanical strength of bonded joints by taking into consideration modifications to the adhesive edges and adherends to attenuate as much as possible the high stress concentration at the level of the adhesive. In this study, a 3D numerical model was developed in Abaqus to evaluate the influence of geometric changes in the adherends’ and adhesive edges on the mechanical strength of a single-lap joint under uniaxial tensile stress. Two modified geometric configurations of the bonded joint were proposed, taking into account on the one hand the presence of an adhesive fillet as the first modification and on the other hand, a removal of material at the level of the free edges of the adherends (adherends notching) as the second modification. The objective is to analyze the impact of these geometric modifications on the reduction of stress concentration in the adhesive and to explore how this new joint design can contribute to improve the strength of bonded joints. The results clearly show that a geometric modification at the level of the two free edges of the two substrates improves the strength of the joint and reduces the high stress concentrations in the adhesive. The joint strength is greatly improved if these modifications are optimized in relation to the overlap length and especially in relation to the thickness of the adherends and the adhesive. Adherend notching or applying an adhesive fillet resulted in a considerable reduction in peel stresses.

Relative Health Risk Reduction from an Advanced Multi-Modal Air Purification System: Evaluation in a Post-Surgical Healthcare Setting.

Advanced air treatment systems have the potential to reduce airborne infection risk, improve indoor air quality (IAQ) and reduce energy consumption, but few studies reported practical implementation and performance. PlasmaShield®, an advanced multi-modal HVAC-integrated system, was directly compared with a standard MERV-13 system in a post-surgical paediatric healthcare setting. The evaluation entailed monitoring of multi-size airborne particles, bioaerosols and key IAQ parameters. Measurements were taken for outside air, supply air and air in the occupied space for 3 days prior to, and after, the installation of the PlasmaShield system. Compared with the existing arrangement, very significant reductions in particle number concentrations were observed in the occupied space, especially with virus-like submicron particles. Significant reductions in airborne culturable bacteria and fungi were observed in the supply air, with more modest reductions in the occupied space. In the case of virus-like particles, there was an eight-fold improvement in equivalent clean air, suggesting a five-fold infection risk reduction for long-range exposure. The data suggest multiple benefits of airborne particle and bioaerosol reduction, with applications beyond healthcare. Long-term studies are recommended to confirm the combined IAQ, health and energy benefits.

Heme metabolism in Strigomonas culicis: Implications of H2O2 resistance induction and symbiont elimination

Monoxenous trypanosomatid Strigomonas culicis harbors an endosymbiotic bacterium, which enables the protozoa to survive without heme supplementation. The impact of H2O2 resistance and symbiont elimination on intracellular heme and Fe2+ availability was analyzed through a comparison of WT strain with both WT H2O2-resistant (WTR) and aposymbiotic (Apo) protozoa. The relative quantification of the heme biosynthetic pathway through label-free parallel reaction monitoring targeted mass spectrometry revealed that H2O2 resistance does not influence the abundance of tryptic peptides. However, the Apo strain showed increased coproporphyrinogen III oxidase and ferrochelatase levels. A putative ferrous iron transporter, homologous to LIT1 and TcIT from Leishmania major and Trypanosoma cruzi, was identified for the first time. Label-free parallel reaction monitoring targeted mass spectrometry also showed that S.culicis Iron Transporter (ScIT) increased 1.6- and 16.4-fold in WTR and Apo strains compared to WT. Accordingly, antibody-mediated blockage of ScIT decreased by 28.0% and 40.0% intracellular Fe2+concentration in both WTR and Apo strains, whereas no effect was detected in WT. In a heme-depleted medium, adding 10μM hemin decreased ScIT transcript levels in Apo, whereas 10μM PPIX, the substrate of ferrochelatase, increased intracellular Fe2+ concentration and ferric iron reduction. Overall, the data suggest mechanisms dependent on de novo heme synthesis (and its substrates) in the Apo strain to overcome reduced heme availability. Given the importance of heme and Fe2+ as cofactors in metabolic pathways, including oxidative phosphorylation and antioxidant systems, this study provides novel mechanistic insights associated with H2O2 resistance in S.culicis.

Optimizing ozone treatment for pathogen removal and disinfection by-product control for potable reuse at pilot-scale

Reclaimed water poses environmental and human health risks due to residual organic micropollutants and pathogens. Ozonation of reclaimed water to control pathogens and trace organics is an important step in advanced water treatment systems for potable reuse of reclaimed water. Ensuring efficient pathogen reduction while controlling disinfection byproducts remains a significant challenge to implementing ozonation in reclaimed water reuse applications. This study aimed to investigate ozonation conditions using a plug flow reactor (PFR) to achieve effective pathogen removal/inactivation while minimizing bromate and N-Nitrosodimethylamine (NDMA) formation. The pilot scale study was conducted using three doses of ozone (0.7, 1.0 and 1.4 ozone/total organic carbon (O3/TOC) ratio) to determine the disinfection performance using actual reclaimed water. The disinfection efficiency was assessed by measuring total coliforms, Escherichia coli (E. coli), Pepper Mild Mottle Virus (PMMoV), Tomato Brown Rugose Fruit Virus (ToBRFV) and Norovirus (HNoV). The ozone CT values ranged from 1.60 to 13.62 mg min L−1, resulting in significant reductions in pathogens and indicators. Specifically, ozone treatment led to concentration reductions of 2.46–2.89, 2.03–2.18, 0.46–1.63, 2.23–2.64 and > 4 log for total coliforms, E. coli, PMMoV, ToBRFV, and HNoV, respectively. After ozonation, concentrations of bromate and NDMA increased, reaching levels between 2.8 and 12.0 μg L−1, and 28–40.0 ng L−1, respectively, for average feed water bromide levels of 86.7 ± 1.8 μg L−1 and TOC levels of 7.2 ± 0.1 mg L−1. The increases in DBP formation were pronounced with higher ozone dosages, possibly requiring removal/control in subsequent treatment steps in some potable reuse applications.

Temporal trends of per- and polyfluoroalkyl substances concentrations: Insights from Australian human biomonitoring 2002–2021 and the U.S. NHANES programs 2003–2018

Perfluorooctanoic acid (PFOA), perfluorooctane sulfonate (PFOS), perfluorohexane sulfonate (PFHxS), and perfluorononanoic acid (PFNA) are persistent contaminants detected in human blood worldwide, raising significant health concerns. In response, countries such as the United States and Australia have implemented regulatory measures to limit their use. This study analysed temporal trends in serum concentrations of these four PFAS and how these trends align with regulatory measures, using data from NHANES (2003–2004 to 2017–2018) and the Australian Human Biomonitoring Program (2002–2003 to 2020–2021). Multiple regression analyses adjusted for age and gender were performed to estimate mean concentration changes over time, and differences within each dataset were assessed. Results indicated significant reductions (p < 0.001) in PFOS, PFOA, and PFHxS concentrations post-2002-2003, while PFNA concentrations increased until 2009–2010 before declining in both Australia and the U.S. Age-related trends in the U.S. during the last monitoring period showed higher PFAS concentrations in the oldest age groups, while in Australia, this trend was evident for PFOS and PFHxS. In Australia, the age group of 0–5 years had PFOA and PFNA concentrations similar to those of adults over 46 years, indicating ongoing exposure. Gender differences were consistent in both programs, with females aged 6–15, 31–45, and 46–60 years exhibiting lower serum concentrations, particularly in the 31–45 years age group. These findings support Australian and U.S. efforts to reduce PFAS exposure through regulatory actions, highlight the need to address ongoing exposure in young children, and consider gender-specific factors affecting PFAS concentrations.

Development of cellulose-based biosorbents from the residue of the peach palm agribusiness and simulation of industrial scale-up for copper removal from Brazilian spirit.

Cachaça (Brazilian spirit) is an alcoholic beverage of cultural and economic importance in Brazil. Its artisanal production is usually conducted in copper alembics, which results in contamination. The development of effective biosorbents from cheap matrices is an alternative to minimize both solid waste generation and copper levels in cachaça. The present work evaluates the obtention of nanocellulose-based materials from the major residue generated during the processing of palm heart from the Brazilian peach palm, through different processing techniques. Materials were characterized by physicochemical composition and their sorbent capacities for copper removal from aqueous solutions, and a simulation was conducted to evaluate potential application in the adequacy of cachaça to meet Brazilian legislation requirements. The different processing methods resulted in different cellulose concentrations, with the highest concentration in the bleached material (B3, 694 g kg-1 of cellulose), and different specific surface areas (1.02-12.4 m2 g-1). Copper adsorption onto nanocellulose obtained from peach palm external sheath is fast, with a predominance of a chemisorption mechanism. Isotherms were best represented by Langmuir's model, suggesting a monolayer adsorption. Simulations indicate that B3 is a suitable material for the removal of copper from cachaça, and small amounts of biosorbent (733.5 g) are required for the reduction of copper concentrations (10 to 3 mg L-1) in 1000 L of cachaça. This study demonstrated that the obtention of biosorbents from peach palm solid residues is promising and this nanocellulose-based material can be used for copper removal from contaminated cachaça. © 2024 Society of Chemical Industry.

The comparative performance study of the EF7 downsized engines; fuel economy besides CO2 reduction

Engine downsizing is considered a strategic idea in fuel economy enhancement as well as reduction. It is defined in the literature as the decrease in engine geometrical dimensions besides its performance being fixed. In this research, the Iranian gasoline-fueled national engine, EF7, has been investigated for 25% downsizing. After introducing the gasoline-fueled and CNG-fueled versions of downsized engines, their performance, besides release rates are studied in detail. A one-dimensional engine simulator coupled with a 3D-CFD model is developed to carry out such an investigation, an experimental test setup is provided to evaluate the accuracy of the provided numerical model, as well. The first version of presented downsized engines, called EF7, is a 3-cylinder engine with the same geometrical characteristics as the base engine, which is equipped with a turbo-charger and dual CVVT technologies. The EF7 is then introduced by fuel shifting to CNG as the second version of downsized engines, and finally, increasing the compression ratio, the EF7 is presented as the third version of studied-downsized engines. The results show almost the same rate of BSFC besides a 3.4% reduction in concentration for EF7, 20.6% fuel economy enhancement, besides 20.8% reduction in the specific release rate for EF7, and 28.8% fuel economy enhancement, besides 25.3% reduction in the specific release rate for EF7 in comparison with the base engine.

Inlet injection as an alternative, simplified method of hydrogen application in a miniature gas turbine

Hydrogen-powered gas turbines have great potential, because, among other things, they allow the elimination of the use of fuels containing carbon in their composition, which involves the elimination of CO2 emissions, which are a product of the combustion of hydrocarbon fuels. The paper presents the results of experimental research conducted on a miniature gas turbine co-powered by hydrogen gas. The aim of the research was to demonstrate the impact of the addition of hydrogen on the operation of the unit and exhaust gas emissions during hydrogen application in a way that does not require engine modification. This was accomplished by applying hydrogen gas through the turbine inlet. Hydrogen gas accounted for up to 0.91% of the total volume of gas flowing through the compressor, which resulted in hydrogen contributing almost 10% of the energy supplied to the engine in the form of fuel. The research focused on measuring fuel consumption, thrust, and temperature, as well as the composition of exhaust gases. The emission of carbon monoxide, nitrogen oxides and the concentration of oxygen and carbon dioxide were measured. The addition of hydrogen resulted in a reduction of the total mass of fuel consumed by over 18%. It led to a significant decrease in the temperature behind the combustion chamber with an increase in the amount of hydrogen applied. The addition of hydrogen also resulted in a reduction in CO2 concentration in exhaust gases by more than 30%, but at the same time, an increase in NOx emissions was recorded. The obtained results were compared with the results of tests presented in the literature, in which hydrogen was supplied to units of analogous structure in a classical way, i.e. directly to the combustion chamber.

Does double pre-notches have a greater impact than single pre-notch on the mechanical and fracture behavior of rock? Insights from three-point bending tests using the numerical approach of grain-based model

The mechanical performance of rock masses is significantly impacted by the existence of cracks. Distribution of the cracks may result in different mechanical or fracture behaviors of rock. To gain a preliminary understanding of such problems, a series of numerical tests of three-point bending (TPB) are designed and carried out with the consideration of single pre-notch and double pre-notches. The numerical method of grain-based model (GBM) approach is employed in this paper, with a validation implemented by comparing the results with previous experiments to demonstrate the reliability of this model. Afterward, a comprehensive investigation, including the mechanical behavior, strength characteristics, crack evolution and progressive failure mechanism of the above mentioned TPB tests are conducted. The conclusions are as follows: (1) During TPB tests, as the offset distance increases, the fracture mode of the single pre-notched specimens gradually transitions from Mode I to Mode II, with the peak fracture toughness occurring at a mixed Mode I-II fracture condition (2p/s = 0.4). Moreover, the failure angle, notch open degree and expansion area all tend to rise regardless of specimens of single or double pre-notches. (2) A thorough exploration of crack evolution shows that the specimens primarily fracture during the crack propagation and failure stages. Shear failure predominates among these stages, with microcracks mostly occurring inside the rock mineral grains. (3) When offset distance increases to a certain degree (2p/s = 0.8), the fracture of specimen ceases to be governed by the pre-notch; instead, it occurs directly from the middle of the beam specimen. This phenomenon can be attributed to the reduction of stress concentration at the notch tip, as inferred from analysis of the contact force chain. (4) In double pre-notched specimen, microcracks initiate at both pre-notches, but the final failure results from crack propagation at one notch tip. Compared to single pre-notched specimen, the presence of double pre-notches exhibits superior fracture resistance performance.

Impact of Changing Inlet Modes in Ski Face Masks on Adolescent Skiing: A Finite Element Analysis Based on Head Models

Due to the material properties of current ski face masks for adolescents, moisture in exhaled air can become trapped within the material fibers and freeze, leading to potential issues such as breathing difficulties and increased risk of facial frostbite after prolonged skiing. This paper proposes a research approach combining computational fluid dynamics (CFD) and ergonomics to address these issues and enhance the comfort of adolescent skiers. We developed head and face mask models based on the head dimensions of 15–17-year-old males. For enclosed cavities, ensuring the smooth expulsion of exhaled air to prevent re-inhalation is the primary challenge. Through fluid simulation of airflow characteristics within the cavity, we evaluated three different inlet configurations. The results indicate that the location of the air inlets significantly affects the airflow characteristics within the cavity. The side inlet design (type II) showed an average face temperature of 35.35 °C, a 38.5% reduction in average CO2 concentration within the cavity, and a smaller vortex area compared to the other two inlet configurations. Although the difference in airflow velocity within the cavity among the three configurations was minimal, the average exit velocity differed by up to 0.11 m/s. Thus, we conclude that the side inlet configuration offers minimal obstruction to airflow circulation and better thermal insulation when used in the design of fully enclosed helmets. This enhances the safety and comfort of adolescent wearers during physical activities in cold environments. Through this study, we aim to further promote the development of skiing education, enhance the overall quality of adolescents’ skiing, and thus provide them with more opportunities for the future.

Taurine modulates host cell responses to Helicobacter pylori VacA toxin.

Colonization of the human stomach with Helicobacter pylori strains producing active forms of the secreted toxin VacA is associated with an increased risk of peptic ulcer disease and gastric cancer, compared with colonization with strains producing hypoactive forms of VacA. Previous studies have shown that active s1m1 forms of VacA cause cell vacuolation and mitochondrial dysfunction. In this study, we sought to define the cellular metabolic consequences of VacA intoxication. Untargeted metabolomic analyses revealed that several hundred metabolites were significantly altered in VacA-treated gastroduodenal cells (AGS and AZ-521) compared with control cells. Pathway analysis suggested that VacA caused alterations in taurine and hypotaurine metabolism. Treatment of cells with the purified active s1m1 form of VacA, but not hypoactive s2m1 or Δ6-27 VacA-mutant proteins (defective in membrane channel formation), caused reductions in intracellular taurine and hypotaurine concentrations. Supplementation of the tissue culture medium with taurine or hypotaurine protected AZ-521 cells against VacA-induced cell death. Untargeted global metabolomics of VacA-treated AZ-521 cells or AGS cells in the presence or absence of extracellular taurine showed that taurine was the main intracellular metabolite significantly altered by extracellular taurine supplementation. These results indicate that VacA causes alterations in cellular taurine metabolism and that repletion of taurine is sufficient to attenuate VacA-induced cell death. We discuss these results in the context of previous literature showing the important role of taurine in cell physiology and the pathophysiology or treatment of multiple pathologic conditions, including gastric ulcers, cardiovascular disease, malignancy, inflammatory diseases, and other aging-related disorders.

Safety, pharmacokinetics, and pharmacodynamics of efzimfotase alfa, a second-generation enzyme replacement therapy: phase 1, dose-escalation study in adults with hypophosphatasia.

Hypophosphatasia (HPP) is a rare, inherited metabolic disease caused by deficient activity of tissue-nonspecific alkaline phosphatase (TNSALP). Efzimfotase alfa (ALXN1850) is a second-generation TNSALP enzyme replacement therapy in development for HPP. This first-in-human open-label, dose-escalating phase 1 trial evaluated efzimfotase alfa safety, tolerability, pharmacokinetics, pharmacodynamics, and immunogenicity. Fifteen adults (5/cohort) with HPP received efzimfotase alfa in doses of 15mg (cohort 1), 45mg (cohort 2), or 90mg (cohort 3) as one intravenous (i.v.) dose followed by 3 weekly subcutaneous (s.c.) doses. The primary objective was to assess safety and tolerability. Secondary objectives included pharmacokinetics, pharmacodynamics of ALP substrates known to be biomarkers of disease (inorganic pyrophosphate [PPi] and pyridoxal 5'-phosphate [PLP]) and immunogenicity. Treatment-emergent adverse events (TEAEs) occurred in 12 (80%) participants. Eight (53%) participants had injection site reactions (ISRs), observed after 10 of 41 (24%) s.c. injections. Most ISR TEAEs were mild and resolved within 1-2d. Peak and total exposures of efzimfotase alfa increased in a greater-than-dose proportional manner over the range of 15-90mg after i.v. and s.c. dosing. The arithmetic mean elimination half-life was approximately 6d; absolute bioavailability was 28.6%-36.8% over the s.c. dose range of 15-90mg. Dose-dependent reductions in plasma concentrations of PPi and PLP relative to baseline reached nadir in the first week after i.v. dosing and were sustained for 3-4wk after the last s.c. dose. Four (27%) participants tested positive for antidrug antibodies (ADAs), 3 of whom were ADA positive before the first dose of efzimfotase alfa. ADAs had no apparent effect on efzimfotase alfa pharmacokinetics/pharmacodynamics. No participants had neutralizing antibodies. Efzimfotase alfa demonstrated acceptable safety, tolerability, and pharmacokinetic profiles and was associated with sustained reductions in biomarkers of disease in adults with HPP, supporting further evaluation in adult and pediatric patients. Registration: ClinicalTrials.gov NCT04980248 (https://clinicaltrials.gov/study/NCT04980248).

Modelling Mediterranean ocean biogeochemistry of the Last Glacial Maximum

Abstract. We present results of simulations performed with a physical–biogeochemical ocean model of the Mediterranean Sea for the Last Glacial Maximum (LGM) and analyse the differences in physical and biochemical states between the historical period and the LGM. Long-term simulations with an Earth system model based on ice sheet reconstructions provide the necessary atmospheric forcing data, oceanic boundary conditions at the entrance to the Mediterranean Sea, and river discharge to the entire basin. Our regional model accounts for changes in bathymetry due to ice sheet volume changes, reduction in atmospheric CO2 concentration, and an adjusted aeolian dust and iron deposition. The physical ocean state of the Mediterranean during the LGM shows a reduced baroclinic water exchange at the Strait of Gibraltar, a more sluggish zonal overturning circulation, and the relocation of intermediate and deep-water-formation areas – all in line with estimates from palaeo-sediment records or previous modelling efforts. Most striking features of the biogeochemical realm are a reduction in the net primary production, an accumulation of nutrients below the euphotic zone, and an increase in the organic matter deposition at the seafloor. This seeming contradiction of increased organic matter deposition and decreased net primary production challenges our view of possible changes in surface biological processes during the LGM. We attribute the origin of a reduced net primary production to the interplay of increased stability of the upper water column, changed zonal water transport at intermediate depths, and lower water temperatures, which slow down all biological processes during the LGM. Cold water temperatures also affect the remineralisation rates of organic material, which explains the simulated increase in the organic matter deposition, which is in good agreement with sediment proxy records. In addition, we discuss changes in an artificial tracer which captures the surface ocean temperature signal during organic matter production. A shifted seasonality of the biological production in the LGM leads to a difference in the recording of the climate signal by this artificial tracer of up to 1 K. This could be of relevance for the interpretation of proxy records like, e.g., alkenones. Our study not only provides the first consistent insights into the biogeochemistry of the glacial Mediterranean Sea but will also serve as the starting point for transient simulations of the last deglaciation.

Reduced seed viability in exchange for transgenerational plant protection: Does the defensive mutualism concept pass the fitness test?

Epichloë endophytes are vertically transmitted via grass seeds and chemically defend their hosts against herbivory. Endophyte-conferred plant defence via alkaloid biosynthesis may occur independently of costs for host plant growth. However, fitness consequences of endophyte-conferred defence and transgenerational effects on herbivore resistance of progeny plants, are rarely studied. The aim of this study was to test whether severe defoliation in mother plants affects their seed production, seed germination rate, and the endophyte-conferred resistance of progeny plants. In a field study, we tested the effects of defoliation and endophyte symbiosis (Epichloë uncinata) on host plant (Festuca pratensis) performance, loline alkaloid concentrations in leaves and seeds, seed biomass and seed germination rates. In a subsequent greenhouse study, we challenged the progeny of the plants from the field study to aphid herbivory and tested whether defoliation of mother plants affects endophyte-conferred resistance against aphids in progeny plants. Defoliation of the mother plants resulted in a reduction of alkaloid concentrations in leaves and elevated the alkaloid concentrations in seeds when compared with non-defoliated endophyte-symbiotic plants. Viability and germination rate of seeds of defoliated endophyte-symbiotic plants were significantly lower compared to those of non-defoliated endophyte-symbiotic plants and endophyte-free (defoliated and non-defoliated) plants. During six weeks growth, seedlings of defoliated endophyte-symbiotic mother plants had elevated alkaloid concentrations, which negatively correlated with aphid performance. Endophyte-conferred investment in higher alkaloid levels in seeds -elicited by defoliation- provided herbivore protection in progenies during the first weeks of plant establishment. Better protection of seeds via high alkaloid concentrations negatively correlated with seed germination indicating trade-off between protection and viability.