Mechanistic insights into quorum quenching

A pan-azole-resistant strain was generated in vitro, in which drug transporter overexpression was a major trait. Analyses suggested a role of the transporter inhibitor milbemycin oxime in inhibiting drug transporters and potentiating azole activity.

The adsorption of biomolecules to the surface of engineered nanomaterials, known as corona formation, defines their biological identity by altering their surface properties and transforming the physical, chemical and biological characteristics of the particles. In the first decade since the term protein corona was coined, studies have focused primarily on biomedical applications and human toxicity. The relevance of the environmental dimensions of the protein corona is still emerging. Often referred to as the eco-corona, a biomolecular coating forms upon nanomaterials as they enter the environment and may include proteins, as well as a diverse array of other biomolecules such as metabolites from cellular activity and/or natural organic matter. Proteins remain central in studies of eco-coronas because of the ease of monitoring and structurally characterizing proteins, as well as their crucial role in receptor engagement and signalling. The proteins within the eco-corona are optimal targets to establish the biophysicochemical principles of corona formation and transformation, as well as downstream impacts on nanomaterial uptake, distribution and impacts on the environment. Moreover, proteins appear to impart a biological identity, leading to cellular or organismal recognition of nanomaterials, a unique characteristic compared with natural organic matter. We contrast insights into protein corona formation from clinical samples with those in environmentally relevant systems. Principles specific to the environment are also explored to gain insights into the dynamics of interaction with or replacement by other biomolecules, including changes during trophic transfer and ecotoxicity. With many challenges remaining, we also highlight key opportunities for method development and impactful systems on which to focus the next phase of eco-corona studies. By interrogating these environmental dimensions of the protein corona, we offer a perspective on how mechanistic insights into protein coronas in the environment can lead to more sustainable, environmentally safe nanomaterials, as well as enhancing the efficacy of nanomaterials used in remediation and in the agri-food sector.

Homolytic activation of peroxydisulfate (PS) by iron sulfides (Fe x S y ) is a promising alternative to conventional electron-transfer methods for generating sulfate radicals (SO 4 •− ), yet the influence of Fe x S y crystallography on the surface-mediated mechanism remains unresolved. In this study, various Fe x S y crystals of pyrite, mackinawite, and troilite were synthesized to perform the first detailed elucidation of the surface-mediated PS activation mechanism. This showed the stoichiometric activation of PS by the prepared Fe x S y was at least 70 times higher than the theoretical value, demonstrating the presence of a highly efficient PS activation pathway. DFT calculations showed that the elongation of the O O bond length from 1.230 to 1.509 Å, observed after bonding with 3 d Fe orbitals of pyrite and troilite, suggests that PS molecules are more easily cleaved by a homolytic process leading to two SO 4 • − . The respective dominant radicals were subsequently determined by kinetic isotope effect, demonstrating that SO 4 • − formation was more pronounced in pyrite (KIE = 2.01), whereas the passivated troilite surface (KIE = 1.42–1.52) and instable mackinawite structure (KIE = 1.92) affected its generation and existence. Furthermore, our findings indicate that Fe IV =O 2+ formation is primarily enabled by the presence of SO 4 • − , which facilitates a one-electron transfer through a homogeneous process. The investigation of PS activation process reveals that iron sulfides containing pyrite supports longer-term PS activation and higher stability compared to troilite and mackinawite. These mechanistic and structure-activity relationship insights are important for the rational design of next-generation Fe x S y catalysts for SO 4 • − -based Advanced Oxidation Processes (AOPs). • The hypothesis of surface-mediated homolytic peroxydisulfate activation by Fe x S y is confirmed. • Pyrite is more reactive and stable for peroxydisulfate activator than troilite and mackinawite. • DFT calculation confirms stretched O O bond of peroxydisulfate when bound to Fe x S y surface. • Fe IV =O 2+ species are formed from Fe(OH)(H 2 O) 5 2+ intermediates by SO 4 •− oxidation at pH < 6.

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Catheter ablation is a good treatment option for atrial fibrillation (AF) in young symptomatic patients. However, there is little information on the efficacy of catheter ablation of early-onset AF between sexes. This study included 1,060 patients under the age 60 years old (837 men, 49.8±7.7 years old, 70.8% paroxysmal AF) who underwent catheter ablation for AF. Sex differences in clinical presentation and ablation outcomes were compared with and without propensity score-matching. During 24.5±18.9 months of follow-up, women showed significantly higher clinical recurrence of AF than men (log-rank, P=0.002). Female sex was independently associated with post-ablation clinical recurrence of AF (adjusted hazard ratio (HR) 2.58 [1.06-6.30], P=0.037). Women had a higher proportion of left ventricular diastolic dysfunction (E/Em, P<0.001), higher prevalence of heart failure (P=0.017), greater left atrial (LA) volume index (P=0.001), lower LA endocardial voltage (P<0.001), and higher parasympathetic nervous activity (root-mean square of differences, P<0.001; high-frequency (HF), P=0.010) than men. After a second ablation procedure (n=111), women still showed a higher clinical recurrence rate than men (log-rank, P=0.003) during 22.9±15.0 months of follow-up. Among patients with early-onset AF who underwent catheter ablation, women showed poorer clinical outcomes than men after de novo and second procedures. Left ventricular dysfunction, LA remodeling, and autonomic nervous function may be potential mechanisms underlying sex differences in catheter ablation outcomes of early-onset AF.

Mycobacterium tuberculosis (Mtb) has the ability to persist within the human host for a long time in a dormant stage and re-emerges when the immune system is compromised. During infection, Mtb is exposed to a number of redox stresses inside macrophages, such as reactive oxygen species and reactive nitrogen intermediates, both having the potential to damage a number of cellular components, including lipids, proteins, and DNA The ability of Mtb to persist inside macrophages suggests the presence of elaborated machineries capable of preserving redox homeostasis and countering oxidoreductive stress. Mtb is equipped with sophisticated proteins and thiols (mycothiol) responsible for antioxidant defense. Most of these proteins as well as mycothiol are unique to mycobacteria and therefore lacking in the human host, like the mycothiol-dependent system composed of the enzymes mycothione reductase (Mtr), myco-redoxin1 (Mrx-1), and the alkyl hydroperoxidase subunit E (MtAhpE), responsible for the reduction of hydrogen peroxide, peroxynitrous acid, organic peroxides or Smycothiolated mixed disulfides, generated by oxidative stress. Clearly, the protein ensemble and mycothiol of the antioxidant defense of Mtb differ substantially from that in the mammalian hosts and thus the chances for a selective inhibition of the mycobacterial antioxidant defense system will be high. In the effort to understand the biological mechanisms of the mycobacterial antioxidant defense orchestra, this work aims to provide structural, enzymatic and mechanistic insights into the Mtb NADPH dependent Mtr (MtMtr), structural details of Mtb Mrx-1 (MtMrx-1) and AhpE (MtAhpE) as well as mechanistic insights into the mycothiol/Mrx-1 dependent recycling of peroxiredoxin MtAhpE.

Azoles inhibit ergosterol biosynthesis, resulting in ergosterol depletion and accumulation of toxic 14alpha-methylated sterols in membranes of susceptible yeast. We demonstrated previously that miconazole induces actin cytoskeleton stabilization in Saccharomyces cerevisiae prior to induction of reactive oxygen species, pointing to an ancillary mode of action. Using a genome-wide agar-based screening, we demonstrate in this study that S. cerevisiae mutants affected in sphingolipid and ergosterol biosynthesis, namely ipt1, sur1, skn1, and erg3 deletion mutants, are miconazole-resistant, suggesting an involvement of membrane rafts in its mode of action. This is supported by the antagonizing effect of membrane raft-disturbing compounds on miconazole antifungal activity as well as on miconazole-induced actin cytoskeleton stabilization and reactive oxygen species accumulation. These antagonizing effects point to a primary role for membrane rafts in miconazole antifungal activity. We further show that this primary role of membrane rafts in miconazole action consists of mediating intracellular accumulation of miconazole in yeast cells.

An implicit aim in cellular infection biology is to understand the mechanisms how viruses, microbes, eukaryotic parasites, and fungi usurp the functions of host cells and cause disease. Mechanistic insight is a deep understanding of the biophysical and biochemical processes that give rise to an observable phenomenon. It is typically subject to falsification, that is, it is accessible to experimentation and empirical data acquisition. This is different from logic and mathematics, which are not empirical, but built on systems of inherently consistent axioms. Here, we argue that modeling and computer simulation, combined with mechanistic insights, yields unprecedented deep understanding of phenomena in biology and especially in virus infections by providing a way of showing sufficiency of a hypothetical mechanism. This ideally complements the necessity statements accessible to empirical falsification by additional positive evidence. We discuss how computational implementations of mathematical models can assist and enhance the quantitative measurements of infection dynamics of enveloped and non-enveloped viruses and thereby help generating causal insights into virus infection biology.

Understanding biomineralization is one of the great challenges of our scientific community. Where biological systems are complex and difficult to study at the molecular or (sub)nanometre level, simplified in vitro models have been successfully applied to gain further mechanistic insights and provide important guidelines for bio-inspired materials synthesis. However, such insights can only be obtained through the use of techniques that are able to provide information on the dynamics of interaction between the organic and inorganic phases at the (sub-)nanometre level. After discussing recent new mechanistic insights in bio(mimetic) mineralization and techniques that can provide information on the early stages of mineral formation, we focus on the use of TEM and TEM-related techniques (diffraction, EDX, EELS) for the study of biominerals and biomimetic mineral formation, also addressing tomography for 3D imaging. Conventional TEM techniques – which require drying of the sample – cannot provide information on the dynamics of mineralization processes. In contrast, using cryogenic TEM (cryoTEM) and cryo-electron tomography samples can be studied in their native hydrated state, which recently allowed the visualization of new ‘non-classical’ mineralization pathways. Also the use of in situ TEM has recently opened new possibilities to obtain a deeper understanding of bio(mimetic) mineralization.

Reviewers remarked that the study described in the preprint was an ambitious, well-planned and comprehensive profiling of serum proteins that have altered expression in patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS).

Phospha-Mannich reactions of benzyl carbamate, aldehydes, and methyl dichlorophosphite followed by aminolysis with amino acid esters or alcoholysis with hydroxyl acid esters produce N-Cbz(benzyloxycarbonyl)-protected phosphonopeptides or phosphonodepsipeptides. However, similar reactions do not work when Cbz-amino amides are used instead of the carbamate. Phospha-Mannich reactions of N-Cbz-amino amides/2-(Cbz-amino)alkanesulfonamides, aldehydes, and dichloroarylphosphines and subsequent aminolysis with amino acid esters or alcoholysis with hydroxyl acid esters yield phosphinopeptides or phosphinodepsipeptides and hybrid sulfonophosphinopeptides or sulfonophosphinodepsipeptides. The different reactivities and mechanistic insights are rationalized that the α-amino alcohols generated from aldehydes and amides/sulfonamides show weaker nucleophilicity than those generated from aldehydes and benzyl carbamate. They can react with stronger electrophilic dichloroarylphosphines rather than weaker electrophilic methyl dichlorophosphite. The nucleophilicity of α-amino alcohols (amine reagents, carbamates, amides, and sulfonamides) and the electrophilicity of phosphorus reagents (dichloroarylphosphines and ethyl dichlorophosphite) control the reactivity of the phospha-Mannich reactions. Phosphorus trichloride is also efficient phosphorus reagent in the phospha-Mannich reactions because it is stronger electrophile as well.

Bioleaching for critical metal recovery from e-waste: Mechanistic insights, hybrid strategies, and future perspectives.

Mechanistic insights into mitigating N2O emissions by the nitrification inhibitor dicyandiamide (DCD) in a tropical sandy soil after six years of manure amendment

The electrochemical reduction of CO2 (ECO2RR) has emerged as a promising route for converting CO2 into value‐added chemicals and fuels using renewable electricity. Among transition metals, copper uniquely enables the formation of C1 and C2 products, but it suffers from poor selectivity and stability in its monometallic form. This review explores recent advances in Cu–Zn and Cu–Bi bimetallic systems, emphasizing how their structural, electronic, and interfacial characteristics influence ECO2RR pathways and product distribution. Mechanistic insights into active site behavior, alloying effects, and the role of surface facets are provided. Limitations such as catalyst degradation and scalability are critically discussed, including a comparing performance across different electrochemical cell configurations. Finally, design guidelines and future research directions are proposed to enhance Cu‐based bimetallic catalysts’ selectivity, stability, and scalability for ECO2RR.

A number of proteases in the subtilisin family derived from environmental or pathogenic microorganisms have been reported to be collagenolytic serine proteases. However, their collagen degradation mechanisms remain unclear. Here, the degradation mechanism of type I collagen fibres by the S8 collagenolytic protease MCP-01, from Pseudoalteromonas sp. SM9913, was studied. Atomic force microscopy observation and biochemical analysis confirmed that MCP-01 progressively released single fibrils from collagen fibres and released collagen monomers from fibrils mainly by hydrolysing proteoglycans and telopeptides in the collagen fibres. Structural and mutational analyses indicated that an enlarged substrate-binding pocket, mainly composed of loops 7, 9 and 11, is necessary for collagen recognition and that the acidic and aromatic residues on these loops form a negatively charged, hydrophobic environment for collagen binding. MCP-01 displayed a non-strict preference for peptide bonds with Pro or basic residues at the P1 site and/or Gly at the P1' site in collagen. His211 is a key residue for the P1-basic-residue preference of MCP-01. Our study gives structural and mechanistic insights into collagen degradation of the S8 collagenolytic protease, which is helpful in developing therapeutics for diseases with S8 collagenolytic proteases as pathogenic factors and in studying environmental organic nitrogen degradation mechanisms.