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Differential measurements of Higgs boson production in the tau-lepton-pair decay channel are presented in the gluon fusion, vector-boson fusion (VBF), VH and t (t) over barH associated production modes, with particular focus on the VBF production mode. The data used to perform the measurements correspond to 140 fb(-1) of proton-proton collisions collected by the ATLAS experiment at the LHC. Two methods are used to perform the measurements: the Simplified Template Cross-Section (STXS) approach and an Unfolded Fiducial Differential measurement considering only the VBF phase space. For the STXS measurement, events are categorized by their production mode and kinematic properties such as the Higgs boson's transverse momentum (p(T)(H)), the number of jets produced in association with the Higgs boson, or the invariant mass of the two leading jets (m(jj)). For the VBF production mode, the ratio of the measured cross-section to the Standard Model prediction for m(jj) > 1.5 TeV and p(T)(H) > 200 GeV (p(T)(H) < 200 GeV) is 1.29(-0.34)(+0.39) (0.12(-0.33)(+0.34)). This is the first VBF measurement for the higher-p(T)(H) criteria, and the most precise for the lower-p(T)(H) criteria. The fiducial cross-section measurements, which only consider the kinematic properties of the event, are performed as functions of variables characterizing the VBF topology, such as the signed Delta phi(jj) between the two leading jets. The measurements have a precision of 30%-50% and agree well with the Standard Model predictions. These results are interpreted in the SMEFT framework, and place the strongest constraints to date on the CP-odd Wilson coefficient c(H (W) over tilde).

We give a comprehensive presentation of the periodic unfolding method for perforated domains, both when the unit hole is a compact subset of the open unit cell and when this is impossible to achieve. In order to apply the method to boundary-value problems with nonhomogeneous Neumann conditions on the boundaries of the holes, the properties of the boundary unfolding operator are also extensively studied. The paper concludes with applications to such problems and examples of reiterated unfolding.

Bovine milk beta-lactoglobulin (BLG) is a small whey protein that is a common ingredient in many foods. Many of the properties of BLG relevant to the food industry are related to its unfolding processes induced by physical or chemical treatments. Unfolding occurs through a number of individual steps, generating transient intermediates through reversible and irreversible modifications. The rate of formation of these intermediates and of their further evolution into different structures often dictates the outcome of a given process. This report addresses the main structural features of the BLG unfolding intermediates under conditions that may facilitate or impair their formation in response to chemical or physical denaturing agents. In consideration of the short lifespan of the transient species generated upon unfolding, this review also discusses how various methodological approaches may be adapted in exploring the process-dependent structural modifications of BLG from a kinetic and/or a thermodynamic standpoint. Some of the conceptual and methodological approaches presented and discussed in this review can provide hints for improving the understanding of transient conformers formation by proteins present in other food systems, as well as when other physical or chemical denaturing agents are acting on proteins much different from BLG in complex food systems.

Allostery is the process by which biological macromolecules transmit the effect of binding at one site to another, often distal, functional site, allowing for the regulation of activity; here facilitation of allostery through dynamic and intrinsically disordered proteins is discussed, and a framework to unify the description of allosteric mechanisms for different systems is proposed. The changing shape of allostery The classic model for understanding allostery, the regulated process by which biological macromolecules (typically enzymes) transmit the effect of binding at one site to another with subsequent change in activity, has focused on unique structures and the structural changes observed between different functional forms. During the past 20 years there has been a realization that allostery is associated with changes in dynamics as well. In this Review, Vincent Hilser and colleagues discuss how allostery can be facilitated by dynamic and intrinsically disordered proteins and propose a framework to unify the description of allosteric mechanisms from different systems. Allostery is the process by which biological macromolecules (mostly proteins) transmit the effect of binding at one site to another, often distal, functional site, allowing for regulation of activity. Recent experimental observations demonstrating that allostery can be facilitated by dynamic and intrinsically disordered proteins have resulted in a new paradigm for understanding allosteric mechanisms, which focuses on the conformational ensemble and the statistical nature of the interactions responsible for the transmission of information. Analysis of allosteric ensembles reveals a rich spectrum of regulatory strategies, as well as a framework to unify the description of allosteric mechanisms from different systems.

Actin, a key component of the cytoskeleton, undergoes significant structural and thermal changes in response to various regulatory factors, including the neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP). In this study, we applied deconvolution analysis to previously obtained differential scanning calorimetry (DSC) data to resolve overlapping thermal transitions in G- and F-actin unfolding. Our findings reveal that PACAP38 and PACAP6-38 significantly alter actin stability, increasing structural cooperativity in G-actin while reducing monomer–monomer interactions in F-actin. These thermodynamic changes suggest a potential role for PACAP in modulating actin polymerization and depolymerization dynamics, contributing to cytoskeletal remodeling.

Commensal and pathogenic bacteria must deal with many different stress conditions to survive in and colonize the human gastrointestinal tract. One major challenge that bacteria encounter in the gut is the high concentration of bile salts, which not only aid in food absorption but also act as effective physiological antimicrobials. The mechanism by which bile salts limit bacterial growth is still largely unknown. Here, we show that bile salts cause widespread protein unfolding and aggregation, affecting many essential proteins. Simultaneously, the bacterial cytosol becomes highly oxidizing, indicative of disulfide stress. Strains defective in reducing oxidative thiol modifications, restoring redox homeostasis, or preventing irreversible protein aggregation under disulfide stress conditions are sensitive to bile salt treatment. Surprisingly, cholate and deoxycholate, two of the most abundant and very closely related physiological bile salts, vary substantially in their destabilizing effects on proteins in vitro and cause protein unfolding of different subsets of proteins in vivo. Our results provide a potential mechanistic explanation for the antimicrobial effects of bile salts, help explain the beneficial effects of bile salt mixtures, and suggest that we have identified a physiological source of protein-unfolding disulfide stress conditions in bacteria.

Fluorinated graphene, a two-dimensional nanomaterial composed of three atomic layers, a central carbon layer sandwiched between two layers of fluorine atoms, has attracted considerable attention across various fields, particularly for its potential use in biomedical applications. Nonetheless, scant effort has been devoted to assessing the potential toxicological implications of this nanomaterial. In this study, we scrutinize the potential impact of fluorinated graphene on a protein model, HP35 by utilizing extensive molecular dynamics (MD) simulation methods. Our MD results elucidate that upon adsorption to the nanomaterial, HP35 undergoes a denaturation process initiated by the unraveling of the second helix of the protein and the loss of the proteins hydrophobic core. In detail, substantial alterations in various structural features of HP35 ensue, including alterations in hydrogen bonding, Q value, and RMSD. Subsequent analyses underscore that hydrophobic and van der Waals interactions (predominant), alongside electrostatic energy (subordinate), exert influence over the adsorption of HP35 on the fluorinated graphene surface. Mechanistic scrutiny attests that the unrestrained lateral mobility of HP35 on the fluorinated graphene nanomaterial primarily causes the exposure of HP35's hydrophobic core, resulting in the eventual structural denaturation of HP35. A trend in the features of 2D nanostructures is proposed that may facilitate the denaturation process. Our findings not only substantiate the potential toxicity of fluorinated graphene but also unveil the underlying molecular mechanism, which thereby holds significance for the prospective utilization of such nanomaterials in the field of biomedicine.

We investigated the fusion of high-speed liquid droplets as a way to record the kinetics of liquid-phase chemical reactions on the order of microseconds. Two streams of micrometer-size droplets collide with one another. The droplets that fused (13 μm in diameter) at the intersection of the two streams entered the heated capillary inlet of a mass spectrometer. The mass spectrum was recorded as a function of the distancexbetween the mass spectrometer inlet and the droplet fusion center. Fused droplet trajectories were imaged with a high-speed camera, revealing that the droplet fusion occurred approximately within a 500-μm radius from the droplet fusion center and both the size and the speed of the fused droplets remained relatively constant as they traveled from the droplet fusion center to the mass spectrometer inlet. Evidence is presented that the reaction effectively stops upon entering the heated inlet of the mass spectrometer. Thus, the reaction time was proportional toxand could be measured and manipulated by controlling the distancex. Kinetic studies were carried out in fused water droplets for acid-induced unfolding of cytochromecand hydrogen–deuterium exchange in bradykinin. The kinetics of the former revealed the slowing of the unfolding rates at the early stage of the reaction within 50 μs. The hydrogen–deuterium exchange revealed the existence of two distinct populations with fast and slow exchange rates. These studies demonstrated the power of this technique to detect reaction intermediates in fused liquid droplets with microsecond temporal resolution.

A hallmark of eukaryotic cells is the ability to compartmentalize essential reactions into membrane-bound and membraneless organelles. Membrane-bound organelles form networks through transport vesicles and interorganellar contact sites. The endoplasmic reticulum (ER) has emerged as a network hub and forms physical connections with nearly every membrane-bound organelle. Lee et al. now identify another class of ER contact sites that appear to help regulate the biogenesis and fission of membraneless ribonucleoprotein (RNP) granules (see the Perspective by Kornmann and Weis). Live-cell fluorescence microscopy of human cells revealed that ER tubule dynamics are spatially and temporally coupled to the fission site of two types of RNP granules, processing bodies (P-bodies) and stress granules. Science , this issue p. eaay7108 ; see also p. 507 Endoplasmic reticulum tubules control ribonucleoprotein particle granule biogenesis and fission. Tethered interactions between the endoplasmic reticulum (ER) and other membrane-bound organelles allow for efficient transfer of ions and/or macromolecules and provide a platform for organelle fission. Here, we describe an unconventional interface between membraneless ribonucleoprotein granules, such as processing bodies (P-bodies, or PBs) and stress granules, and the ER membrane. We found that PBs are tethered at molecular distances to the ER in human cells in a tunable fashion. ER-PB contact and PB biogenesis were modulated by altering PB composition, ER shape, or ER translational capacity. Furthermore, ER contact sites defined the position where PB and stress granule fission occurs. We thus suggest that the ER plays a fundamental role in regulating the assembly and disassembly of membraneless organelles.

Highly sophisticated mechanisms that modulate protein structure and function, which involve synthesis and degradation, have evolved to maintain cellular homeostasis. Perturbations in these mechanisms can lead to protein dysfunction as well as deleterious cell processes. Therefore in recent years the etiology of a great number of diseases has been attributed to failures in mechanisms that modulate protein structure. Interconnections among metabolic and cell signaling pathways are critical for homeostasis to converge on mechanisms associated with protein folding as well as for the preservation of the native structure of proteins. For instance, imbalances in secretory protein synthesis pathways lead to a condition known as endoplasmic reticulum (ER) stress which elicits the adaptive unfolded protein response (UPR). Therefore, taking this into consideration, a key part of this paper is developed around the protein folding phenomenon, and cellular mechanisms which support this pivotal condition. We provide an overview of chaperone protein function, UPR via, spatial compartmentalization of protein folding, proteasome role, autophagy, as well as the intertwining between these processes. Several diseases are known to have a molecular etiology in the malfunction of mechanisms responsible for protein folding and in the shielding of native structure, phenomena which ultimately lead to misfolded protein accumulation. This review centers on our current knowledge about pathways that modulate protein folding, and cell responses involved in protein homeostasis.