RESUMEN

BACKGROUND: Internet gaming disorder (IGD) is mainly characterized by its core dysfunction in higher-order brain cortices involved in inhibitory control, whose neurobiological basis remains unclear. Then, we will investigate local intrinsic neural activity (INA) alterations in IGD, ascertain whether these potential alterations are related to clinical characteristics, and further explore the underlying molecular architecture. METHOD: In this study, we performed the fractional amplitude of low-frequency fluctuation (fALFF) and regional homogeneity (ReHo) derived from resting-state functional magnetic resonance imaging (rs-fMRI) to explore the impact of IGD on local INA. Correlation analysis revealed the relationship between ReHo and fALFF in terms of group differences and clinical characteristics. Moreover, correlations between fALFF, ReHo, and PET- and SPECT-driven maps were investigated to elucidate the specific molecular architecture alternations in IGD. Finally, receiver operating characteristic curve (ROC) analysis was used to show the potential abilities of fALFF and ReHo in distinguishing individuals with IGD (IGDs) from healthy controls (HCs). RESULT: Compared with HCs, IGDs revealed increased ReHo and fALFF in the prefrontal cortex. Significantly decreased ReHo was observed in the temporal lobe, occipital lobe, and cerebellum. In addition, the ReHo values in the cerebellum_7b_R were positively correlated with internet addiction severity. ROC curve analysis showed that ReHo and fALFF-altered brain regions could effectively distinguish IGDs from HCs. More importantly, cross-modal correlations revealed local INA changes in brain regions associated with the monoamine neurotransmitter system and the less studied cholinergic/GABAergic system. CONCLUSION: These results suggest that local functional impairments are shown in the audiovisual and inhibitory control circuits in IGDs. This may be associated with underlying neurotransmitter system alterations. Therefore, this study provides the possibility of GABAergic receptor agonists and cholinergic receptor inhibitors for the treatment of IGD.

Asunto(s)

RESUMEN

The therapeutic outcomes of patients with eosinophilic chronic rhinosinusitis (ECRS) remain unsatisfactory, largely because the underlying mechanisms of eosinophilic inflammation are uncertain. Here, it is shown that the nasal secretions of ECRS patients have high eosinophil extracellular trap (EET) and cell-free DNA (cfDNA) levels. Moreover, the cfDNA induced EET formation by activating toll-like receptor 9 (TLR9) signaling. After demonstrating that DNase I reduced eosinophilic inflammation by modulating EET formation, linear polyglycerol-amine (LPGA)-coated TiS2 nanosheets (TLPGA) as functional 2D nanoplatforms with low cytotoxicity, mild protein adsorption, and increased degradation rate is developed. Due to the more flexible linear architecture, TLPGA exhibited higher cfDNA affinity than the TiS2 nanosheets coated with dendritic polyglycerol-amine (TDPGA). TLPGA reduced cfDNA levels in the nasal secretions of ECRS patients while suppressing cfDNA-induced TLR9 activation and EET formation in vitro. TLPGA displayed exceptional biocompatibility, preferential nasal localization, and potent inflammation modulation in mice with eosinophilic inflammation. These results highlight the pivotal feature of the linear molecular architecture and 2D sheet-like nanostructure in the development of anti-inflammation nanoplatforms, which can be exploited for ECRS treatment.

Asunto(s)

RESUMEN

The Poaceae family of plants provides cereal crops that are critical for human and animal nutrition, and also, they are an important source of biomass. Interacting plant cell wall components give rise to recalcitrance to digestion; thus, understanding the wall molecular architecture is important to improve biomass properties. Xylan is the main hemicellulose in grass cell walls. Recently, we reported structural variation in grass xylans, suggesting functional specialisation and distinct interactions with cellulose and lignin. Here, we investigated the functions of these xylans by perturbing the biosynthesis of specific xylan types. We generated CRISPR/Cas9 knockout mutants in Brachypodium distachyon XAX1 and GUX2 genes involved in xylan substitution. Using carbohydrate gel electrophoresis, we identified biochemical changes in different xylan types. Saccharification, cryo-SEM, subcritical water extraction and ssNMR were used to study wall architecture. BdXAX1A and BdGUX2 enzymes modify different types of grass xylan. Brachypodium mutant walls are likely more porous, suggesting the xylan substitutions directed by both BdXAX1A and GUX2 enzymes influence xylan-xylan and/or xylan-lignin interactions. Since xylan substitutions influence wall architecture and digestibility, our findings open new avenues to improve cereals for food and to use grass biomass for feed and the production of bioenergy and biomaterials.

Asunto(s)

RESUMEN

ε-Poly-l-lysine (ε-PL) is a natural homo-poly(amino acid) which can be produced by microorganisms. With the advantages in broad-spectrum antimicrobial activity, biodegradability, and biocompatibility, ε-PL has been widely used as a preservative in the food industry. Different molecular architectures endow ε-PL and ε-PL-based materials with versatile applications. However, the microbial synthesis of ε-PL is currently limited by low efficiencies in genetic engineering and molecular architecture modification. This review presents recent advances in ε-PL production and molecular architecture modification of microbial ε-PL, with a focus on the current challenges and solutions for the improvement of the productivity and diversity of ε-PL. In addition, we highlight recent examples where ε-PL has been applied to expand the versability of edible films and nanoparticles in various applications. Commercial production and the challenges and future research directions in ε-PL biosynthesis are also discussed. Currently, although the main use of ε-PL is as a food preservative, ε-PL and ε-PL-based polymers have shown excellent application potential in biomedical fields. With the development of synthetic biology, the design and synthesis of ε-PL with a customized molecular architecture are possible in the near future. ε-PL-based polymers with specific functions will be a new trend in biopolymer manufacturing.

Asunto(s)

RESUMEN

Short surfactant-like amphiphilic peptide, A3K, resembling a surfactant with a hydrophobic tail (A3) and a polar headgroup (K), is experimentally determined to form a membrane. Although the peptides are known to exist as ß-strands, the exact packing architecture stabilizing the membrane is unknown. Earlier simulation studies have reported successful packing configurations through trial and error. In this work, we present a systematic protocol to identify the best peptide configurations for different packing patterns. The influence of stacking peptides in square and hexagonal packing geometry with the neighboring peptides in parallel and antiparallel orientations was explored. The best peptide configurations were determined from the free energy of bringing 2-4 peptides together as a bundle that can be stacked into a membrane. The stability of the assembled bilayer membrane was further investigated through molecular dynamics simulation. The role of peptide tilting, interpeptide distance, the nature and the extent of interactions, and the conformational degrees of freedom on the stability of the membrane is discussed. The consistency with the experimental findings suggests hexagonal antiparallel as the most relevant molecular architecture.

Asunto(s)

RESUMEN

The incorporation of polycarboxylate ether superplasticizer (PCE)-type polymers and silica fume (SF) in high-performance concretes (HPC) leads to remarkable rheological and mechanical improvements. In the fresh state, PCEs are adsorbed on cement particles and dispersants, promoting the workability of the concrete. Silica fume enables very well-compacted concrete to be obtained, which is characterized by high mechanical parameters in its hardened state. Some PCEs are incompatible with silica fume, which can result in slump loss and poor rheological behavior. The main objective of this research is to study the influence of three types of PCEs, which all have different molecular architectures, on the rheological and mechanical behavior of high-performance concretes containing 10% SF as a partial replacement of cement. The results show that the carboxylic density of PCE has an influence on its compatibility with SF.

RESUMEN

Schizophrenia is a self-disorder characterized by disrupted brain dynamics and architectures of multiple molecules. This study aims to explore spatiotemporal dynamics and its association with psychiatric symptoms. Resting-state functional magnetic resonance imaging data were collected from 98 patients with schizophrenia. Brain dynamics included the temporal and spatial variations in functional connectivity density and association with symptom scores were evaluated. Moreover, the spatial association between dynamics and receptors/transporters according to prior molecular imaging in healthy subjects was examined. Patients demonstrated decreased temporal variation and increased spatial variation in perceptual and attentional systems. However, increased temporal variation and decreased spatial variation were revealed in higher order networks and subcortical networks in patients. Specifically, spatial variation in perceptual and attentional systems was associated with symptom severity. Moreover, case-control differences were associated with dopamine, serotonin and mu-opioid receptor densities, serotonin reuptake transporter density, dopamine transporter density, and dopamine synthesis capacity. Therefore, this study implicates the abnormal dynamic interactions between the perceptual system and cortical core networks; in addition, the subcortical regions play a role in the dynamic interaction among the cortical regions in schizophrenia. These convergent findings support the importance of brain dynamics and emphasize the contribution of primary information processing to the pathological mechanism underlying schizophrenia.

Asunto(s)

RESUMEN

Recent advances in cryo-electron microscopy have marked only the beginning of the potential of this technique. To bring structure into cell biology, the modality of cryo-electron tomography has fast developed into a bona fide in situ structural biology technique where structures are determined in their native environment, the cell. Nearly every step of the cryo-focused ion beam-assisted electron tomography (cryo-FIB-ET) workflow has been improved upon in the past decade, since the first windows were carved into cells, unveiling macromolecular networks in near-native conditions. By bridging structural and cell biology, cryo-FIB-ET is advancing our understanding of structure-function relationships in their native environment and becoming a tool for discovering new biology.

Asunto(s)

RESUMEN

Xylan is the most abundant non-cellulosic polysaccharide in grass cell walls, and it has important structural roles. The name glucuronoarabinoxylan (GAX) is used to describe this variable hemicellulose. It has a linear backbone of ß-1,4-xylose (Xyl) residues that may be substituted with α-1,2-linked (4-O-methyl)-glucuronic acid (GlcA), α-1,3-linked arabinofuranose (Araf), and sometimes acetylation at the O-2 and/or O-3 positions. The role of these substitutions remains unclear, although there is increasing evidence that they affect the way xylan interacts with other cell wall components, particularly cellulose and lignin. Here, we used substitution-dependent endo-xylanase enzymes to investigate the variability of xylan substitution in grass culm cell walls. We show that there are at least three different types of xylan: (i) an arabinoxylan with evenly distributed Araf substitutions without GlcA (AXe); (ii) a glucuronoarabinoxylan with clustered GlcA modifications (GAXc); and (iii) a highly substituted glucuronoarabinoxylan (hsGAX). Immunolocalization of AXe and GAXc in Brachypodium distachyon culms revealed that these xylan types are not restricted to a few cell types but are instead widely detected in Brachypodium cell walls. We hypothesize that there are functionally specialized xylan types within the grass cell wall. The even substitutions of AXe may permit folding and binding on the surface of cellulose fibrils, whereas the more complex substitutions of the other xylans may support a role in the matrix and interaction with other cell wall components.

Asunto(s)

RESUMEN

The assembly of membraneless compartments by phase separation has recently been recognized as a mechanism for spatial and temporal organization of biomolecules within the cell. The functions of such mesoscale assemblies, termed biomolecular condensates, depend on networks of multivalent interactions between proteins, their structured and disordered domains, and commonly also include nucleic acids. Cryo-electron tomography is an ideal tool to investigate the three-dimensional architecture of such pleomorphic interaction networks at nanometer resolution and thus form inferences about function. However, preparation of suitable cryo-electron microscopy samples of condensates may be prone to protein denaturation, low retention of material on the sample carrier, and contamination associated with cryo-sample preparation and transfers. Here, we describe a series of protocols designed to obtain high-quality cryo-electron tomography data of biomolecular condensates reconstituted in vitro. These include critical screening by light microscopy, cryo-fixation by plunge freezing, sample loading into an electron microscope operated at liquid nitrogen temperature, data collection, processing of the data into three-dimensional tomograms, and their interpretation.

Asunto(s)

RESUMEN

Shape memory polymers (SMPs) as a relatively new class of smart materials have gained increasing attention in academic research and industrial developments (e.g., biomedical engineering, aerospace, robotics, automotive industries, and smart textiles). SMPs can switch their shape, stiffness, size, and structure upon being exposed to external stimuli. Electrospinning technique can endow SMPs with micro-/nanocharacteristics for enhanced performance in biomedical applications. Dynamically changing micro-/nanofibrous structures have been widely investigated to emulate the dynamical features of the ECM and regulate cell behaviors. Structures such as core-shell fibers, developed by coaxial electrospinning, have also gained potential applications as drug carriers and artificial blood vessels. The clinical applications of micro-/nanostructured SMP fibers include tissue regeneration, regulating cell behavior, cell growth templates, and wound healing. This review presents the molecular architecture of SMPs, the recent developments in electrospinning techniques for the fabrication of SMP micro-/nanofibers, the biomedical applications of SMPs as well as future perspectives for providing dynamic biomaterials structures.

RESUMEN

The molecular architecture and rheological behavior of linear and branched polybutylene succinate blends have been investigated using size-exclusion chromatography, small-amplitude oscillatory shear and extensional rheometry, in view of their processing using cast and blown extrusion. Dynamic viscoelastic properties indicate that a higher branched polybutylene succinate amount in the blend increases the relaxation time due to an increased long-chain branching degree. Branched polybutylene succinate exhibits pronounced strain hardening under uniaxial elongation, which is known to improve processability. Under extensional flow, the 50/50 wt % blend exhibits the same behavior as linear polybutylene succinate.

RESUMEN

Dual glucagon-like peptide-1/glucagon receptor agonists have emerged as promising candidates for the treatment of diabetes and obesity. Issues of degradation sensitivity and rapid renal clearance are addressed, for example, by the conjugation of peptides to fatty acid chains, promoting reversible albumin binding. We use combined dynamic and static light scattering to directly measure the self-assembly of a set of dual peptide agonists based on the exendin-4 structure with varying fatty acid chain lengths in terms of apparent molecular mass and hydrodynamic radius (RS). We use NMR spectroscopy to gain an insight into the molecular architecture of the assembly. We investigate conformational changes of the monomeric subunits resulting from peptide self-assembly and assembly stability as a function of the fatty acid chain length using circular dichroism and fluorescence spectroscopy. Our results demonstrate that self-assembly of the exendin-4-derived dual agonist peptides is essentially driven by hydrophobic interactions involving the conjugated acyl chains. The fatty acid chain length affects assembly equilibria and the assembly stability, although the peptide subunits in the assembly retain a dynamic secondary structure. The assembly architecture is characterized by juxtaposition of the fatty acyl side chains and a hydrophobic cluster of the peptide moiety. This cluster experiences local conformational changes in the assembly compared to the monomeric unit leading to a reduction in solvent exposure. The N-terminal half of the peptide and a C-terminal loop are not in contact with neighboring peptide subunits in the assemblies. Altogether, our study contributes to a thorough understanding of the association characteristics and the tendency toward self-assembly in response to lipidation. This is important not only to achieve the desired bioavailability but also with respect to the physical stability of peptide solutions.

Asunto(s)

RESUMEN

This work describes a novel fluorescent 2,1,3-benzothiadiazole derivative designed to act as a water-soluble and selective bioprobe for plasma membrane imaging. The new compound was efficiently synthesized in a two-step procedure with good yields. The photophysical properties were evaluated and the dye proved to have an excellent photostability in several solvents. DFT calculations were found in agreement with the experimental data and helped to understand the stabilizing intramolecular charge-transfer process from the first excited state. The new fluorescent derivative could be applied as selective bioprobe in several cell lines and displayed plasma-membrane affinity during the imaging experiments for all tested models.

RESUMEN

The title compound, C15H10ClNO5, is relatively planar with the two aromatic rings being inclined to each other by 3.56 (11)°. The central -C(=O)-C-O-C(=O)- bridge is slightly twisted, with a C-C-O-C torsion angle of 164.95 (16)°. In the crystal, mol-ecules are linked by C-H⋯O and C-H⋯Cl hydrogen bonds, forming layers parallel to the (101) plane. The layers are linked by a further C-H⋯O hydrogen bond, forming a three-dimensional supra-molecular structure. There are a number of offset π-π inter-actions present between the layers [inter-centroid distances vary from 3.8264 (15) to 3.9775 (14) Å]. Hirshfeld surface analyses, the d norm surfaces, electrostatic potential and two-dimensional fingerprint plots were examined to verify the contributions of the different inter-molecular contacts within the supra-molecular structure. The shape-index surface shows that two sides of the mol-ecule are involved in the same contacts with neighbouring mol-ecules, and the curvedness plot shows flat surface patches that are characteristic of planar stacking.

RESUMEN

Multivalent ligand-receptor interactions play essential roles in biological recognition and signaling. As the receptor arrangement on the cell surface can alter the outcome of cell signaling and also provide spatial specificity for ligand binding, controlling the presentation of ligands has become a promising strategy to manipulate or selectively target protein receptors. The lack of adjustable universal tools to control ligand positions at the size of a few nanometers has prompted the development of polyproline tri-helix macrocycles as scaffolds to present ligands in designated patterns. Model lectin Helix pomatia agglutinin has shown selectivity toward the matching GalNAc ligand pattern matching its binding sites arrangement. The GalNAc pattern selectivity is also observed on intact asialoglycoprotein receptor oligomer on human hepatoma cells showing the pattern-selective interaction can be achieved not only on isolated protein oligomers but also the receptors arranged on the cell surface. As the scaffold design allows convenient creation of versatile ligand patterns, it can be expected as a promising tool to probe the arrangement of receptors on the cell surface and as nanomedicine to manipulate signaling or cell recognition.

Asunto(s)

RESUMEN

Voltage-dependent potassium channels (Kv channels) are crucial regulators of cell excitability that participate in a range of physiological and pathophysiological processes. These channels are molecular machines that display a mechanism (known as gating) for opening and closing a gate located in a pore domain (PD). In Kv channels, this mechanism is triggered and controlled by changes in the magnitude of the transmembrane voltage sensed by a voltage-sensing domain (VSD). In this review, we consider several aspects of the VSD⁻PD coupling in Kv channels, and in some relatives, that share a common general structure characterized by a single square-shaped ion conduction pore in the center, surrounded by four VSDs located at the periphery. We compile some recent advances in the knowledge of their architecture, based in cryo-electron microscopy (cryo-EM) data for high-resolution determination of their structure, plus some new functional data obtained with channel variants in which the covalent continuity between the VSD and PD modules has been interrupted. These advances and new data bring about some reconsiderations about the use of exclusively a classical electromechanical lever model of VSD⁻PD coupling by some Kv channels, and open a view of the Kv-type channels as allosteric machines in which gating may be dynamically influenced by some long-range interactional/allosteric mechanisms.

Asunto(s)

RESUMEN

Canonical TRP channels (TRPCs) are a particularly enigmatic family of signaling molecules with multimodal sensing features, being involved in a wide range of biological functions. Until very recently, the main hurdle towards comprehensive mechanistic understanding of TRPC signaling has been the lack of structural information. This has changed early this year by several reports on TRPC architectures resolved by single particle cryo-EM analysis. These studies confirmed recently elaborated concepts on TRPC structure-function relations, and unveiled unanticipated features and complexity in the TRPC sensing machinery.

Asunto(s)

RESUMEN

The exploration of novel molecular architectures is crucial for the design of high-performance ambipolar polymer semiconductors. Here, a "triple-acceptors architecture" strategy to design the ambipolar polymer DPP-2T-DPP-TBT is introduced. The utilization of this architecture enables DPP-2T-DPP-TBT to achieve deep-lying highest occupied molecular orbital (HOMO)/lowest unoccupied molecular orbital (LUMO) levels of -5.38/-4.19 eV, and strong intermolecular interactions, which are favorable for hole/electron injection and intermolecular hopping through π-stacking. All these factors result in excellent ambipolar transport characteristics and promising applications in complementary-like circuits for DPP-2T-DPP-TBT under ambient conditions with high hole/electron mobilities and a gain value of up to 3.01/3.84 cm2 V-1 s-1 and 171, respectively, which are among the best performances in ambipolar polymer organic thin-film transistors and associated complementary-like circuits, especially in top-gate device configuration with low-cost glass as substrates. These results demonstrate that the "triple-acceptors architecture" strategy is an effective way for designing high-performance ambipolar polymer semiconductors.

RESUMEN

The crystals of two new salts, 2,6-di-amino-4-chloro-pyrimidin-1-ium 5-chloro-salicylate, C4H6ClN4+·C7H4ClO3-, (I), and bis-(2,6-di-amino-4-chloro-pyrimidin-1-ium) naphthalene-1,5-di-sulfonate, 2C4H6ClN4+·C10H6O6S22-, (II), have been synthesized and characterized by single-crystal X-ray diffraction. In both compounds, the N atom of the pyrimidine group in between the amino substituents is protonated and the pyrimidinium cation forms a pair of N-H⋯O hydrogen bonds with the carboxyl-ate/sulfonate ion, leading to a robust R22(8) motif (supra-molecular heterosynthon). In compound (I), a self-complementary base pairing involving the other pyrimidinium ring nitro-gen atom and one of the amino groups via a pair of N-H⋯N hydrogen bonds [R22(8) homosynthon] is also present. In compound (II), the crystallographic inversion centre coincides with the inversion centre of the naphthalene-1,5-di-sulfonate ion and all the sulfonate O atoms are hydrogen-bond acceptors, generating fused-ring motifs and a quadruple DDAA array. A halogen-bond (Cl⋯Cl) inter-action is present in (I) with a distance and angle of 3.3505 (12) Šand 151.37 (10)°, respectively. In addition, a C-Cl⋯π inter-action and a π-π inter-action in (I) and a π-π inter-action in (II) further stabilize these crystal structures.