Assessing the Mechanism of Rac1b: An All-Atom Simulation Study of the Alternative Spliced Variant of Rac1 Small Rho GTPase.

The Rho GTPase family plays a key role in cell migration, cytoskeletal dynamics, and intracellular signaling. Rac1 and its splice variant Rac1b, characterized by the insertion of an Extraloop, are frequently associated with cancer. These small GTPases switch between an active GTP-bound state and an inactive GDP-bound state, a process that is regulated by specific protein modulators.

The Effect of Chalcogen-Chalcogen Bond Formation in the New Delhi Metallo-β-Lactamase 1 Enzyme to Counteract Antibiotic Resistance.

New Delhi metallo-β-lactamase 1 (NDM-1) is an enzyme involved in the drug resistance of many bacteria against most of the widely adopted antibiotics, such as penicillins, cephalosporins, and carbapenems. Consequently, inhibiting NDM-1 swiftly has gained significant interest as a strategy to counteract this bacterial defense mechanism, thereby restoring the effectiveness of antibiotics. Among the inhibitors tested against the enzyme, ebselen () showed particularly promising results.

Predicting Conformational Ensembles of Intrinsically Disordered Proteins: From Molecular Dynamics to Machine Learning.

Intrinsically disordered proteins and regions (IDP/IDRs) are ubiquitous across all domains of life. Characterized by a lack of a stable tertiary structure, IDP/IDRs populate a diverse set of transiently formed structural states that can promiscuously adapt upon binding with specific interaction partners and/or certain alterations in environmental conditions. This malleability is foundational for their role as tunable interaction hubs in core cellular processes such as signaling, transcription, and translation.

Extracellular vesicles released by LPS-stimulated spinal organotypic slices spread neuroinflammation into naïve slices through connexin43 hemichannel opening and astrocyte aberrant calcium dynamics.

Introduction: Neuroinflammation is a hallmark of multiple neurodegenerative diseases, shared by all pathological processes which primarily impact on neurons, including Central Nervous System (CNS) injuries. In reactive CNS, activated glia releases extracellular vesicles (EVs), nanosized membranous particles known to play a key role in intercellular communication. EVs mediate neuroinflammatory responses and might exacerbate tissue deterioration, ultimately influencing neurodegenerative disease progression.

Tracing Allostery in the Spliceosome Ski2-like RNA Helicase Brr2.

RNA ATPases/helicases remodel substrate RNA-protein complexes in distinct ways. The different RNA ATPases/helicases, taking part in the spliceosome complex, reshape the RNA/RNA-protein contacts to enable premature-mRNA splicing. Among them, the bad response to refrigeration 2 (Brr2) helicase promotes U4/U6 small nuclear (sn)RNA unwinding via ATP-driven translocation of the U4 snRNA strand, thus playing a pivotal role during the activation, catalytic, and disassembly phases of splicing.

Assessing the mechanism of fast-cycling cancer-associated mutations of Rac1 small Rho GTPase.

Rho-GTPases proteins function as molecular switches alternating from an active to an inactive state upon Guanosine triphosphate (GTP) binding and hydrolysis to Guanosine diphosphate (GDP). Among them, Rac subfamily regulates cell dynamics, being overexpressed in distinct cancer types. Notably, these proteins are object of frequent cancer-associated mutations at Pro29 (P29S, P29L, and P29Q).

Viral RNA Replication Suppression of SARS-CoV-2: Atomistic Insights into Inhibition Mechanisms of RdRp Machinery by ddhCTP.

The nonstructural protein 12, known as RNA-dependent RNA polymerase (RdRp), is essential for both replication and repair of the viral genome. The RdRp of SARS-CoV-2 has been used as a promising candidate for drug development since the inception of the COVID-19 spread. In this work, we performed an investigation on the insertion of the naturally modified pyrimidine nucleobase ddhCTP into the SARS-CoV-2 RdRp active site, in a comparative analysis with the natural one (CTP).

Delivery of graphene oxide nanosheets modulates glutamate release and normalizes amygdala synaptic plasticity to improve anxiety-related behavior.

Graphene oxide nanosheets (GO) were reported to alter neurobiological processes involving cell membrane dynamics. GO ability to reversibly downregulate specifically glutamatergic synapses underpins their potential in future neurotherapeutic developments. Aberrant glutamate plasticity contributes to stress-related psychopathology and drugs which target dysregulated glutamate represent promising treatments.

Graphene Oxide Nanosheets Hamper Glutamate Mediated Excitotoxicity and Protect Neuronal Survival In An In vitro Stroke Model.

Small graphene oxide (s-GO) nanosheets reversibly downregulate central nervous system (CNS) excitatory synapses, with potential developments as future therapeutic tools to treat neuro-disorders characterized by altered glutamatergic transmission. Excitotoxicity, namely cell death triggered by exceeding ambient glutamate fueling over-activation of excitatory synapses, is a pathogenic mechanism shared by several neural diseases, from ischemic stroke to neurodegenerative disorders. In this work, CNS cultures were exposed to oxygen-glucose deprivation (OGD) to mimic ischemic stroke in vitro, and it is show that the delivery of s-GO following OGD, during the endogenous build-up of secondary damage and excitotoxicity, improved neuronal survival.

High-Performance Implantable Sensors based on Anisotropic Magnetoresistive LaSrMnO for Biomedical Applications.

We present the design, fabrication, and characterization of an implantable neural interface based on anisotropic magnetoresistive (AMR) magnetic-field sensors that combine reduced size and high performance at body temperature. The sensors are based on LaSrMnO (LSMO) as a ferromagnetic material, whose epitaxial growth has been suitably engineered to get uniaxial anisotropy and large AMR output together with low noise even at low frequencies. The performance of LSMO sensors of different film thickness and at different temperatures close to 37 °C has to be explored to find an optimum sensitivity of ∼400%/T (with typical detectivity values of 2 nT·Hz at a frequency of 1 Hz and 0.

Graphene Oxide Nanosheets Reduce Astrocyte Reactivity to Inflammation and Ameliorate Experimental Autoimmune Encephalomyelitis.

In neuroinflammation, astrocytes play multifaceted roles that regulate the neuronal environment. Astrocytes sense and respond to pro-inflammatory cytokines (CKs) and, by a repertoire of intracellular Ca signaling, contribute to disease progression. Therapeutic approaches wish to reduce the overactivation in Ca signaling in inflammatory-reactive astrocytes to restore dysregulated cellular changes.

Graph lesion-deficit mapping of fluid intelligence.

Fluid intelligence is arguably the defining feature of human cognition. Yet the nature of its relationship with the brain remains a contentious topic. Influential proposals drawing primarily on functional imaging data have implicated 'multiple demand' frontoparietal and more widely distributed cortical networks, but extant lesion-deficit studies with greater causal power are almost all small, methodologically constrained, and inconclusive.

Role of Monovalent Ions in the NKCC1 Inhibition Mechanism Revealed through Molecular Simulations.

The secondary active Na-K-Cl cotransporter 1 (NKCC1) promotes electroneutral uptake of two chloride ions, one sodium ion and one potassium ion. NKCC1 regulates Cl homeostasis, thus being implicated in transepithelial water transport and in neuronal excitability. Aberrant NKCC1 transport is linked to a variety of human diseases.

TEGylated Double-Walled Carbon Nanotubes as Platforms to Engineer Neuronal Networks.

In the past two decades, important results have been obtained on the application of carbon nanotubes (CNTs) as components of smart interfaces promoting neuronal growth and differentiation. Different forms of CNTs have been employed as scaffolds, including raw CNTs and functionalized CNTs, characterized by a different number of walls, mainly single-walled CNTs (SWCNTs) or multiwalled CNTs (MWCNTs). However, double-walled carbon nanotubes (DWCNTs), which present interesting electronic and transport properties, have barely been studied in the field.

All-Atom Simulations Elucidate the Impact of U2AF2 Cancer-Associated Mutations on Pre-mRNA Recognition.

The U2AF2 splicing factor, made of two tandem RNA recognition motifs (RRMs) joined by a flexible linker, selects the intronic polypyrimidine sequence of premature mRNA, thus ensuring splicing fidelity. Increasing evidence links mutations of key splicing factors, including U2AF2, to a variety of cancers. Nevertheless, the impact of U2AF2 cancer-associated mutations on polypyrimidine recognition remains unclear.

The conformational plasticity of the selectivity filter methionines controls the in-cell Cu(I) uptake through the CTR1 transporter.

Copper is a trace element vital to many cellular functions. Yet its abnormal levels are toxic to cells, provoking a variety of severe diseases. The high affinity copper transporter 1 (CTR1), being the main in-cell copper [Cu(I)] entry route, tightly regulates its cellular uptake via a still elusive mechanism.

An oomycete NLP cytolysin forms transient small pores in lipid membranes.

Microbial plant pathogens secrete a range of effector proteins that damage host plants and consequently constrain global food production. Necrosis and ethylene-inducing peptide 1-like proteins (NLPs) are produced by numerous phytopathogenic microbes that cause important crop diseases. Many NLPs are cytolytic, causing cell death and tissue necrosis by disrupting the plant plasma membrane.

Multi-model mapping of phonemic fluency.

The voluntary generation of non-overlearned responses is usually assessed with phonemic fluency. Like most frontal tasks, it draws upon different complex processes and systems whose precise nature is still incompletely understood. Many claimed aspects regarding the pattern of phonemic fluency performance and its underlying anatomy remain controversial.

All-Atom Simulations Uncover the Molecular Terms of the NKCC1 Transport Mechanism.

The secondary-active Na-K-Cl cotransporter 1 (NKCC1), member of the cation-chloride cotransporter (CCC) family, ensures the electroneutral movement of Cl, Na, and K ions across cellular membranes. NKCC1 regulates Cl homeostasis and cell volume, handling a pivotal role in transepithelial water transport and neuronal excitability. Aberrant NKCC1 transport is hence implicated in a variety of human diseases (hypertension, renal disorders, neuropathies, and cancer).

Molecular Mechanisms of the Blockage of Glioblastoma Motility.

Glioblastoma (GBM) is the most common and lethal brain tumor. GBM has a remarkable degree of motility and is able to infiltrate the healthy brain. In order to perform a rationale-based drug-repositioning study, we have used known inhibitors of two small Rho GTPases, Rac1 and Cdc42, which are upregulated in GBM and are involved in the signaling processes underlying the orchestration of the cytoskeleton and cellular motility.

Atomic-Level Mechanism of Pre-mRNA Splicing in Health and Disease.

Intron removal from premature-mRNA (pre-mRNA splicing) is an essential part of gene expression and regulation that is required for the production of mature, protein-coding mRNA. The spliceosome (SPL), a majestic machine composed of five small nuclear RNAs and hundreds of proteins, behaves as an eminent transcriptome tailor, efficiently performing splicing as a protein-directed metallo-ribozyme. To select and excise long and diverse intronic sequences with single-nucleotide precision, the SPL undergoes a continuous compositional and conformational remodeling, forming eight distinct complexes throughout each splicing cycle.