Alpha-synuclein (αSyn) is one of the most abundant proteins in the nervous system and is currently associated with devastating synucleinopathies, yet its biology extends far beyond this. In this review, we suggest that αSyn-driven disease emerges within specific neural circuits through the combined effects of cell-type-specific roles, subcellular environments, post-translational modifications (PTMs), and co-pathology. These interacting and additive dimensions, rather than αSyn alone, generate the pathological diversity, shaping whether pathology manifests as Parkinson’s disease (PD), Parkinson’s disease dementia (PDD), dementia with Lewy bodies (DLB), multiple system atrophy (MSA), or mixed dementia phenotypes. We integrate recent advances on the physiological roles of αSyn in neurons and glia (astrocytes, oligodendrocytes, and microglia), its compartment-dependent (e.g., synaptic and nuclear) functions, and the molecular transitions (e.g., mediated by pS129) that convert functional assemblies into pathogenic conformers. Building on this foundation, we outline mechanisms through which these factors contribute to disease-specific vulnerability, progression, and clinical heterogeneity. Finally, we highlight how this multidimensional perspective on αSyn biology can inform the development of next-generation biomarkers that support precision therapies across distinct disorders.

Empirical investigation of nuclear correlation function distributions in lattice QCD

The role of the LOX family in cancer.

Nuclear excitation functions for medical isotope production: Targeted radionuclide therapy via natIr(d,x)193mPt.

Originally identified in the 1990s as an extracellular matrix (ECM) protein, Cellular Communication Network factor 3 (CCN3) was recognized as a member of a structurally related family of six proteins sharing a conserved tetramodular organization and broad regulatory functions in biological processes such as cell proliferation, attachment, migration, differentiation, wound healing, and angiogenesis, as well as in pathological conditions including fibrosis and tumorigenesis. Among these proteins, CCN3 rapidly emerged as the first tumor-suppressive member capable of negatively regulating cell growth in both normal and pathological contexts. A conceptual shift emerged following observations that, in addition to full-length CCN3 detected in the extracellular matrix, amino-truncated CCN3 proteoforms are targeted to the nucleus. In addition to physically interacting with the Rpb7 subunit of RNA polymerase II (Pol II), CCN3 binds to the promoter region of PAI-2 and exhibits transcriptional regulatory activity both in vitro and ex vivo. The dual localization and functional versatility of CCN3 led to the proposal that this protein may function as a "moonlighting" factor capable of integrating extracellular cues with nuclear transcriptional regulation. This conceptual framework, however, has remained relatively underexplored. The nuclear localization of other family members, together with the more recent observation that nuclear CCN6 physically interacts with RNA polymerase II, may extend this concept to the entire CCN protein family. By revisiting and integrating a substantial body of published data that has remained insufficiently acknowledged, this review aims to underscore the biological significance of CCN proteoforms in the nuclei of tumor cells. The demonstration of physical interactions between CCN3 and components of the central transcriptional machinery invites reconsideration of the prevailing ECM-centered view of CCN proteins and opens new perspectives on their biological roles.

We present a theoretical calculation for the A = 2 , 3 , and 4 nuclear contact coefficients within the generalized contact formalism, using both local and nonlocal chiral potentials. The hyperspherical harmonics method is employed to calculate the nuclear wave functions, from which we derive two-body momentum distributions and density functions to extract the contact coefficients. We have extracted the contact coefficients from two-body momentum distributions or from density functions, for a given nucleus and potential, and we have found that the generalized contact formalism predictions are verified in the triplet spin channel for local and nonlocal potentials. On the other hand, some significant tensions exist for the singlet channels, especially when studied with nonlocal potentials. We have also analyzed the model-independence of the ratios between the contact coefficients, which we have found to be quite satisfied. This study extends previous works based on local interaction models only.

We analyze the entanglement between electronic and nuclear motions in molecular wave functions widely used by theoretical chemists, namely, (i) Born-Oppenheimer factorization in the adiabatic picture, (ii) the transformation into a diabatic picture, (iii) the use of a Born-Huang expansion, and (iv) the eigenfunction of the full molecular Hamiltonian. Our showcase is based on two one-electron one-dimensional molecular Hamiltonians (H2+ and the Shin-Metiu model). We find that within the Born-Oppenheimer approximation, any molecular state (although factorizable) is always entangled, and its entanglement content may be assessed by the variation of the electronic wave function along the different nuclear geometries, with the nuclear wave function indeed playing the role of a tester. The presence of avoided crossings among the adiabatic potential energy curves brings about dramatic changes in the entanglement content of the wave function: sharp avoided crossings favor a diabatic picture (real crossings between potential energy curves), while in broad avoided crossings, the adiabatic picture prevails. The total eigenfunction of the molecular Shin-Metiu Hamiltonian indicates that nuclear densities accommodate well within the diabatic curves for strong adiabatic couplings but within adiabatic curves for weak ones. Consequently, we find that the electron-nuclei entanglement content is a valid witness to unveil strong or weak nonadiabatic couplings in molecules. In terms of entanglement, we also find that the Born-Huang expansion, based on Born-Oppenheimer adiabatic electronic states, does not provide a correct trend of entanglement compared with that of the total molecular eigenfunction, thus indicating a very slow convergence of this expansion.

We expanded our previous mapping of the peptide condensation reaction mechanism from the linear dipeptide formation to the cyclization reaction that results in diketopiperazines. The overarching theme of our computational investigations is a reaction network that connects all intermediates via proton-transfer pathways. We conducted the simulations designed to be predictive in a range of environments, such as the gas phase, hydrothermal aqueous conditions, deliquescent salts, and bulk water. While the free-energy profiles are similar to the linear peptide, the presence of the cis amide bond leading to a pre-arranged vicinity of the two reacting groups and the role of explicit solvent molecules revealed new mechanistic insights that differentiate the linear versus cyclic peptide formation/hydrolysis reactions. The rate-determining step corresponds to the final water-elimination reaction using the most realistic computational models with both implicit and explicit water solvation models at neutral pH. At high pH, the highest barrier corresponds to the C-N bond formation at a significantly lower free energy, while at low pH, the water elimination step's barrier increases by close to 30%; thus, effectively shutting down the reaction in agreement with experiments. Due to the central role of proton transfer, we studied the impact of nuclear wave functions on all active H-centers. By utilizing two quantum protons, we document up to 0.1 Å impact on H positions, ca. 20 kJ mol-1 tunneling effects, and a significant change in the shape of the potential energy surface in comparison with the classical DFT calculations. The calculated reaction rates well reproduce the experimentally determined values under hydrothermal conditions.

Selenium is an essential trace element whose dysregulation is associated with diverse disease risks; however, its specific role in hepatic metabolism remains poorly defined. Here we delineate a novel selenium-selenoprotein H (SELENOH)-PPARα signaling axis that is critical for hepatic lipid homeostasis. We first uncovered a global impairment of selenoprotein translation as a key feature of metabolic dysfunction-associated steatohepatitis (MASH) in human patients and mouse models. Both dietary selenium supplementation and genetically rescuing selenoprotein biosynthesis attenuated MASH pathology, establishing a causal link. Through a targeted screen, we pinpointed SELENOH as the key hepatoprotective selenoprotein governing hepatic fatty acid oxidation (FAO). Diverging from the canonical redox functions of selenoproteins, SELENOH operates as a scaffolding coactivator for the nuclear receptor PPARα. SELENOH binds to ligand-activated PPARα and orchestrates the assembly and chromatin recruitment of the PPARα-P300 transactivation complex to drive FAO gene expression. This nexus is disrupted in MASH livers due to SELENOH deficiency but is reconstituted by selenium supplementation. These findings altogether define selenium homeostasis as a fundamental regulator of nuclear receptor function and unveil promising therapeutic avenues for MASH.

Angelman syndrome (AS) is a neurodevelopmental disorder caused by UBE3A loss. In humans, UBE3A generates three isoforms that localize to distinct subcellular compartments-one mainly nuclear and two cytoplasmic. The nuclear and most highly expressed cytoplasmic UBE3A isoform are highly conserved in mice, whereas the cytoplasmic human isoform accounting for just ~1% of total UBE3A has no mouse counterpart. Loss of the nuclear-enriched UBE3A isoform causes AS and behavioral deficits in mice; no specific contribution of the predominant cytoplasmic UBE3A isoform has yet been identified. Because the nuclear-enriched isoform constitutes ~80% of total UBE3A protein, it is unclear if its outsized phenotypic impact upon deletion is due to a loss of nuclear UBE3A function or simply a dramatic reduction in overall UBE3A levels. If the former, overexpression of the cytoplasmic UBE3A isoform would be unable to rescue AS phenotypes. To test this, we developed a mouse model that overexpresses the cytoplasmic UBE3A isoform (mIso2-OE) and crossed it with an AS mouse model to yield wildtype (WT), mIso2-OE, AS, and AS/mIso2-OE mice, the latter of which lacked the endogenous nuclear UBE3A isoform (mIso3) in neurons. Unexpectedly, we found that overexpression of the cytoplasmic UBE3A isoform alone rescued most tested AS-related behavioral deficits, except for kindling-induced epileptogenesis or seizure-linked perineuronal net (PNN) accumulation in AS mice. Thus, while many AS phenotypes may be caused by isoform non-selective reductions in UBE3A levels, AS-associated epilepsies appear linked to isoform-selective nuclear UBE3A loss. This information is expected to inform AS gene therapy studies.

Archaic introgression introduced functionally relevant variants into modern humans, yet small-scale insertions remain understudied. Here, we leverage 2519 modern human genomes and four high-coverage archaic hominin genomes to systematically characterize nuclear mitochondrial DNA segments (NUMTs). We uncover 483 polymorphic NUMTs across globally diverse human populations and 10 in archaic genomes. By combining overlap with Neanderthal-derived and Denisovan-derived haplotypes, phylogenetic analyses, insertion time estimates, and haplotype colocalization, we identify five NUMTs introduced into modern humans via archaic hominin introgression. Functional analyses reveal that introgressed NUMTs can modulate gene expression, including allele-specific up-regulation of the immune-related gene RASGRP3, and reshape three-dimensional chromatin structure at loci such as SCD5 and HNRNPD. These findings highlight an underappreciated mechanism by which archaic mitochondrial fragments shape nuclear genome function and evolution. Our study reframes NUMTs not as passive genomic fossils but as dynamic elements influencing modern human diversity and adaptation.

A metallic metabolic nano-regulator reprograms the PKM2/HIF-1α/DLAT axis to amplify tumor-specific cuproptosis.

Nonequilibrium polymer models for chromatin.

Many epigenetic drugs lack specificity, which may lead to drug resistance and long-term safety concerns. There is an urgent need to develop more precise nuclear-targeted drugs to reduce adverse reactions and harmful effects. The development of nuclear drugs relies on the exploration of new nuclear targeting mechanisms. This review delves into nuclear protein posttranslational modifications (PTMs), highlighting their roles in nuclear function and influence on cell fate. It showcases the diversity of PTMs, including acetylation, novel acylations, phosphorylation, ubiquitylation, oxidative modifications, itaconation, and citrullination, and differentiates the roles of these modifications between nuclear and non-nuclear proteins. The review partially highlights how nuclear PTMs impact key biological processes, gene expression, and cell function by interacting with cell metabolism. Additionally, it explores the regulatory mechanisms of nuclear PTMs and their implications in diseases such as cancers, and degenerative, metabolic, and inflammatory conditions, suggesting nuclear protein PTMs as potential therapeutic targets. It underscores the need for precise techniques and treatments to study PTMs and introduces the "metabolite-nuclear protein PTM-genome" axis as a novel conceptual framework for future research and therapeutic strategies.

A 19 nt fragment that spans the SARS-CoV-2 furin cleavage site (FCS) is identical to the reverse complement of a proprietary human DNA repair gene sequence. Rather than interpreting this overlap as evidence of a laboratory event, this article uses it as a theoretical springboard to explore underappreciated biorisk concerns, specifically in the context of cancer research. Although they are RNA viruses, coronaviruses are capable of hijacking host DNA damage response (DDR) pathways, exploiting nuclear functions to enhance replication and evade innate immunity. Under selective pressures (antivirals, DDR antagonists, or large-scale siRNA libraries designed to silence critical host genes), escape mutants may arise with fitness advantages. Parallel observations involving in vivo RNA interference via chimeric viruses lend plausibility to some of the key aspects underlying unappreciated biorisks. The mechanistic insights that incorporate DNA repair mechanisms, CoVs in the nucleus, specifics of viruses in cancer research, anticancer drugs, automated gene silencing experiments, and gene sequence overlaps identify gaps in biorisk policies, even those unaccounted for by the potent "Sequences of Concern" paradigm. Key concerning attributes, including genome multifunctionality, such as NLS/FCS in SARS-CoV-2, antisense sequences, and their combination, are further described in more general terms. The article concludes with recommendations pairing modern technical safeguards with enduring ethical principles.

A bstract Recent studies have demonstrated that the far-forward physics program of the Large Hadron Collider (LHC) can be useful to probe the hadron structure with GeV-TeV neutrinos and muons. In particular, these studies indicate that the measurement of the muon-ion and neutrino-ion cross-sections by the same experiment is feasible. In this paper, we investigate the impact of nuclear effects on the muon-tungsten ( μW ) and neutrino-tungsten ( νW ) deep inelastic scattering (DIS) events at FASER ν and its proposed upgrade FASER ν 2. We estimate the rates associated with the inclusive cross-sections and for events with a charm tagged in the final state considering different parameterizations for the nuclear parton distribution functions. These results point out that muon and neutrino-induced interactions probe complementary kinematical ranges and that a simultaneous analysis of associated events will allow to test the universality (or not) of the nuclear effects. Moreover, we propose the study of the ratio between the charm tagged and inclusive events in order to discriminate between the distinct modeling of the nuclear effects at small- x . Our results indicate that a future experimental reconstruction of μW and νW DIS events at the LHC is a promising way to improve our understanding of nuclear effects and decrease the current uncertainties in parton distribution functions.

Orthoflaviviruses are RNA viruses responsible for significant diseases in humans, domesticated animals and wildlife. Their NS5 protein is central in viral replication, functioning both as an RNA-dependent RNA polymerase and a methyltransferase, while also modulating cellular processes, including the interferon response. Although viral replication is cytoplasmic, the NS5 protein of several mosquito-borne orthoflaviviruses cycles between the cytoplasm and the nucleus of infected human cells. However, the nuclear localization and function of NS5 of tick-borne orthoflaviviruses, such as tick-borne encephalitis virus (TBEV), remained poorly understood. Microscopy analysis and cell fractionation revealed that the NS5 protein of TBEV localized to both the cytoplasm and nucleoplasm of infected cells. Mutagenesis studies identified critical residues required for its nuclear targeting. Mutating these residues in a TBEV replicon abolished viral replication. Immunoprecipitation-mass spectrometry analyses performed in two human cell lines infected with TBEV recovered 352 NS5 partners. Among them, 187 were nuclear or partially nuclear. By integrating our interactome data with that of Powassan virus (POWV), another tick-borne orthoflavivirus, we refined a list of 20 high-confidence NS5 partners, including splicing factors and chromatin modulators. Functional analysis revealed that seven of these nuclear partners significantly modulated viral replication, further underscoring the importance of nuclear NS5 in the viral life cycle. Our work advances our understanding of the nuclear function of the NS5 proteins of tick-borne orthoflaviviruses.ImportanceTick-borne orthoflaviviruses are emerging globally, spreading across Europe, Asia, and North America, where they infect humans, domesticated animals, and wildlife. These viruses produce a protein called NS5, which drives viral replication and helps evade the innate immune response. We observed that the NS5 protein of tick-borne encephalitis virus (TBEV) localized both in the cytoplasm and nucleoplasm of infected human cells. We identified the specific residues responsible for its nuclear addressing and showed that it interacts with numerous nuclear proteins, including some involved in regulating gene expression. Seven of these nuclear partners significantly influenced viral replication, highlighting the importance of NS5’s nuclear activity. This work sheds light on how tick-borne orthoflaviviruses manipulate host cells, deepening our understanding of their replication strategies.

The Keap1-Nrf2 signaling pathway is a central regulator of transcriptional responses to oxidative stress and is strongly linked to diverse pathologies, particularly cancer. In the cytoplasm, Keap1 (Kelch-like ECH-associated protein 1) promotes proteasomal degradation of Nrf2 (NF-E2-related factor 2). Oxidative stimuli disrupt the Keap1-Nrf2 interaction, facilitating Nrf2 nuclear accumulation and activation of antioxidant and detoxifying genes. Recent evidence suggests that Keap1 family proteins also enter the nucleus, bind chromatin, and regulate transcription, but the underlying mechanisms remain less understood. Here, we show that the Drosophila Keap1 ortholog, dKeap1, accumulates in the nucleus and gradually assembles stable nuclear foci in cells following oxidative treatment. FRAP analyses revealed reduced mobility of dKeap1 within these foci. Both the N-terminal (NTD) and C-terminal (CTD) domains of dKeap1 were required for foci formation. Two intrinsically disordered regions (IDRs) were identified within the CTD, and CTD-YFP fusion proteins readily formed condensates in vitro. Conversely, deletion of the Kelch domain resulted in robust cytoplasmic foci even under basal conditions, and in vitro assays also indicated that the Kelch domain suppresses dKeap1 condensate formation. Together, these findings reveal a novel molecular mechanism for the nuclear function of dKeap1, providing new insight into the broader roles of Keap1 factors in oxidative response, development, and disease.

The TAT protein transduction domain (TAT-PTD) is an effective tool for delivering therapeutic proteins into cells, yet its efficiency is often constrained by an incompletely understood intracellular fate. In this study, we identify a previously unrecognized proteolytic cascade that restricts the nuclear accumulation of TAT-fusion proteins. After cellular uptake, TAT-EGFP undergoes N-terminal cleavage by matrix metalloproteinase-3 (MMP-3), an event that depends on an upstream calpain-MMP-3 activation axis. This cleavage removes the intrinsic nuclear localization signal of the TAT-PTD, trapping the protein in the cytoplasm and thereby abolishing its nuclear function. Importantly, this entire process was blocked by specific inhibitors of calpain or MMP-3, which restored nuclear accumulation of the intact protein. In addition, site-directed mutagenesis conferring resistance to cleavage, as observed in the ARA and AAR mutants, demonstrated that the two C-terminal arginines of the TAT-PTD are essential for this susceptibility. These findings elucidate, for the first time, a molecular mechanism underlying a key pathway that limits the nuclear delivery of TAT-based vectors, providing a rational foundation for the design of cleavage-resistant delivery systems with improved therapeutic efficacy.

Frontotemporal dementia linked to chromosome 3 (FTD3) is caused by a splice site point mutation in CHMP2B, resulting in the production of mutant proteins CHMP2BIn5 and CHMP2BΔ10. Here, we found that wildtype CHMP2B (CHMP2BWT) is mostly present in the cytoplasm, but CHMP2BIn5 is mislocalized to the nucleus of human induced pluripotent stem cell (iPSC)-derived cortical neurons. To understand the underlying mechanism, we identified a previously unreported nuclear export signal (NES) in the C-terminus of CHMP2B. Functional assays, including CRM1 inhibition and site-directed mutagenesis of key hydrophobic residues, demonstrated that this NES motif is both necessary and sufficient for nuclear export of CHMP2BWT and ALS-associated CHMP2BQ206H, and its loss in CHMP2BIn5 is responsible for the observed nuclear mislocalization. CHMP2BΔ10 remains in the cytoplasm due to the presence of an artificial NES in the C-terminus. These results reveal the presence of an NES in CHMP2B and highlight the need to dissect the gain-of-toxic nuclear functions of CHMP2BIn5 in FTD3 pathogenesis.