Superficial acral fibromyxoma (SAFM) is a rare, benign, slow-growing fibroblastic tumour of the soft tissue that is part of the group of myxoid soft-tissue neoplasms. It is a rare entity and usually ...occurs in the acral regions. We report the case of a 64-year-old man who presented to the emergency room for a lesion expected to have occurred as a result of an ingrown toenail. Because this patient had a history of repeated recurrences despite multiple surgical wedge excisions, we performed a complete surgical excision, and the pathological analysis confirmed the suspected diagnosis of SAFM. There was no recurrence at the 6-month follow-up. This case highlights the fact that this tumour is still misunderstood and underrecognized by surgeons and this often leads to delayed diagnosis. Although it is a rare entity, clinicians should be aware of this tumour in cases of recurring ingrown toenails.
Clinical and experimental studies indicate that muscarinic acetylcholine receptors are potential pharmacological targets for the treatment of neurological diseases. Although these receptors have been ...described in human, bovine and rat cerebral microvascular tissue, a subtype functional characterization in mouse brain endothelium is lacking. Here, we show that all muscarinic acetylcholine receptors (M
-M
) are expressed in mouse brain microvascular endothelial cells. The mRNA expression of M
, M
, and M
correlates with their respective protein abundance, but a mismatch exists for M
and M
mRNA versus protein levels. Acetylcholine activates calcium transients in brain endothelium via muscarinic, but not nicotinic, receptors. Moreover, although M
and M
are the most abundant receptors, only a small fraction of M
is present in the plasma membrane and functions in ACh-induced Ca
signaling. Bioinformatic analyses performed on eukaryotic muscarinic receptors demonstrate a high degree of conservation of the orthosteric binding site and a great variability of the allosteric site. In line with previous studies, this result indicates muscarinic acetylcholine receptors as potential pharmacological targets in future translational studies. We argue that research on drug development should especially focus on the allosteric binding sites of the M
and M
receptors.
Sequences that form DNA secondary structures, such as G-quadruplexes (G4s) and intercalated-Motifs (iMs), are abundant in the human genome and play various physiological roles. However, they can also ...interfere with replication and threaten genome stability. Multiple lines of evidence suggest G4s inhibit replication, but the underlying mechanism remains unclear. Moreover, evidence of how iMs affect the replisome is lacking. Here, we reconstitute replication of physiologically derived structure-forming sequences to find that a single G4 or iM arrest DNA replication. Direct single-molecule structure detection within solid-state nanopores reveals structures form as a consequence of replication. Combined genetic and biophysical characterisation establishes that structure stability and probability of structure formation are key determinants of replisome arrest. Mechanistically, replication arrest is caused by impaired synthesis, resulting in helicase-polymerase uncoupling. Significantly, iMs also induce breakage of nascent DNA. Finally, stalled forks are only rescued by a specialised helicase, Pif1, but not Rrm3, Sgs1, Chl1 or Hrq1. Altogether, we provide a mechanism for quadruplex structure formation and resolution during replication and highlight G4s and iMs as endogenous sources of replication stress.
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative diseases that exist on a clinico-pathogenetic spectrum, designated ALS/FTD. The most common genetic cause ...of ALS/FTD is expansion of the intronic hexanucleotide repeat (GGGGCC)
in C9orf72. Here, we investigate the formation of nucleic acid secondary structures in these expansion repeats, and their role in generating condensates characteristic of ALS/FTD. We observe significant aggregation of the hexanucleotide sequence (GGGGCC)
, which we associate to the formation of multimolecular G-quadruplexes (mG4s) by using a range of biophysical techniques. Exposing the condensates to G4-unfolding conditions leads to prompt disassembly, highlighting the key role of mG4-formation in the condensation process. We further validate the biological relevance of our findings by detecting an increased prevalence of G4-structures in C9orf72 mutant human motor neurons when compared to healthy motor neurons by staining with a G4-selective fluorescent probe, revealing signal in putative condensates. Our findings strongly suggest that RNA G-rich repetitive sequences can form protein-free condensates sustained by multimolecular G-quadruplexes, highlighting their potential relevance as therapeutic targets for C9orf72 mutation-related ALS/FTD.
The nitrogen mustard Chlorambucil (Chl) generates covalent adducts with double-helical DNA and inhibits cell proliferation. Among these adducts, interstrand cross-links (ICLs) are the most toxic, as ...they stall replication by generating DNA double strand breaks (DSBs). Conversely, intrastrand cross-links generated by Chl are efficiently repaired by a dedicated Nucleotide Excision Repair (NER) enzyme. We synthesized a novel cross-linking agent that combines Chl with the G-quadruplex (G4) ligand PDS (PDS-Chl). We demonstrated that PDS-Chl alkylates G4 structures at low μM concentrations, without reactivity toward double- or single-stranded DNA. Since intramolecular G4s arise from a single DNA strand, we reasoned that preferential alkylation of such structures might prevent the generation of ICLs, while favoring intrastrand cross-links. We observed that PDS-Chl selectively impairs growth in cells genetically deficient in NER, but did not show any sensitivity to the repair gene BRCA2, involved in double-stranded break repair. Our findings suggest that G4 targeting of this clinically important alkylating agent alters the overall mechanism of action. These insights may inspire new opportunities for intervention in diseases specifically characterized by genetic impairment of NER, such as skin and testicular cancers.
Web search result clustering aims to facilitate information search on the Web. Rather than the results of a query being presented as a flat list, they are grouped on the basis of their similarity and ...subsequently shown to the user as a list of clusters. Each cluster is intended to represent a different meaning of the input query, thus taking into account the lexical ambiguity (i.e., polysemy) issue. Existing Web clustering methods typically rely on some shallow notion of textual similarity between search result snippets, however. As a result, text snippets with no word in common tend to be clustered separately even if they share the same meaning, whereas snippets with words in common may be grouped together even if they refer to different meanings of the input query.
In this article we present a novel approach to Web search result clustering based on the automatic discovery of word senses from raw text, a task referred to as Word Sense Induction. Key to our approach is to first acquire the various senses (i.e., meanings) of an ambiguous query and then cluster the search results based on their semantic similarity to the word senses induced. Our experiments, conducted on data sets of ambiguous queries, show that our approach outperforms both Web clustering and search engines.
Regulation of the epigenome is critical for healthy cell function but can become disrupted with age, leading to aberrant epigenetic profiles including altered DNA methylation. Recent studies have ...indicated that DNA methylation homeostasis can be compromised by the formation of DNA secondary structures known as G-quadruplexes (G4s), which form in guanine-rich regions of the genome. G4s can be recognised and bound by certain methylation-regulating enzymes, and in turn perturb the surrounding methylation architecture. However, the effect G4 formation has on DNA methylation at critical epigenetic sites remains elusive and poorly explored. In this work, we investigate the association between G4 sequences and prominent DNA methylation sites, termed ‘ageing clocks’, that act as bona fide dysregulated regions in aged and cancerous cells. Using a combination of in vitro (G4-seq) and in cellulo (BG4-ChIP) G4 distribution maps, we show that ageing clocks sites are significantly enriched with G4-forming sequences. The observed enrichment also varies across species and cell lines, being least significant in healthy cells and more pronounced in tumorigenic cells. Overall, our results suggest a biological significance of G4s in the realm of DNA methylation, which may be important for further deciphering the driving forces of diseases characterised by epigenetic abnormality, including ageing.
The current global water crisis is seriously challenging the water management, requiring an extensive sweeping adaptation for consumption and production patterns. Several international organisations ...recommend addressing water crisis through effective participatory practices. Taking into account the notion of environmental democracy and the legal implications of the right to water, this paper questions the public participation in the water services management in the European Union. Supervisor entities’ cases are examined, and the idea of a participatory comanagement model is proposed. The aim is to clarify the legal foundations of water democracy, by suggesting possible solutions to support an increased public engagement.
•Autonomy of the water democracy from cost-benefit analysis.•Right to water as fundamental basis of the water democracy notion.•Supervisor entities as inefficient implementation of the water democracy notion.•Direct participation in water services as optimum in water conflicts situations.
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