Anna Mantzouratou

Preimplantation human embryos frequently exhibit aneuploidy and chromosomal mosaicism, yet emerging evidence suggests they may possess mechanisms for ploidy correction that can mitigate these abnormalities. Several potential pathways have been proposed, including selective apoptosis of abnormal cells, cellular exclusion of aneuploid blastomeres, compartmentalization of abnormal cells into extraembryonic tissues, and chromosomal rescue events (such as trisomic or monosomic rescue), while in some embryos, no correction occurs, leading to persistence of aneuploid cell lineages. Follow-up studies on mosaic embryo transfer outcomes indicate that some embryos can eliminate or segregate aneuploid cells, leading to successful live births. However, the extent to which self-correction occurs, and the precise biological mechanisms underlying these processes, remain poorly understood. The likelihood of successful correction depends on the proportion and distribution of aneuploid cells as current evidence shows that embryos with high-level mosaicism have reduced developmental potential. This mini-review integrates current biological insights into ploidy correction mechanisms with clinical outcome data from mosaic embryo transfers, highlighting both the potential and limitations of embryonic self-correction hypotheses. By examining the interplay between mechanism studies and clinical observations, it underscores the challenges in predicting embryo viability and the necessity for standardized approaches in ART. Future research could help in defining the molecular and developmental pathways governing ploidy correction to improve embryo selection strategies and refine ART guidelines.

Endometriosis is a chronic, estrogen-driven inflammatory disorder affecting approximately 10% of reproductive-aged women globally. Despite increasing genomic insights into advanced-stage disease, the genetic underpinnings of early-stage endometriosis remain poorly understood, limiting opportunities for timely diagnosis and intervention. This study explores the contribution of regulatory variants, including those derived from ancient hominin introgression, and their interaction with modern environmental exposures in shaping endometriosis susceptibility. We conducted a dual-phase literature review to identify genes implicated in endometriosis pathophysiology and endocrine-disrupting chemical (EDC) sensitivity. Five genes ( IL-6, CNR1, IDO1, TACR3 , and KISS1R ) were selected based on tissue expression, pathway involvement, and EDC reactivity. Whole-genome sequencing (WGS) data from the Genomics England 100,000 Genomes Project were analysed in nineteen females with clinically confirmed endometriosis. Variant enrichment, co-localisation, and linkage disequilibrium analyses were conducted, and functional impact was evaluated using public regulatory databases. Six regulatory variants were significantly enriched in the endometriosis cohort compared to matched controls and the general Genomics England population. Notably, co-localised IL-6 variants rs2069840 and rs34880821—located at a Neandertal-derived methylation site—demonstrated strong linkage disequilibrium and potential immune dysregulation. Variants in CNR1 and IDO1 , some of Denisovan origin, also showed significant associations. Several of these variants overlapped EDC-responsive regulatory regions, suggesting gene-environment interactions may exacerbate risk. These findings propose a novel perspective of endometriosis susceptibility, in which ancient regulatory variants and contemporary environmental exposures converge to modulate immune and inflammatory responses. This integrative approach identified new potential biomarkers for early-stage detection of endometriosis.

An EBSL-encoding plasmid, pESBL-PH, was identified during a nosocomial outbreak of Klebsiella pneumoniae ST628 at a United Kingdom general district hospital in 2018. The plasmid from the earliest 2018 K. pneumoniae strain discovered during the outbreak was assembled using both Oxford nanopore long reads and illumina short reads, yielding a fully closed plasmid, pESBL-PH-2018. pESBL-PH-2018 was queried against the complete NCBI RefSeq Plasmid Database, comprising 93,823 plasmids, which was downloaded on 16 July 2024. To identify structurally similar plasmids, strict thresholds were applied, including a mash similarity ≥0.98. This returned 61 plasmids belonging to 13 unique sequence types (STs) hosts. The plasmids were detected from 13 unique countries, dating from 2012 to 2023. The AMR region of the plasmids varied. Interestingly IS26-mediated tandem amplification of resistance genes, including the ESBL gene bla_CTX-M-15 was identified in two independent strains, raising their copy number to three. Furthermore, the genomic background of strains carrying a pESBL-PH-2018-like plasmid were analyzed, revealing truncation of the chromosomal ompK36 porin gene and carbapenem resistance gene carriage on accessory plasmids in 17.85% and 26.78% of strains with a complete chromosome available. This analysis reveals the widespread dissemination of an ESBL-encoding plasmid in a background of resistance-encoding strains, requiring active surveillance.

Endometriosis is a chronic gynaecological disease characterised by inflammation and can cause infertility and severe chronic pelvic pain. It is a complex disease and potentially multifactorial and tends to affect women in the same family with heritability shown to be between 47-51%. Previous studies have identified over forty single nucleotide polymorphisms associated with advanced stages of endometriosis; however, no variants have been associated with earlier endometriosis stages to date. Due to being a multifactorial condition, it is also likely that interactions with the modern environment may lead to an altered genetic susceptibility to endometriosis. The aim of this study was to identify endometriosis risk variants in selected human populations within the Genomics England database and investigate the pathways these variants could act upon within the presence of modern environmental stressors and pollutants. This study focussed on the variants of regulatory sequences of the genome likely to be impacted by environmental and genetic influencers of endometriosis. A combination of systematic analysis and data interrogation in the Genomics England 100,000 genomes project were undertaken. Participant data was extracted from participants with a diagnosis of endometriosis at various stages. Variant frequency analysis and statistical testing identified six novel regulatory variants significantly enriched in the endometriosis cohort. The strongest association was observed for two IL-6 variants, which co-localized more frequently than expected by chance, suggesting a potential regulatory interaction. Although the sample size was limited, this study provides novel insights into how genetic regulatory variation and environmental pollutants may collectively influence endometriosis risk. The findings suggest that genetic susceptibility to endometriosis may be shaped by modern industrial exposures, with potential implications for personalised risk assessment and prevention strategies. Future research should validate these findings in larger populations and explore functional mechanisms underlying gene - environment interactions to develop targeted interventions for individuals at risk. The study introduces a unique perspective by linking ancient Neanderthal and Denisovan genetic variants to modern disease risk in the context of environmental exposure. We propose those industrial pollutants—particularly endocrine-disrupting chemicals (EDCs)—may epigenetically disrupt immune and reproductive gene regulation, thereby amplifying disease risk in genetically susceptible individuals. This is an early-stage, hypothesis-generating study and has not yet undergone peer review. Findings should not be interpreted as clinical advice or diagnostic tools. Future research with larger cohorts and functional validation is warranted.

Klebsiella pneumoniae (K. pneumoniae) cultures from a hospital-wide outbreak in the UK, which lasted for over 12 months, were sequenced. We sought to sequence and genetically characterise the outbreak strain. Antibiotic Susceptibility Testing (AST) was performed on 65 K. pneumoniae isolates saved from the outbreak. All isolates were sequenced using the Oxford Nanopore Technologies (ONT) MinION flowcell: 10 isolates, including the isolate with the earliest collection date in 2017, were additionally sequenced on the NovaSeq 6000 platform to build high-accuracy nanopore-illumina assemblies. Among the sequenced strains, 60 were typed as ST628. 96.6% (n = 58/60) ST628 strains harboured a large ~247-kb FIB(K) plasmid carrying up to 11 antimicrobial resistance genes, including the extended-spectrum beta-lactamase (ESBL) gene, bla_CTX-M-15. Clonality between the outbreak isolates was confirmed using single nucleotide polymorphism (SNP) typing. The outbreak strains were phylogenetically related to clinical ST628 strains identified in 2012, 6 years prior to the outbreak. A rare ESBL K. pneumoniae K2 ST628 strain harbouring a multi-drug resistant (MDR) plasmid encoding the ESBL gene bla_CTX-M-15 was detected across multiple independent wards during the protracted nosocomial outbreak. Surveillance of this strain is recommended to prevent future nosocomial outbreaks.

Colistin is a last resort antibiotic for the treatment of carbapenemase producing Klebsiella pneumoniae. The disruption of the mgrB gene by insertion sequences (ISs) is a mechanism mediating colistin resistance. Plasmids encode mobilizable IS elements which integrate into the mgrB gene in K. pneumoniae causing gene inactivation and colistin resistance. The species prevalence of mgrB‐gene disrupting insertion elements ISL3 (ISKpn25), IS5 (ISKpn26), ISKpn14, and IS903B present on plasmids were assessed. IS containing plasmids were also scanned for antimicrobial resistance genes, including carbapenem resistant genes. Plasmids encoding ISs are abundant in K. pneumoniae. IS903B was found in 28 unique Inc groups, while ISKpn25 was largely carried by IncFIB(pQil) plasmids. ISKpn26 and ISKpn14 were most often found associated with IncFII(pHN7A8) plasmids. Of the 34 unique countries which contained any of the IS elements, ISKpn25 was identified from 26. ISKpn26, ISKpn14, and IS903B ISs were identified from 89.3%, 44.9%, and 23.9% plasmid samples from China. Plasmids carrying ISKpn25, ISKpn14, and ISKpn26 IS have a 4.6‐, 6.0‐, and 6.6‐fold higher carbapenemase gene count, respectively, relative to IS903B‐carrying plasmids. IS903B bearing plasmids have a 20‐, 5‐, and 5‐fold higher environmental source isolation count relative to ISKpn25, ISKpn14, and ISKpn26 bearing plasmids. ISKpn25 present on IncFIB(pQil) sourced from clinical settings is established across multiple countries, while ISKpn26, ISKpn14, and IS903B appear most often in China. Carbapenemase presence in tandem with IS elements may help promote an extensively drug resistant profile in K. pneumoniae limiting already narrow treatment options.

Colistin is a last resort antibiotic for the treatment of carbapenemase producing Klebsiella pneumoniae (CRKP). In line with rising colistin use worldwide, colistin resistant Klebsiella pneumoniae ( K. pneumoniae ) isolates have emerged. The disruption of mgrB by insertion sequences (ISs) has been widely reported worldwide representing a mechanism mediating colistin resistance. Evidence suggests plasmids encode mobilizable IS elements which preferentially integrate into the mgrB gene in K. pneumoniae causing gene inactivation and colistin resistance. Recognised IS elements targeting mgrB include ISL3 (ISKpn25), IS5 (ISKpn26), ISKpn14 and IS903B-like elements. K. pneumoniae represents the single largest species carrying plasmids encoding these IS elements. For IS presence among species, 1000 BLASTn hits were downloaded and filtered for plasmids. Additionally, the top 120 BLASTn non-duplicate circularised plasmid contig hits for each IS element were typed for incompatibility (Inc) group and carbapenemase gene presence. IS903B was found in 28 unique Inc groups, while ISKpn25 was largely carried by IncFIB(pQil) plasmids. ISKpn26 and ISKpn14 were most often found associated with IncFII(pHN7A8) plasmids. Of the 34 unique countries which contained any of the IS elements, ISKpn25 was identified from 26. ISKpn26, ISKpn14, and IS903B insertion sequences were identified from 89.3%, 44.9% and 23.9% plasmid samples from China. Plasmids carrying ISKpn25, ISKpn14, and ISKpn26 IS elements are 12.18, 27.0, and 44.43 times more likely to carry carbapenemase genes relative to plasmids carrying the IS element IS903B. Moreover, plasmids carrying ISKpn26, ISKpn25, and ISKpn14 were 6.10, 28.82, and 31.47 times more likely to be sourced from a clinical environmental setting than the environment relative to IS903B IS harboring plasmid. ISKpn25 present on IncFIB(pQil) sourced from clinical settings is established across multiple countries, while ISKpn26, ISKpn14, and IS903B appear most often in China. High carbapenemase presence in tandem with IS elements may help promote an extensively drug resistant profile in K. pneumoniae limiting already narrow therapeutic treatment options.

Chromosome breakage is a fairly widespread phenomenon in preimplantation embryos affecting at least 10% of day 3 cleavage stage embryos. It may be detected during preimplantation genetic diagnosis (PGD). For carriers of structural chromosomal abnormalities, PGD involves the removal and testing of single blastomeres from cleavage stage embryos, aiming towards an unaffected pregnancy. Twenty-two such couples were referred for PGD, and biopsied blastomeres on day 3 and untransferred embryos (day 5/6) were tested using fluorescence in situ hybridisation (FISH) with appropriate probes. This study investigated whether chromosome breakage (a) was detected more frequently in cases where the breakpoint of the aberration was in the same chromosomal band as a fragile site and (b) was influenced by maternal age, sperm parameters, reproductive history, or the sex of the carrier parent. The frequency of breakage seemed to be independent of fragile sites, maternal age, reproductive history, and sex of the carrier parent. However, chromosome breakage was very significantly higher in embryos from male carriers with poor sperm parameters versus embryos from male carriers with normal sperm parameters. Consequently, embryos from certain couples were more prone to chromosome breakage, fragment loss, and hence chromosomally unbalanced embryos, independently of meiotic segregation.