Screening for homologous recombination genes
Related Articles
Global implementation and evaluation of atrial fibrillation screening in the past two decades – a narrative review
Advances in screening technology have been made in tandem with the aging population and increasing atrial fibrillation (AF) prevalence. While several randomized controlled trials demonstrate the efficacy of AF screening, less evidence has been synthesized addressing the implementation and evaluation of AF screening programs. We systematically searched the PubMed database from 1st January 2000 to 18th January 2024. The search terms included “atrial fibrillation” and “screening” and their synonyms. Articles that described screening implementation, including screening methods, were included. Editorial, commentary, engineering, and basic science articles were excluded. 1767 abstracts were screened, of which 138 full articles were reviewed, and 87 studies were included: 90% from high-income, 8% from upper-middle-income and 2% from lower-middle-income countries/ regions. The screening initiatives included general practice (n = 31), remote self-screening (n = 30), pharmacy (n = 11), community centers and villages (n = 10), hospital (n = 4), and nursing home (n = 1). Most studies used handheld ECG devices (n = 72, 83%), some used wearable devices (n = 13, 15%), and two (2%) used implantable cardiac devices. Comparator groups were described in 17% (15/87) studies: all 6 remote self-screening trials showed superior AF detection rates compared to usual care (these studies applied intermittent screening using handheld ECG devices over 2 weeks to 12 months or wearing ECG patches for continuous monitoring over 2–4 weeks), but 9 trials using systematic and opportunistic screening in primary care settings showed mixed results. Among 72 studies without comparator groups, 18 reported new AF detection rates below 1%, 48 reported 1–10%, 5 reported above 10%, and one reported an AF incidence rate of 2.25% patient-years (95% CI 2.03–2.48). Only 22% (19/87) of studies reported on the implementation evaluation (12 by surveys and 7 by interviews), surveying participant acceptability, usability, and satisfaction, and some studies in general practice and pharmacy interviewing participants and qualitatively evaluating the enablers and barriers to implementation. These studies reported barriers of lack of resources and referral pathways and enablers of having a designated staff member to lead implementation at point-of-care settings. AF screening implementation studies were mainly conducted in high-income countries/ regions. Detection rates were highest in older and higher risk groups, and if longer continuous ECG monitoring was used. Few studies reported details of the implementation of AF screening programs concerning cost, scalability, or comparative effectiveness of remote technology-driven screening approaches versus lower-tech approaches such as pulse palpation. Despite AF screening recommendations existing for some time, we seem to lack the data to effectively scale these initiatives.
One-step Cre-loxP organism creation by TAx9
The creation of organisms with Cre-loxP conditional gene recombination systems often faces challenges, particularly when creating the initial (F0) generation with both a Cre recombinase and a DNA site flanked by loxP elements (floxed site). The primary reason is that it is difficult to synthesize a single plasmid with both the Cre gene and the floxed site, since Cre-mediated recombination spontaneously occurs when the plasmid is amplified in Escherichia coli bacterial cells. Here, we introduce an artificial nucleic acid sequence TATATATATATATATATA, named TAx9, that enables the integration of both the Cre gene and the floxed site into a single plasmid. TAx9 effectively blocks spontaneous Cre-mediated recombination in E. coli cells. Using this system, we created an F0 generation of transgenic newts and CRISPR-Cas9 knock-in mice with tissue-specific Cre recombination triggered by tamoxifen. TAx9 technology will be a powerful strategy for creating organisms capable of conditional genetic modification in the F0 generation, accelerating various life science research by reducing the time and cost for ultimately establishing and maintaining lines of genetically modified organisms.
Antibiotic resistance mediated by gene amplifications
Apart from horizontal gene transfer and sequence-altering mutational events, antibiotic resistance can emerge due to the formation of tandem repeats of genomic regions. This phenomenon, also known as gene amplification, has been implicated in antibiotic resistance in both laboratory and clinical scenarios, where the evolution of resistance via amplifications can affect treatment efficacy. Antibiotic resistance mediated by gene amplifications is unstable and consequently can be difficult to detect, due to amplification loss in the absence of the selective pressure of the antibiotic. Further, due to variable copy numbers in a population, amplifications result in heteroresistance, where only a subpopulation is resistant to an antibiotic. While gene amplifications typically lead to resistance by increasing the expression of resistance determinants due to the higher copy number, the underlying mechanisms of resistance are diverse. In this review article, we describe the various pathways by which gene amplifications cause antibiotic resistance, from efflux and modification of the antibiotic, to target modification and bypass. We also discuss how gene amplifications can engender resistance by alternate mutational outcomes such as altered regulation and protein structure, in addition to just an increase in copy number and expression. Understanding how amplifications contribute to bacterial survival following antibiotic exposure is critical to counter their role in the rise of antimicrobial resistance.
ZBTB16/PLZF regulates juvenile spermatogonial stem cell development through an extensive transcription factor poising network
Spermatogonial stem cells balance self-renewal with differentiation and spermatogenesis to ensure continuous sperm production. Here, we identify roles for the transcription factor zinc finger and BTB domain-containing protein 16 (ZBTB16; also known as promyelocytic leukemia zinc finger (PLZF)) in juvenile mouse undifferentiated spermatogonia (uSPG) in promoting self-renewal and cell-cycle progression to maintain uSPG and transit-amplifying states. Notably, ZBTB16, Spalt-like transcription factor 4 (SALL4) and SRY-box transcription factor 3 (SOX3) colocalize at over 12,000 promoters regulating uSPG and meiosis. These regions largely share broad histone 3 methylation and acetylation (H3K4me3 and H3K27ac), DNA hypomethylation, RNA polymerase II (RNAPol2) and often CCCTC-binding factor (CTCF). Hi-C analyses show robust three-dimensional physical interactions among these cobound promoters, suggesting the existence of a transcription factor and higher-order active chromatin interaction network within uSPG that poises meiotic promoters for subsequent activation. Conversely, these factors do not notably occupy germline-specific promoters driving spermiogenesis, which instead lack promoter–promoter physical interactions and bear DNA hypermethylation, even when active. Overall, ZBTB16 promotes uSPG cell-cycle progression and colocalizes with SALL4, SOX3, CTCF and RNAPol2 to help establish an extensive and interactive chromatin poising network.
Accelerated differentiation of neo-W nuclear-encoded mitochondrial genes between two climate-associated bird lineages signals potential co-evolution with mitogenomes
There is considerable evidence for mitochondrial-nuclear co-adaptation as a key evolutionary driver. Hypotheses regarding the roles of sex-linkage have emphasized Z-linked nuclear genes with mitochondrial function (N-mt genes), whereas it remains contentious whether the perfect co-inheritance of W genes with mitogenomes could hinder or facilitate co-adaptation. Young (neo-) sex chromosomes that possess relatively many N-mt genes compared to older chromosomes provide unprecedented hypothesis-testing opportunities. Eastern Yellow Robin (EYR) lineages in coastal and inland habitats with different climates are diverged in mitogenomes, and in a ~ 15.4 Mb nuclear region enriched with N-mt genes, in contrast with otherwise-similar nuclear genomes. This nuclear region maps to passerine chromosome 1A, previously found to be neo-sex in the inland EYR genome. To compare sex-linked Chr1A-derived genes between lineages, we assembled and annotated the coastal EYR genome. We found that: (i) the coastal lineage shares a similar neo-sex system with the inland lineage, (ii) neo-W and neo-Z N-mt genes are not more diverged between lineages than are comparable non-N-mt genes, and showed little evidence for broad positive selection, (iii) however, W-linked N-mt genes are more diverged between lineages than are their Z-linked gametologs. The latter effect was ~7 times stronger for N-mt than non-N-mt genes, suggesting that W-linked N-mt genes might have diverged between lineages under environmental selection through co-evolution with mitogenomes. Finally, we identify a candidate gene driver for divergent selection, NDUFA12. Our data represent a rare example suggesting a possible role for W-associated mitochondrial-nuclear interactions in climate-associated adaptation and lineage differentiation.
Responses