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PubMed2026

An inducer-independent, single-plasmid CRISPR-Cas9 system for genome editing in Bacillus species.

Advances in molecular biology tools are essential for streamlining and accelerating genetic engineering of cells across industrial and academic applications. While CRISPR-Cas improves genome editing efficiency, current systems have limitations and are often host specific, which restricts their versatility. This study describes a versatile CRISPR-Cas9 system for genome editing in industrially relevant Bacillus species. By adapting the well-established pJOE8999 vector-based CRISPR-Cas9 genome editing system, we constructed an inducer-independent, broad-host-range genome editing system. It maintains the benefits of low toxicity to the target cell and the cloning host as well as the ease to use of a single-plasmid CRISPR-Cas9 system. We utilized the constitutive Sigma70-type promoter from the conserved veg gene of Bacillus, to develop and test the suitability of promoter variants of different strengths for Cas9 expression. Successful gene deletions in three different Bacillus species demonstrated the versatility of the modified system for this industrially important genus. This was further confirmed by the integration of a reporter gene fusion and the introduction of a single point mutation in the genome of Bacillus licheniformis. This one-step CRISPR-based transformation protocol developed in this study enables fast genome editing workflows with minimal hands-on time. KEY POINTS: • Editing and screening of promoter variants for balanced Cas9 expression in Bacillus. • Development of a versatile inducer-independent, single-plasmid CRISPR-Cas-based system. • Verification of the modified CRISPR-based system for genome editing in different Bacilli.

CRISPR-Cas Systems↗
PubMed2004

[Ebers Papyrus. The book of medical knowledge of the 16th century B.C. Egyptians].

In 2nd century B.C. Clemens Alexanrinus was sure, that the Egyptians collected all their knowledge in 42 secret books. of which last six contained medical knowledge. Despite this and records of other ancient authors, for long time the opinion about the history of medicine was not changed. In traditional view the role of Hippocrates and the Greeks was emphasized. In 19th century egyptologist began finding Egyptian papyri, whose contents concerned medical matters. The first medical papyrus was published by Georg Ebers in 1875. The Ebers Papyrus is a scroll 20,23 meters in length and contains 108 columns of text. I is dated at the reign of Amenophis I (1536 B.C.). This papyrus was published and translated by different researches (the most valuable is German edition Grundriss de Medizin de alten ägypter, and based on this Paul Ghalioungui edition). In the opinion of Grundriss, chaotic arrangement of medical advices in papyrus suggest different originals from which they drew. The text of The Ebers Papyrus is ordered in series of prescriptions, which are grouped according to different diseases, illnesses and injuries. ALmost all of those groups have introduction by the formula: "Here begins.." used on 36 occasions. They are, however, often varied and disorganised. The owner of this papyrus was probably a physician - the text mentions about "physician secrets". Herodotus writes, that Egyptian physicians were specialized, which seems to be confirmed by The Ebers Papyrus.

Egypt↗
PubMed1989

Apolipoprotein B48 RNA editing in chimeric apolipoprotein EB mRNA.

Apolipoprotein (apo) B occurs in two forms, apoB100 (512 kDa) and apoB48 (240 kDa); both are derived from the same gene. A novel mechanism involving editing of the apoB mRNA causes the formation of apoB48; the first base of codon 2153 is changed from cytosine to uracil, converting a glutamine codon to a premature stop codon. To identify the apoB mRNA sequence elements recognized by the apoB mRNA editing mechanism, two apoB cDNA fragments (354 and 63 base pairs) with codon 2153 near their centers were inserted into a high expression vector of another secreted apolipoprotein, apoE. The resulting vectors, pHEB-354 and -63, were transfected into Chinese hamster ovary cells, HepG2 cells, and apoB48-producing CaCo-2 cells. The secreted chimeric apolipoproteins (apoEB354 and apoEB63) were analyzed for premature truncation, and the mRNA was analyzed for the presence of an edited base. The pHEB-354 construct produced a truncated protein only in CaCo-2 cells, whereas pHEB-63 produced no truncated protein in any of the three cell types. The mRNA was converted to cDNA and amplified by the polymerase chain reaction technique. Differential hybridization of the polymerase chain reaction products with CAA (Gln) and TAA (Stop) specific probes detected an edited base only in cDNA from CaCo-2 cells transfected with pHEB-354, in agreement with the protein analysis. We conclude that the nucleotide sequence of the apoB cDNA insert in pHEB-354 contains sufficient information to be edited in CaCo-2 cells. In these cells, a cryptic polyadenylation site was activated in the edited pHEB-354 mRNA. As a result, CaCo-2 cells transfected with pHEB-354 produced a short, edited pHEB-354 mRNA and a long, unedited pHEB-354 mRNA. Chinese hamster ovary cells transfected with pHEB-354 or CaCo-2 cells transfected with pHEB-63 produced only a full length transcript. Amplification of the pHEB-354 cDNA using 3'-primers upstream and downstream of the poly(A) addition site and hybridization with the TAA probe confirmed these results. This unusual mRNA editing apparently occurs before polyadenylation, probably in the nucleus.

Adenocarcinoma↗
PubMed2006

Recurrent headache in chinese children: any agreement between clinician diagnosis and symptom-based diagnoses using the International Classification of Headache Disorders (Second Edition)?

There has been a lack of published data on the pattern of recurrent headache in Chinese children. The validity of the International Classification of Headache Disorders criteria has not been evaluated in Chinese children. We performed a retrospective medical record review of 124 children aged <18 years with an International Classification of Diseases coding of headache followed up in a general outpatient clinic in a university-based hospital over a 3-year period (2000-2002). The aims of our study were to (1) study the pattern of recurrent headache in Chinese children and (2) study any agreement between clinical diagnoses made by our board-certified pediatricians and symptom-based diagnoses using the second edition of the International Classification of Headache Disorders (International Classification of Headache Disorders-II). The most common type was unclassified headache (70.2%), followed by infrequent episodic tension-type headache (24.2%) and migraine without aura (5.6%). A family history of headache or migraine was more commonly found in children with infrequent episodic tension-type headache or migraine without aura (P = .0109). The co-occurrence of abdominal pain with infrequent episodic tension-type headache was 30%; for unclassified headache, it was 19.5%. Dysmenorrhea occurred in 7.1% of girls with infrequent episodic tension-type headache and 8.6% of girls with unclassified headache. However, migraine without aura was not associated with abdominal pain or dysmenorrhea. Children with migraine without aura were more frequently referred to child neurologists (P = .0207) and admitted (P = .0000). Neurologic investigations, including electroencephalography, computed tomography, or magnetic resonance imaging of the brain, were performed in less than 30% of cases. Abnormal results were found in only seven cases; with two referred to a neurosurgeon and none requiring surgical intervention. Thus, by using the clinical diagnosis of our board-certified pediatricians as the standard, the sensitivity and specificity of International Classification of Headache Disorders-II-based definition of migraine without aura was 23.1% and 93.4%, respectively, and for infrequent episodic tension-type headache, it was 37.5% and 76%, respectively. The typical characteristics of migraine tend to emerge later and might have led to underdiagnosis of the younger age group, with a higher rate of referral and inpatient management. The new edition of the International Classification of Headache Disorders criteria is still restrictive in clinical practice and might not be able to reflect current pediatric practice. Further studies with a defined study period or recurrent headache might be more useful in analyzing the use of these new International Classification of Headache Disorders criteria in the diagnosis of recurrent headache in children.

Adolescent↗
PubMed1998

An Internet-based ontology editor for medical appropriateness criteria.

Appropriateness criteria and practice guidelines seek to promote the cost-effectiveness use of medical interventions, and can be most useful when integrated with computer-based patient records and order-entry systems. Building an abstract model (ontology) of appropriateness criteria can require considerable effort among investigators at geographically dispersed institutions. To facilitate the construction and maintenance of ontologies for clinical appropriateness criteria, the author developed an Internet-based system for viewing and editing the knowledge model. The system, called NEON (Network-based Editor for ONtologies), uses the World Wide Web as a platform-independent user interface. NEON allows users to edit the indexing terms and the semantic network that form the ontology for a set of appropriateness criteria. Ontologies built using the system can be imported and exported using an open, internationally standardized format based on the Standard Generalized Markup Language (SGML).

Artificial Intelligence↗
PubMed2002

A general edit distance between RNA structures.

Arc-annotated sequences are useful in representing the structural information of RNA sequences. In general, RNA secondary and tertiary structures can be represented as a set of nested arcs and a set of crossing arcs, respectively. Since RNA functions are largely determined by molecular confirmation and therefore secondary and tertiary structures, the comparison between RNA secondary and tertiary structures has received much attention recently. In this paper, we propose the notion of edit distance to measure the similarity between two RNA secondary and tertiary structures, by incorporating various edit operations performed on both bases and arcs (i.e., base-pairs). Several algorithms are presented to compute the edit distance between two RNA sequences with various arc structures and under various score schemes, either exactly or approximately, with provably good performance. Preliminary experimental tests confirm that our definition of edit distance and the computation model are among the most reasonable ones ever studied in the literature.

Algorithms↗
PubMed2006

Memory editing: Knowledge, criteria, and alignment.

Within this article, a general organisational framework for this special issue of Memory is provided. The organising structure is based on a straightforward hypothesis that editing mechanisms are based on three independent constructs: knowledge, criteria, and alignment. Supporting evidence for this general framework taken from the literature generally, and this special issue of Memory specifically, is reviewed. In the concluding section, future directions for research in the area of memory editing are outlined.

Cognition↗
PubMed1997

[Results of resected lung cancer based on the new UICC TNM classification, 5th edition].

The UICC (Union Internationale Contre le Cancer) TNM Classification for lung cancer staging, 5th edition, has been published this year in accordance with the regulations following the last 10 years of the 4th edition's in use since 1987. What is new in this latest edition is that Stage I and II became classified as IA and IB, and IIA and IIB respectively. Furthermore, the new mode of classification can be found in that T3N0M0 is now acknowledged as of IIB, and T4 in such case where the pulmonary tumors, except for that of primary, exist within the same lobe, and M1 when found in other lobes. T3N0M0, excluding Pancoast tumor, has a relatively good prognosis, therefore, it should belong to Stage II rather than Stage III. However, it will become necessary to treat Pancoast tumor separately, given its poor prognosis. In the case of the same histological type, differential diagnosis of either multiple cancer or intra pulmonary metastasis could become highly difficult, therefore, such cases should not be classified by TNM Stage at present. Nevertheless, there should be a further discussion with regards to the method of description of classification. As indicated in the results reviewed at the National Cancer Center Hospital, the new TNM classification should be seen as appropriate, and we hope to bring about the 6th edition in 10 years time, as the fruit of the analyses of various opinions and data gathered from the doctors who are all specialists in this field.

Carcinoma↗
PubMed2001

A mRNA determinant of gRNA-directed kinetoplastid editing.

Several mitochondrial mRNAs of the kinetoplastid protozoa do not encode a functional open reading frame until they have been edited through the addition or deletion of U nucleotides at specific sites. Genetic information specifying the location and extent of editing is present on guide RNAs (gRNAs). The sequence adjacent to most mRNA editing sites has a high purine content which previously has been proposed to facilitate the editing reaction through base-pairing to a poly(U) tail at the 3' end of the gRNA. We demonstrate here that gRNA binding alone is insufficient to create an editing site and that the mRNA sequence near an editing site is an additional determinant affecting the efficiency of the reaction.

Animals↗
PubMed1999

A framework and tools for authoring, editing, documenting, sharing, searching, navigating, and executing computer-based clinical guidelines.

With the spread of managed care and integrated delivery networks, an increased emphasis has been placed on the cost-effectiveness of clinical practices. The need has been recognized to use guidelines to support education, and to integrate them into clinical practice. A specification for guideline representation that would facilitate computer-based clinical guideline sharing has been developed by the InterMed Collaboratory. Called GLIF (GuideLine Interchange Format), this specification and its proposed extensions have been the basis for our implementation of a framework and suite of integrated software tools for guideline authoring and editing, packaging in XML, Internet distribution, navigation, eligibility determination, and automatic execution.

Eligibility Determination↗
PubMed2004

Widespread A-to-I RNA editing of Alu-containing mRNAs in the human transcriptome.

RNA editing by adenosine deamination generates RNA and protein diversity through the posttranscriptional modification of single nucleotides in RNA sequences. Few mammalian A-to-I edited genes have been identified despite evidence that many more should exist. Here we identify intramolecular pairs of Alu elements as a major target for editing in the human transcriptome. An experimental demonstration in 43 genes was extended by a broader computational analysis of more than 100,000 human mRNAs. We find that 1,445 human mRNAs (1.4%) are subject to RNA editing at more than 14,500 sites, and our data further suggest that the vast majority of pre-mRNAs (greater than 85%) are targeted in introns by the editing machinery. The editing levels of Alu-containing mRNAs correlate with distance and homology between inverted repeats and vary in different tissues. Alu-mediated RNA duplexes targeted by RNA editing are formed intramolecularly, whereas editing due to intermolecular base-pairing appears to be negligible. We present evidence that these editing events can lead to the posttranscriptional creation or elimination of splice signals affecting alternatively spliced Alu-derived exons. The analysis suggests that modification of repetitive elements is a predominant activity for RNA editing with significant implications for cellular gene expression.

5' Untranslated Regions↗
PubMed2005

[Summary of 'General Rule for Clinical and Pathological Studies on Prostate Cancer (the 3rd Edition)'].

'General Rule for Clinical and Pathological Studies on Prostate Cancer(The 1st edition)' was published at 1985 by Japanese Urological Association and The Japanese Society of Pathology. It was revised in 1992 and the 2nd edition was published. Current diagnostic tests including prostate specific antigen (PSA) and biopsy technique have changed diagnosis and treatment of prostate cancer greatly. The 3rd edition was published in 2001 based on these changes. Here, the feature of the 3rd edition is outlined.

Biomarkers↗
PubMed2025

CRISPR for cystic fibrosis: Advances and insights from a systematic review.

Cystic fibrosis (CF) is a severe genetic disorder caused by loss-of-function mutations in the CFTR gene. Gene-editing approaches have the potential to correct such mutations. This systematic review outlines the mechanisms of the main CRISPR-based technologies, and, through cross-study comparisons, analyzes 27 research articles that applied them to target CF-causing variants. We report and discuss the strategy design, target cell selection, editing efficiency, prevalence of editing byproducts, and levels of CFTR functional restoration achieved in each work, with the aim of providing technical insights for further exploration of CRISPR-based gene-editing approaches. Our findings show that the F508del and W1282X mutations were the most extensively studied CF-causing variants, though over fifteen mutations were targeted overall. The majority of works under review explored the use of homology-directed repair or base editing, with a growing number of studies reporting efficient prime editing. Some studies tackled multiple individual mutations, compared different editors, or tested strategies across various models, while others focused on approaches that rescue CFTR function without directly correcting a mutation. Several works also proposed strategies that could address multiple variants with a single approach, while others highlighted technical difficulties in editing certain regions of the CFTR gene. This cross-study comparison also emphasizes the need for standardized reporting of editing efficiency and functional recovery, and stresses the importance of further single-cell RNA sequencing and in vivo studies to reach clinically relevant conclusions. As gene-editing techniques continue to evolve, and with over 60 ongoing CRISPR-based clinical trials, there is growing optimism for meaningful advancements in CF gene-editing therapeutics.

Cystic Fibrosis↗
PubMed2026

LAML-Pro: joint maximum likelihood inference of cell genotypes and cell lineage trees.

MOTIVATION: Recent dynamic lineage tracing technologies use genome editing to induce heritable mutations, or edits, that accumulate across successive cell divisions. These edits are measured using single-cell sequencing or imaging, providing data to reconstruct cell lineages at single-cell resolution. Current computational approaches to infer cell lineage trees, or phylogenies, from these data perform two separate steps: (i) Identify each cell's edits (genotype) from the raw sequencing or imaging data; (ii) Infer a cell lineage tree from the cell genotypes. However, genotyping cells is an inexact process and genotype errors can yield an inaccurate lineage tree. For example, using fluorescence based-imaging to measure edits results in a high fraction (&#x2248;25%-50%) of uncertain or erroneous genotypes. RESULTS: We introduce Lineage Analysis via Maximum Likelihood with PRobabilistic Observations (LAML-Pro), an algorithm that jointly infers cell genotypes and a cell lineage tree. LAML-Pro is based on the Probabilistic Mixed-type Missing Observation (PMMO) model, which we derive to describe both the genome editing and genotype observation processes. LAML-Pro constructs lineage trees from thousands of cells in under an hour by leveraging the sparsity of transitions under the PMMO model. On simulated data, we demonstrate that LAML-Pro corrects genotype errors and infers substantially more accurate trees than existing methods which are vulnerable to genotype errors. Applied to data from two recent imaging-based lineage tracing systems, LAML-Pro reduces genotype errors by 5-fold and produces more spatially coherent lineage trees compared to existing methods. AVAILABILITY AND IMPLEMENTATION: LAML-Pro is implemented in C++ and is available as both a command-line interface and as a Python library at: github.com/raphael-group/LAML-Pro.

Cell Lineage↗
PubMed2025

A probe-based capture enrichment method for detection of A-to-I editing in low abundance transcripts.

Exactly two decades ago, the ability to use high-throughput RNA sequencing technology to identify sites of editing by ADARs was employed for the first time. Since that time, RNA sequencing has become a standard tool for researchers studying RNA biology and led to the discovery of RNA editing sites present in a multitude of organisms, across tissue types, and in disease. However, transcriptome-wide sequencing is not without limitations. Most notably, RNA sequencing depth of a given transcript is correlated with expression, and sequencing depth impacts the ability to robustly detect RNA editing events. This chapter focuses on a method for enrichment of low-abundance transcripts that can facilitate more efficient sequencing and detection of RNA editing events. An important note is that while we describe aspects of the protocol important for capturing intron-containing transcripts, this probe-based enrichment method could be easily modified to assess editing within any low-abundance transcript. We also provide some perspectives on the current limitations as well as important future directions for expanding this technology to gain more insights into how RNA editing can impact transcript diversity.

RNA Editing↗
PubMed2026

LAML-Pro: Joint Maximum Likelihood Inference of Cell Genotypes and Cell Lineage Trees.

MOTIVATION: Recent dynamic lineage tracing technologies use genome editing to induce heritable mutations, or edits, that accumulate across successive cell divisions. These edits are measured using single-cell sequencing or imaging, providing data to reconstruct cell lineages at single-cell resolution. Current computational approaches to infer cell lineage trees, or phylogenies, from these data perform two separate steps: (1) Identify each cell's edits (genotype) from the raw sequencing or imaging data; (2) Infer a cell lineage tree from the cell genotypes. However, genotyping cells is an inexact process and genotype errors can yield an inaccurate lineage tree. For example, using fluorescence based-imaging to measure edits results in a high fraction (&#x2248; 25-50%) of uncertain or erroneous genotypes. RESULTS: We introduce Lineage Analysis via Maximum Likelihood with PRobabilistic Observations (LAML-Pro), an algorithm that jointly infers cell genotypes and a cell lineage tree. LAML-Pro is based on the Probabilistic Mixed-type Missing Observation (PMMO) model, which we derive to describe both the genome editing and genotype observation processes. LAML-Pro constructs lineage trees from thousands of cells in under an hour by leveraging the sparsity of transitions under the PMMO model. On simulated data, we demonstrate that LAML-Pro corrects genotype errors and infers substantially more accurate trees than existing methods which are vulnerable to genotype errors. Applied to data from two recent imaging-based lineage tracing systems, LAML-Pro reduces genotype errors by 5-fold and produces more spatially coherent lineage trees compared to existing methods. AVAILABILITY AND IMPLEMENTATION: LAML-Pro is freely available at: github.com/raphael-group/LAML-Pro.

Journal Article↗