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PubMed1995

Scientific writing and editing: a new role for the library.

Traditional library instruction programs teach scientists how to find and manage information, but not how to report their research findings effectively. Since 1990, the William H. Welch Medical Library has sponsored classes on scientific writing and, since 1991, has offered a fee-based editing service for affiliates of the Johns Hopkins Medical Institutions. These programs were designed to fill an educational gap: Although formal instruction was offered to support other phases of the scientific communication process, the medical institutions had no central resource designed to help scientists develop and improve their writing skills. The establishment of such a resource at Welch has been well received by the community. Attendance at classes has grown steadily, and in 1993 a credit course on biomedical writing was added to the curriculum. The editing service, introduced in late 1991, has generated more requests for assistance than can be handled by the library's editor. This service not only extends the library's educational outreach but also generates a revenue stream. The Welch program in scientific writing and editing, or elements of it, could provide a model for other academic medical libraries interested in moving in this new direction.

Baltimore↗
PubMed2025

CRISPR-based gene knockout in the model haloarchaeon Haloferax mediterranei.

Halophilic archaea, a specialized group of extremophiles that inhabit hypersaline environments, exhibit distinctive physiological and metabolic features. Traditional genetic manipulation of these organisms, predominantly reliant on homologous recombination techniques, suffers from limitations such as complex procedures and extended timelines, which hinder functional genomics research and the development of practical applications. This study established a CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats)-mediated gene knockout system in the model halophilic archaeon Haloferax mediterranei. A polyethylene glycol (PEG)-mediated transformation method was used to deliver a plasmid carrying a mini-CRISPR array into H. mediterranei. The crtB gene, involved in pigment synthesis, was successfully knocked out, demonstrating the feasibility of CRISPR-based editing in H. mediterranei. To further validate the reliability and targeting accuracy of the system, the hlyR4 gene, encoding an extracellular serine protease, was also disrupted. The CRISPR-mediated gene knockout efficiency for hlyR4 reached 27%, significantly higher than the approximately 3% efficiency achieved with conventional homologous recombination. The establishment of this CRISPR-based gene knockout system provides a more efficient genetic tool for H. mediterranei and lays a new experimental foundation for exploiting microbial resources from extreme environments. In this study, H. mediterranei was selected as the model organism for haloarchaea. For the first time, we successfully constructed a CRISPR-based gene knockout system in a model halophilic archaeon. This system provides a solution for CRISPR-based gene knockout tools, which are currently unavailable in model halophilic archaea, and offers an effective tool for functional genomics studies in extremophiles.

Haloferax mediterranei↗
PubMed2024

Bioinformatic approaches for accurate assessment of A-to-I editing in complete transcriptomes.

A-to-I RNA editing is an RNA modification that alters the RNA sequence relative to the its genomic blueprint. It is catalyzed by double-stranded RNA-specific adenosine deaminase (ADAR) enzymes, and contributes to the complexity and diversification of the proteome. Advancement in the study of A-to-I RNA editing has been facilitated by computational approaches for accurate mapping and quantification of A-to-I RNA editing based on sequencing data. In this chapter we review some of the main computational approaches currently used, describe potential hurdles, challenges and pitfalls, and discuss possible ways to mitigate them.

RNA Editing↗
PubMed2025

Sensitive, direct detection of non-coding off-target base editor unwinding and editing in primary cells.

Base editors create precise nucleotide changes in DNA, but their off-target activity remains challenging to quantify. Here, we develop and deploy a direct, in cellulo sequencing assay that simultaneously measures both Cas9-mediated unwinding and deaminase editing of genomic DNA (beCasKAS). Our strategy nominates >460-fold more potential off-target sites than other methods by enriching for Cas9-dependent R-loops immediately preceding editing. Using beCasKAS in primary human T-cells, we observe that mRNA-encoded ABE8e and PAMless ABE8e-SpRY base editors have distinct off-target profiles that can be mitigated by optimizing mRNA dose. Finally, we combine beCasKAS with base-resolution deep learning models to risk-stratify off-target edits by their likelihood of epigenetic dysregulation. Collectively, beCasKAS offers a sensitive and facile tool to optimize the balance between base editor on- and off-target activity.

Journal Article↗
PubMed2024

Bone-marrow-homing lipid nanoparticles for genome editing in diseased and malignant haematopoietic stem cells.

Therapeutic genome editing of haematopoietic stem cells (HSCs) would provide long-lasting treatments for multiple diseases. However, the in vivo delivery of genetic medicines to HSCs remains challenging, especially in diseased and malignant settings. Here we report on a series of bone-marrow-homing lipid nanoparticles that deliver mRNA to a broad group of at least 14 unique cell types in the bone marrow, including healthy and diseased HSCs, leukaemic stem cells, B cells, T cells, macrophages and leukaemia cells. CRISPR/Cas and base editing is achieved in a mouse model expressing human sickle cell disease phenotypes for potential foetal haemoglobin reactivation and conversion from sickle to non-sickle alleles. Bone-marrow-homing lipid nanoparticles were also able to achieve Cre-recombinase-mediated genetic deletion in bone-marrow-engrafted leukaemic stem cells and leukaemia cells. We show evidence that diverse cell types in the bone marrow niche can be edited using bone-marrow-homing lipid nanoparticles.

Animals↗
PubMed2006

Editing (out) generated study words in a recognition exclusion task: Effects of response signal delay and generation procedure.

Three experiments investigated participants' ability to exclude generated study words from "old" judgements on an exclusion task in which a response signal delay (RSD) was manipulated. In Experiment 1, words were generated by mentally conjoining components of two compound words, and a conjunction test condition was included (e.g., presentation of the lure checkpoint after studying checklist and needlepoint without generating the target). The exclusion error rate for generated words was higher than the conjunction error rate for a short RSD group but lower than the conjunction error rate for a long RSD group. The decrease in the familiarity effect across RSDs was extended to a conceptual cue generation procedure in Experiments 2 and 3, but an anagram generation procedure did not show similar evidence of recollection-based exclusions. The earliest indication of recollection-based editing of generated words occurred in a 2250-ms RSD (Experiment 3). An extension of a multi-factor transfer appropriate processing theory (deWinstanley, Bjork, & Bjork, 1996) of generation effects that incorporates influences of familiarity and recollection is advocated.

Attention↗
PubMed2026

Innovative CRISPR/Cas9-Based Strategy for Allele-Specific HLA Peptidome Analysis Using a Pan-HLA Antibody.

Human leukocyte antigen (HLA) immunopeptidomics is restricted by the limited availability of allele-specific antibodies and by potential artifacts introduced by HLA overexpression systems. To address these challenges, we developed a CRISPR/Cas9-based strategy that selectively deletes undesired classical class I alleles while preserving a single endogenous allele, thereby enabling allele-resolved peptidome profiling with a pan-HLA class I antibody. As a proof of concept, we edited JY cells to eliminate HLA-B∗07:02 and HLA-C∗07:02 while retaining HLA-A∗02:01 (ΔBC clones). Peptide-HLA complexes were immunoprecipitated from WT and ΔBC clones using either the pan-HLA class I antibody W6/32 or the A∗02:01-specific antibody PA2.1, followed by nanoLC-MS/MS and computational HLA assignment. Deletion of HLA-B and HLA-C alleles caused an expected ∼55% reduction in total class I surface expression. Despite this, W6/32 immunoprecipitation from ΔBC clones recovered a comparable peptide yield to PA2.1 in WT cells. Binding predictions showed that most peptides identified in ΔBC clones using W6/32 were assigned to HLA-A∗02:01, with near-complete loss of HLA-B∗07:02- and HLA-C∗07:02-derived peptides. Sequence logo analysis confirmed the canonical A∗02:01 motif across conditions. The ΔBC W6/32 immunopeptidome exhibited a high degree of overlap (∼88%) with the WT PA2.1 repertoire, supporting the specificity and fidelity of the approach. These findings establish CRISPR-based editing of HLA alleles as a viable strategy for allele-specific immunopeptidome analysis using pan-HLA antibodies, supporting its potential application beyond this proof-of-concept system, reducing reliance on allele-specific reagents and facilitating the study of underrepresented HLA alleles.

Humans↗
PubMed1996

[CT-angiography in planning stereotaxic biopsies].

Twenty-one patients referred for stereotactic biopsy were studied by CT angiography. Helical CT with 1 mm collimation was obtained (pitch of 1:1). Multiplanar reconstructions were performed; maximum intensity projections and shaded-surface displays were generated by connectivity-based editing tools. The visualization of cerebral vessels was excellent. No further conventional angiography was needed. Improved information was obtained about localization of the intracranial lesion and its relationship to neighboring vessels. No bleeding complications were detected by CT after stereotactic biopsy.

Adult↗
PubMed2026

Emerging Therapies for Angelman Syndrome.

Angelman syndrome (AS) is a complex neurogenetic disorder characterized by severe global developmental delay, motor dysfunction, and epilepsy, primarily resulting from the lack of functional ubiquitin protein ligase E3A (UBE3A) protein expression in neurons. While current management remains largely symptomatic, the therapeutic landscape for AS is rapidly evolving. Emerging strategies aim to restore UBE3A function through upstream interventions, such as gene replacement therapy or unsilencing of the imprinted paternal allele, which is present but transcriptionally silenced in neurons due to genomic imprinting. This imprinting is mediated by the distal portion of a long non-coding RNA known as the UBE3A-antisense transcript (UBE3A-ATS). This UBE3A-ATS has become a key therapeutic target, with several approaches developed to unsilence the paternal allele, including antisense oligonucleotides (ASOs), CRISPR-based editing, synthetic microRNA, and other modalities. To date, three ASO programs have demonstrated promising signals in early clinical development, with reported improvements in clinical outcomes and electroencephalography (EEG) biomarkers. Given the potential for improved outcomes with early intervention, the inclusion of AS in broader genomic newborn screening programs is currently being explored. An early-intervention approach, or combination of approaches, holds significant promise for transforming the lives of individuals affected by AS with outcomes dependent on their age or genotype.

Humans↗
PubMed2026

A transcription factor-focused CRISPR screen identifies SKI as a BCL11A-independent repressor of ζ-globin.

The regulation of α-like globin genes, particularly the embryonic ζ-globin gene (HBZ), remains incompletely understood. To identify transcriptional regulators of HBZ, we establish a GFP reporter system based on the HBZ-P2A-GFP allele in erythroid cell lines and conduct a CRISPR/Cas9 screen targeting 1639 transcription factors. This screen identifies SKI as a potent HBZ repressor. Functional validation shows that SKI loss increases HBZ expression without impairing erythropoiesis, whereas SKI overexpression suppresses HBZ. Tet-on-inducible SKI overexpression and auxin-inducible SKI degradation indicate that SKI rapidly represses HBZ transcription. Transcriptome profiling further reveals that SKI deletion activates HBZ while minimally affecting other erythroid genes. Mechanistically, genome-wide occupancy analyses show that SKI binds the distal enhancers HS-10 and HS-40, with partial co-occupancy by BCL11A. Despite this overlap, dual knockout of SKI and BCL11A synergistically increases HBZ expression, as does base editing of the SKI-binding site within HS-10. We also identify a naturally occurring variant (chr16:193207G>A) within this enhancer in α-thalassemia patients with elevated ζ-globin levels. Together, these findings establish SKI as a direct, BCL11A-independent transcriptional repressor of ζ-globin. This work advances our understanding of globin gene regulation and suggests targeted ζ-globin reactivation as a potential therapeutic strategy for α-thalassemia.

Enhancer↗
PubMed1991

The effects of flicker on eye movement control.

Groups of typists with extensive experience of screen-based editing and groups of students with no such experience carried out a reading task under three conditions of illumination (50-Hz flicker, 100-Hz flicker, and steady illumination). Subjects read a sentence, which was followed by the presentation of a single stimulus word on the same line to the right-hand side of the display. The task was to decide whether or not the stimulus was present in the sentence. Subjects were free to re-inspect the sentence when making the decision. Eye movements were measured as subjects completed the task. In comparison with students, typists adopted a more cautious reading style, making more right-to-left saccades, shorter saccades, and more corrective eye movements. Flicker affected the performance of both groups of subjects in the first pass, leading to shorter saccades. In the second pass, its effect for students was to shorten the extent of large saccades made to check the presence of the stimulus word. In the group of typists, flicker led to an increase in the variability of saccade extent and a doubling in the number of small corrective saccades. The results are consistent with the view that flicker has two distinct effects on reading, both of which are potentially disruptive. The first relates to an increase in the number of prematurely triggered saccades, which are, as a result, less accurate. The second is an increase in the number of saccades perturbed in flight, which land short of their intended target. These two mechanisms may have different consequences for readers, depending on their reading style.

Adult↗
PubMed2025

LCORL and STC2 Variants Increase Body Size and Growth Rate in Cattle and Other Animals.

Natural variants can significantly improve growth traits in livestock and serve as safe targets for gene editing, thus being applied in animal molecular design breeding. However, such safe and large-effect mutations are severely lacking. Using ancestral recombination graphs, we investigated recent selection signatures in beef cattle breeds, pinpointing sweep-driving variants in the LCORL and STC2 loci with notable effects on body size and growth rate. The ACT-to-A frameshift mutation in LCORL occurs mainly in central-European cattle, and stimulates growth. Remarkably, convergent truncating mutations were also found in commercial breeds of sheep, goats, pigs, horses, dogs, rabbits, and chickens. In the STC2 gene, we identified a missense mutation (A60P) located within the conserved region across vertebrates. We validated the two natural mutations in gene-edited mouse models, where both variants in homozygous carriers significantly increase the average weight by 11%. Our findings provide insights into a seemingly recurring gene target of body size enhancing truncating mutations across domesticated species, and offer valuable targets for gene editing-based breeding in animals.

Animals↗
PubMed2026

Synonymous mutations in essential genes infrequently produce fitness effects in human cell lines.

The assumption that synonymous mutations are fitness-neutral is central to many foundational results in the fields of genetics, genomics, evolutionary biology, and medicine. However, recent results suggest synonymous mutations have pervasive and strong fitness effects. These vigorously debated studies in non-human model systems have even suggested that the proportion of synonymous mutations and their fitness effect sizes are similar to non-synonymous mutations. To probe the fitness effect of synonymous mutations, we utilized recent advances in base editing to test 8558 potential synonymous mutations in 128 highly essential genes in human cell lines. Importantly, our library design excluded splice-proximal sites, ensuring a direct test of codon-level synonymous effects independent of splicing disruption. We find that synonymous mutations rarely have fitness effects on growth, occurring around 37.9-fold (95% CI: 22.16-81.48-fold) less frequently than missense mutations. In this experimental context, these findings demonstrate that synonymous mutations impact cellular fitness far less frequently than missense mutations. These results deviate from earlier reports of widespread synonymous fitness effects in yeast, yet they align with recent prime editing data observed in other human cell lines.

Humans↗
PubMed2001

Adaptive behavior of 4- through 8-year-old children with Williams syndrome.

The adaptive behavior of forty-one 4- through 8-year-olds with Williams syndrome was assessed using the Vineland Adaptive Behavior Scales-Interview Edition. Based on the cognitive and personality profiles characteristic of children with this syndrome, we predicted that the domains of Socialization and Communication would be relative strengths, whereas Daily Living Skills and Motor Skills would be relative weaknesses. We also expected that Socialization Skills would be more advanced than Communication skills, and that within the Socialization domain, interpersonal skills would be stronger than play/leisure or coping skills. All predictions were confirmed. Adaptive behavior standard score was not related to CA. The children earned similar overall standard scores on the Vineland and the Differential Ability Scales. Interrelations among adaptive behavior, cognitive abilities, and personality characteristics are discussed.

Activities of Daily Living↗
PubMed2004

Annotation of parasite genomes.

Genome annotation is the application of useful biological descriptions to sequence data. Different levels of time and effort can be invested to produce correspondingly different depths of annotation depending on what methods are employed. Researchers using genome data should, therefore, understand how annotations are generated to assess their validity correctly and to determine what level of inferences can be made accordingly. Thorough annotation requires a large range of procedures, most of which involve manual reviews of all available evidence. First, gene structures often are computed algorithmically and edited based on in-depth analyses of the underlying sequence data. Second, functional predictions draw on data from various sources. Finally, the use of structured and controlled descriptions, such as those provided by gene ontology, can be used so that final descriptions are not only consistent and unambiguous, but capable of being used in further downstream analyses such as cross-species comparisons.

Algorithms↗
PubMed2006

The family transmission of adolescent alcohol abuse and dependence.

OBJECTIVE: This study examines the familial transmission of alcohol abuse and dependence to adolescents. METHOD: Male adolescents recruited from a treatment program for substance problems, matched controls, and all available biological parents and siblings were assessed with a structured psychiatric interview assessing Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, based diagnoses of alcohol abuse and alcohol dependence. A total of 2,612 individuals from 911 families were interviewed. Structural equation modeling estimated tetrachoric correlations among family members, the proportion of variance in abuse and dependence attributable to parent-offspring transmission, and the effects of assortative mating and horizontal transmission among siblings. RESULTS: Tetrachoric correlations among siblings and parent-offspring ranged from .19 to .34 for abuse and dependence. Mother-father correlations were .14 and .37 for abuse and dependence, respectively. Modeling of familial transmission showed that 33% of the variance in abuse and 56% of the variance in dependence was accounted for by factors transmitted from parents. The effects of assortative mating could not be dropped from the abuse model without significant loss of model fit but could be dropped from the dependence model. Horizontal transmission among siblings could be dropped from both models without significant loss of fit. CONCLUSIONS: These results suggest that aggregation of alcohol abuse and alcohol dependence in families of male probands is significantly influenced by parental transmission of risk but is not reliably influenced by horizontal sibling effects such as sibling interactions or cohort effects. Spousal resemblance was found to be an important source of familial aggregation for alcohol abuse but not alcohol dependence.

Adolescent↗
PubMed2026

Target, silence, replace: a review on RNA-based drugs in modern medicine.

RNA therapies have evolved into a revolutionary approach in contemporary medicine for treating various diseases by directly targeting RNA molecules engaged in disease pathogenesis. These therapeutic agents regulate biological processes through diverse mechanisms, including modulation of RNA function and gene expression. Medical applications of RNA are greatly enhanced by its structure, adaptability, and capacity for targeted binding. Among these traits is its ability to bind to certain molecules unique to those chemicals. RNA-based treatments have emerged from advancements in the production, modification, and cellular transport of RNA molecules. Several RNA drugs have been approved whereas some are under trial for few diseases. RNA therapeutics can function at the level of RNAs, DNAs and proteins. The evolution of mRNA vaccines during the COVID-19 epidemic emphasizes the exciting potential of RNA therapies in the treatment of diseases. This article provides a comprehensive overview of the several forms of RNA therapies, including small-interfering RNA (siRNA), messenger RNA (mRNA), and antisense-oligonucleotides (ASOs), together with information on their action mechanisms and delivery strategies that improve cellular absorption and shield RNA molecules from degradation. Further, CRISPR-based editing of the genome can be employed for modification of target RNA sequences for various disorders. Development of RNA aptamers have also been identified as pivotal RNA-therapeutic candidate. Additionally, we have explained mechanistic details and examples of drugs approved for RNA therapy. Emphasizing their potential to enhance patient outcomes and fulfil unmet medical requirements, we also highlight the clinical development of RNA therapies in treating cancer and other infectious diseases.

RNA interference↗
PubMed1999

[Handwritten documents of 'Antidotarius magnus'].

The 'Antidotarius magnus'--compiled about 1080 by the archbishop of Salerno, Alphanus--deals with the pharmacological methods of healing and contains nearly 1073 antidots. We have discovered 13 Latin manuscripts of the 'Antidotarius magnus' in the libraries of Basel, Bern, Cambridge, Erfurt, Florence, London, Oxford, Paris and Parma. One should remember that the MS Taurin.I.VI.24 had been totally destroyed in 1904, but this manuscript is still noted in the catalogues of Pasin, Giacosa and Thorndike/Kibre. The most remarkable manuscript--the MS Palat.lat.747--is preserved in the National Library at Florence. The MS Palat.lat.747 is dated to 1153 and seems to be similar to the archetype. We are currently preparing a critical edition based on the oldest manuscripts.

Antidotes↗