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Human Mutation Dec 2019Cytosine base editors (CBEs) and adenine base editors (ABEs), which are generally composed of an engineered deaminase and a catalytically impaired CRISPR-Cas9 variant,... (Review)
Review
Cytosine base editors (CBEs) and adenine base editors (ABEs), which are generally composed of an engineered deaminase and a catalytically impaired CRISPR-Cas9 variant, are new favorite tools for single base substitution in cells and organisms. In this review, we summarize the principle of base-editing systems and elaborate on the evolution of different platforms of CBEs and ABEs, including their deaminase, Cas9 variants, and editing outcomes. Moreover, we highlight their applications in mouse and human cells and discuss the challenges and prospects of base editors. The ABE- and CBE systems have been used in gene silencing, pathogenic gene correction, and functional genetic screening. Single base editing is becoming a new promising genetic tool in biomedical research and gene therapy.
Topics: Aminohydrolases; Animals; CRISPR-Cas Systems; Cytosine Deaminase; Gene Editing; Gene Silencing; Humans; Mice; Polymorphism, Single Nucleotide
PubMed: 31131955
DOI: 10.1002/humu.23819 -
Molecular Therapy : the Journal of the... Sep 2020CRISPR-mediated DNA base editors, which include cytosine base editors (CBEs) and adenine base editors (ABEs), are promising tools that can induce point mutations at... (Review)
Review
CRISPR-mediated DNA base editors, which include cytosine base editors (CBEs) and adenine base editors (ABEs), are promising tools that can induce point mutations at desired sites in a targeted manner to correct or disrupt gene expression. Their high editing efficiency, coupled with their ability to generate a targeted mutation without generating a DNA double-strand break (DSB) or requiring a donor DNA template, suggests that DNA base editors will be useful for treating genetic diseases, among other applications. However, this hope has recently been challenged by the discovery of DNA base editor shortcomings, including off-target DNA editing, the generation of bystander mutations, and promiscuous deamination effects in both DNA and RNA, which arise from the main DNA base editor constituents, a Cas nuclease variant and a deaminase. In this review, we summarize information about the DNA base editors that have been developed to date, introduce their associated potential challenges, and describe current efforts to minimize or mitigate those issues of DNA base editors.
Topics: CRISPR-Associated Protein 9; CRISPR-Cas Systems; DNA; DNA Breaks, Double-Stranded; DNA Replication; Deamination; Gene Editing; Humans; Point Mutation; RNA, Guide, CRISPR-Cas Systems
PubMed: 32763143
DOI: 10.1016/j.ymthe.2020.07.021 -
Polish Journal of Radiology 2017A number of tumors and tumor-like non-neoplastic lesions with different cell types on histology occur in the skull base. A wide variety in disease and lesion appearance... (Review)
Review
A number of tumors and tumor-like non-neoplastic lesions with different cell types on histology occur in the skull base. A wide variety in disease and lesion appearance often complicates the process of radiological diagnosis. The main role of radiographic imaging is the detection and characterization of skull base lesions, with evaluation of the extent of invasion or preservation of adjacent critical organs. Evaluation of the skull base anatomy and surgical planning by using image guidance are also important for surgeons. Computed tomography (CT) and magnetic resonance (MR) imaging are the preferred modalities for the evaluation of skull base lesions. CT and MR are used for lesion detection, tissue characterization and assessment of neurovascular and bone involvement by the lesions. Both modalities provide useful information, one sometimes of greater value than the other. T1-weighted MR imaging is useful in detecting skull base lesions, typically surrounded by abundant fatty bone marrow. T2-weighted MR imaging is generally useful for tumor tissue characterization. CT surpasses MR imaging in evaluating intratumoral calcification and bone destruction or hyperostosis. To date, imaging features have been well-reported in individual skull base tumors; however, correct diagnosis by imaging alone still presents a challenge. Knowledge of clinical issues and awareness of variants of skull base tumors are of help in making a diagnosis. The purpose of this article is to review pertinent clinical issues, typical imaging appearances and certain imaging variations of common skull base lesions.
PubMed: 28811848
DOI: 10.12659/PJR.901937 -
European Journal of Medical Research May 2024The base excess value (BE, mmol/L), not standard base excess (SBE), correctly calculated including pH, pCO (mmHg), sO (%) and cHb (g/dl) is a diagnostic tool for several... (Review)
Review
The base excess value (BE, mmol/L), not standard base excess (SBE), correctly calculated including pH, pCO (mmHg), sO (%) and cHb (g/dl) is a diagnostic tool for several in vivo events, e.g., mortality after multiple trauma or shock, acidosis, bleeding, clotting, artificial ventilation. In everyday clinical practice a few microlitres of blood (arterial, mixed venous or venous) are sufficient for optimal diagnostics of any metabolic acidosis or alkalosis.The same applies to a therapeutic tool-then referred to as potential base excess (BEpot)-for several in vitro assessments, e.g., solutions for infusion, sodium bicarbonate, blood products, packed red blood cells, plasma. Thus, BE or BEpot has been a parameter with exceptional clinical significance since 2007.
Topics: Humans; Acidosis; Acid-Base Imbalance; Acid-Base Equilibrium; Alkalosis
PubMed: 38735983
DOI: 10.1186/s40001-024-01796-6 -
Beilstein Journal of Organic Chemistry 2018Förster resonance energy transfer (FRET) between a donor nucleobase analogue and an acceptor nucleobase analogue, base-base FRET, works as a spectroscopic ruler and... (Review)
Review
Förster resonance energy transfer (FRET) between a donor nucleobase analogue and an acceptor nucleobase analogue, base-base FRET, works as a spectroscopic ruler and protractor. With their firm stacking and ability to replace the natural nucleic acid bases inside the base-stack, base analogue donor and acceptor molecules complement external fluorophores like the Cy-, Alexa- and ATTO-dyes and enable detailed investigations of structure and dynamics of nucleic acid containing systems. The first base-base FRET pair, tC-tC, has recently been complemented with among others the adenine analogue FRET pair, qAN1-qA, increasing the flexibility of the methodology. Here we present the design, synthesis, photophysical characterization and use of such base analogues. They enable a higher control of the FRET orientation factor, , have a different distance window of opportunity than external fluorophores, and, thus, have the potential to facilitate better structure resolution. Netropsin DNA binding and the B-to-Z-DNA transition are examples of structure investigations that recently have been performed using base-base FRET and that are described here. Base-base FRET has been around for less than a decade, only in 2017 expanded beyond one FRET pair, and represents a highly promising structure and dynamics methodology for the field of nucleic acids. Here we bring up its advantages as well as disadvantages and touch upon potential future applications.
PubMed: 29441135
DOI: 10.3762/bjoc.14.7 -
Theoretical Biology & Medical Modelling Sep 2018The acidity of human body fluids, expressed by the pH, is physiologically regulated in a narrow range, which is required for the proper function of cellular metabolism....
BACKGROUND
The acidity of human body fluids, expressed by the pH, is physiologically regulated in a narrow range, which is required for the proper function of cellular metabolism. Acid-base disorders are common especially in intensive care, and the acid-base status is one of the vital clinical signs for the patient management. Because acid-base balance is connected to many bodily processes and regulations, complex mathematical models are needed to get insight into the mixed disorders and to act accordingly. The goal of this study is to develop a full-blood acid-base model, designed to be further integrated into more complex human physiology models.
RESULTS
We have developed computationally simple and robust full-blood model, yet thorough enough to cover most of the common pathologies. Thanks to its simplicity and usage of Modelica language, it is suitable to be embedded within more elaborate systems. We achieved the simplification by a combination of behavioral Siggaard-Andersen's traditional approach for erythrocyte modeling and the mechanistic Stewart's physicochemical approach for plasma modeling. The resulting model is capable of providing variations in arterial pCO2, base excess, strong ion difference, hematocrit, plasma protein, phosphates and hemodilution/hemoconcentration, but insensitive to DPG and CO concentrations.
CONCLUSIONS
This study presents a straightforward unification of Siggaard-Andersen's and Stewart's acid-base models. The resulting full-blood acid-base model is designed to be a core part of a complex dynamic whole-body acid-base and gas transfer model.
Topics: Acid-Base Equilibrium; Acid-Base Imbalance; Humans; Hydrogen-Ion Concentration; Models, Biological; Models, Chemical; Models, Theoretical
PubMed: 30196793
DOI: 10.1186/s12976-018-0086-9 -
International Journal of Molecular... Aug 2021The increasing number and complexity of structures containing RNA chains in the Protein Data Bank (PDB) have led to the need for automated structure annotation methods... (Review)
Review
The increasing number and complexity of structures containing RNA chains in the Protein Data Bank (PDB) have led to the need for automated structure annotation methods to replace or complement expert visual curation. This is especially true when searching for tertiary base motifs and substructures. Such base arrangements and motifs have diverse roles that range from contributions to structural stability to more direct involvement in the molecule's functions, such as the sites for ligand binding and catalytic activity. We review the utility of computational approaches in annotating RNA tertiary base motifs in a dataset of PDB structures, particularly the use of graph theoretical algorithms that can search for such base motifs and annotate them or find and annotate clusters of hydrogen-bond-connected bases. We also demonstrate how such graph theoretical algorithms can be integrated into a workflow that allows for functional analysis and comparisons of base arrangements and sub-structures, such as those involved in ligand binding. The capacity to carry out such automatic curations has led to the discovery of novel motifs and can give new context to known motifs as well as enable the rapid compilation of RNA 3D motifs into a database.
Topics: Algorithms; Databases, Nucleic Acid; Molecular Sequence Annotation; Nucleotide Motifs; RNA; Software; Workflow
PubMed: 34445259
DOI: 10.3390/ijms22168553 -
Folia Neuropathologica 2022Tumour-to-meningioma metastasis (TTMM) is an uncommon phenomenon, however repeatedly found in the literature. Meningiomas occur to be the most frequent target of... (Review)
Review
Tumour-to-meningioma metastasis (TTMM) is an uncommon phenomenon, however repeatedly found in the literature. Meningiomas occur to be the most frequent target of metastatic expansion of systemic cancers. Meningiomas often vary in symptoms and treatment, and this largely depends on the tumour location. Due to their variable locations, they can be classified as convexity meningiomas, which includes falcine and parasagittal tumours, and cranial base, which includes tumours located in the olfactory groove, sphenoid wing, petrous bone and other cranial base locations. The aim of this study was to analyse all data regarding metastases to cranial base meningiomas. We performed a literature search to locate all cases of metastases to cranial base meningiomas in PubMed and Medline databases using the following key words: metastasis to meningioma, meningioma metastasis, and cranial base meningioma. We collected patient and cancer parameters, exact meningioma location and clinical presentations including characteristics which may suggest TTMM. We found 100 articles describing 111 patients of metastasis to cranial base meningioma. Among these articles, 55 cases (49.55%) included metastases to non-skull base meningiomas. In 24 cases (21.62%), the location of meningioma was not precisely described or other data were unavailable, in particular histopathological examination. The most common location of TTMM was sphenoid wing, which was found in 9 patients. The other locations included cerebellopontine angle in 5 patients, and tuberculum sellae in 3 cases. 81.25% cases of TTMM were reported in women, and the most common cancer origins were the breast (28.3%), lung (18.7%), kidney (9.38%) and prostate (9.38%). In two cases the metastatic origin was unclear, and in 15.6% of cases the patients were in remission for more than 1 year. In 78.1% of cases patients presented focal deficits, followed by increased intracranial pressure, and seizures. In almost one-third of cases, TTMM first appeared from a previously unknown cancer. Rapid clinical presentation of cranial nerve palsies may suggest the dual nature of intracranial pathology. The metastasis to cranial base meningioma should be suspected in patients with oncological background, regardless of meningioma parameters or cancer status.
Topics: Male; Humans; Female; Meningeal Neoplasms; Meningioma; Skull Base Neoplasms; Skull Base; Treatment Outcome
PubMed: 36734379
DOI: 10.5114/fn.2022.123500 -
Laboratory Animals Feb 2022Genome editing by programmable RNA-dependent Cas endonucleases has revolutionised the field of genome engineering, achieving targeted genomic change at unprecedented...
Genome editing by programmable RNA-dependent Cas endonucleases has revolutionised the field of genome engineering, achieving targeted genomic change at unprecedented efficiencies with considerable application in laboratory animal research. Despite its ease of use and wide application, there remain concerns about the precision of this technology and a number of unpredictable consequences have been reported, mostly resulting from the DNA doublestrand break (DSB) that conventional CRISPR editing induces. In order to improve editing precision, several iterations of the technology been developed over the years. Base editing is one of most successful developments, allowing for single base conversions but without the need for a DSB. Cytosine and adenine base editing are now established as reliable methods to achieve precise genome editing in animal research studies. Both cytosine and adenine base editors have been applied successfully to the editing of zygotes, resulting in the generation of animal models. Similarly, both base editors have achieved precise editing of point mutations in somatic cells, facilitating the development of gene therapy approaches. Despite rapid progress in optimising these tools, base editing can address only a subset of possible base conversions within a relatively narrow window and larger genomic manipulations are not possible. The recent development of prime editing, originally defined as a simple 'search and replace' editing tool, may help address these limitations and could widen the range of genome manipulations possible. Preliminary reports of prime editing in animals are being published, and this new technology may allow significant advancements for laboratory animal research.
Topics: Adenine; Animals; Animals, Laboratory; CRISPR-Cas Systems; Cytosine; Gene Editing
PubMed: 33596731
DOI: 10.1177/0023677221993895 -
AJNR. American Journal of Neuroradiology Mar 2021Skull base osteomyelitis is a relatively rare condition, generally occurring as a complication of advanced otologic or sinus infection in immunocompromised patients.... (Review)
Review
Skull base osteomyelitis is a relatively rare condition, generally occurring as a complication of advanced otologic or sinus infection in immunocompromised patients. Skull base osteomyelitis is generally divided into 2 broad categories: typical and atypical. Typical skull base osteomyelitis occurs secondary to uncontrolled infection of the temporal bone region, most often from necrotizing external otitis caused by in a patient with diabetes. Atypical skull base osteomyelitis occurs in the absence of obvious temporal bone infection or external auditory canal infection. It may be secondary to advanced sinusitis or deep face infection or might occur in the absence of a known local source of infection. Atypical skull base osteomyelitis preferentially affects the central skull base and can be caused by bacterial or fungal infections. Clinically, typical skull base osteomyelitis presents with signs and symptoms of otitis externa or other temporal bone infection. Both typical and atypical forms can produce nonspecific symptoms including headache and fever, and progress to cranial neuropathies and meningitis. Early diagnosis can be difficult both clinically and radiologically, and the diagnosis is often delayed. Radiologic evaluation plays a critical role in the diagnosis of skull base osteomyelitis, with CT and MR imaging serving complementary roles. CT best demonstrates cortical and trabecular destruction of bone. MR imaging is best for determining the overall extent of disease and best demonstrates involvement of marrow space and extraosseous soft tissue. Nuclear medicine studies can also be contributory to diagnosis and follow-up. The goal of this article was to review the basic pathophysiology, clinical findings, and key radiologic features of skull base osteomyelitis.
Topics: Diagnostic Imaging; Humans; Osteomyelitis; Skull Base
PubMed: 33478944
DOI: 10.3174/ajnr.A7015