-
Clinical Journal of the American... Dec 2015Acid-base homeostasis and pH regulation are critical for both normal physiology and cell metabolism and function. The importance of this regulation is evidenced by a... (Review)
Review
Acid-base homeostasis and pH regulation are critical for both normal physiology and cell metabolism and function. The importance of this regulation is evidenced by a variety of physiologic derangements that occur when plasma pH is either high or low. The kidneys have the predominant role in regulating the systemic bicarbonate concentration and hence, the metabolic component of acid-base balance. This function of the kidneys has two components: reabsorption of virtually all of the filtered HCO3(-) and production of new bicarbonate to replace that consumed by normal or pathologic acids. This production or generation of new HCO3(-) is done by net acid excretion. Under normal conditions, approximately one-third to one-half of net acid excretion by the kidneys is in the form of titratable acid. The other one-half to two-thirds is the excretion of ammonium. The capacity to excrete ammonium under conditions of acid loads is quantitatively much greater than the capacity to increase titratable acid. Multiple, often redundant pathways and processes exist to regulate these renal functions. Derangements in acid-base homeostasis, however, are common in clinical medicine and can often be related to the systems involved in acid-base transport in the kidneys.
Topics: Acid-Base Equilibrium; Acid-Base Imbalance; Ammonia; Animals; Bicarbonates; Carbon Dioxide; Humans; Hydrogen-Ion Concentration; Kidney; Models, Biological; Renal Elimination; Renal Reabsorption
PubMed: 26597304
DOI: 10.2215/CJN.07400715 -
Medical Review (2021) Feb 2023Single-nucleotide variants account for about half of known pathogenic genetic variants in human. Genome editing strategies by reversing pathogenic point mutations with... (Review)
Review
Single-nucleotide variants account for about half of known pathogenic genetic variants in human. Genome editing strategies by reversing pathogenic point mutations with minimum side effects have great therapeutic potential and are now being actively pursued. The emerge of precise and efficient genome editing strategies such as base editing and prime editing provide powerful tools for nucleotide conversion without inducing double-stranded DNA breaks (DSBs), which have shown great potential for curing genetic disorders. A diverse toolkit of base editors has been developed to improve the editing efficiency and accuracy in different context of application. Here, we summarized the evolving of base editors (BEs), their limitations and future perspective of base editing-based therapeutic strategies.
PubMed: 37724105
DOI: 10.1515/mr-2022-0044 -
Tomography (Ann Arbor, Mich.) Jun 2023The skull base provides a platform for supporting the brain while serving as a conduit for major neurovascular structures. In addition to malignant lesions originating... (Review)
Review
The skull base provides a platform for supporting the brain while serving as a conduit for major neurovascular structures. In addition to malignant lesions originating in the skull base, there are many benign entities and developmental variants that may simulate disease. Therefore, a basic understanding of the relevant embryology is essential. Lesions centered in the skull base can extend to the adjacent intracranial and extracranial compartments; conversely, the skull base can be secondarily involved by primary extracranial and intracranial disease. CT and MRI are the mainstay imaging methods and are complementary in the evaluation of skull base lesions. Advances in cross-sectional imaging have been crucial in the management of patients with skull base pathology, as this represents a complex anatomical area that is hidden from direct clinical exam. Furthermore, the clinician must rely on imaging studies for therapy planning and to monitor treatment response. It is crucial to have a thorough understanding of skull base anatomy and its various pathologies, as well as to recognize the appearance of treatment-related changes. In this review, we aim to describe skull base tumors and tumor-like lesions in an anatomical compartmental approach and present imaging methods that aid in diagnosis, management, and follow-up.
Topics: Humans; Skull Base Neoplasms; Diagnostic Imaging; Brain
PubMed: 37489465
DOI: 10.3390/tomography9040097 -
Endocrinology and Metabolism (Seoul,... Aug 2022Pituitary surgery has advanced considerably in recent years with the exploration and development of various endoscopic approaches and techniques. Different endoscopic... (Review)
Review
Pituitary surgery has advanced considerably in recent years with the exploration and development of various endoscopic approaches and techniques. Different endoscopic skull base approaches are being applied to access sellar tumors in different locations. Moreover, extracapsular dissection and cavernous sinus exploration have enabled gross total resection of sellar tumors where it could not have been achieved in the past. Techniques for skull base reconstruction have also progressed, allowing surgeons to remove larger and more complicated tumors than before. This review article discusses different endoscopic skull base approaches, surgical techniques for removing pituitary adenomas, and reconstruction methods for repairing postoperative low-flow and high-flow cerebrospinal fluid leakage.
Topics: Cerebrospinal Fluid Leak; Endoscopy; Humans; Pituitary Diseases; Pituitary Neoplasms; Postoperative Complications; Retrospective Studies; Skull Base Neoplasms
PubMed: 35982611
DOI: 10.3803/EnM.2022.1546 -
Frontiers in Chemistry 2018Single nucleotide polymorphisms (SNPs) affect base pair stacking, which is the primary factor for maintaining the stability of DNA. However, the mechanism of how SNPs...
Single nucleotide polymorphisms (SNPs) affect base pair stacking, which is the primary factor for maintaining the stability of DNA. However, the mechanism of how SNPs lead to phenotype variations is still unclear. In this work, we connected SNPs and base pair stacking by a 3-mer base pair stacking free energy matrix. The SNPs with large base pair stacking free energy differences led to phenotype variations. A molecular dynamics (MD) simulation was then applied. Our results showed that base pair stacking played an important role in the transcription factor (TF)-DNA interaction. Changes in DNA structure mainly originate from TF-DNA interactions, and with the increased base pair stacking free energy, the structure of DNA approaches its free type, although its binding affinity was increased by the SNP. In addition, quantitative models using base pair stacking features revealed that base pair stacking can be used to predict TF binding specificity. As such, our work combined knowledge from bioinformatics and structural biology and provided a new understanding of the relationship between SNPs and phenotype variations. The 3-mer base pair stacking free energy matrix is useful in high-throughput screening of SNPs and predicting TF-DNA binding affinity.
PubMed: 30713839
DOI: 10.3389/fchem.2018.00666 -
Neuroendocrinology 2020Skull base chordomas account for less than 0.2% and chondrosarcomas for less than 0.15% of all intracranial tumors. Although their clinical and imaging presentations are... (Review)
Review
Skull base chordomas account for less than 0.2% and chondrosarcomas for less than 0.15% of all intracranial tumors. Although their clinical and imaging presentations are similar, they derive from different origins. Chordomas arise from embryonic remnants of the primitive notochord and chondrosarcomas from primitive mesenchymal cells or from the embryonic rest of the cranial cartilaginous matrix. Both entities are characterized by infiltration and destruction of the surrounding bone and soft tissue and a high locoregional recurrence rate. Chondrosarcomas, when treated with similar complex strategies, display a much better prognosis than chordomas. The overall survival is approximately 65% for chordomas and 80% for chondrosarcomas at 5 years and 30 and 50%, respectively, at 10 years. Chordomas are divided into the following 3 histological types: classical (conventional), chondroid, and dedifferentiated. Chondrosarcomas have conventional, mesenchymal, clear cell, and dedifferentiated subgroups. Both tumor entities often present with nonspecific symptoms, and headaches are the most reported initial symptom. Computed tomography and magnetic resonance imaging are required to determine the tumor localization and the extent of tumor growth. The treatment philosophy is to maximize tumor resection, minimize morbidity, and preserve function. Neurosurgical approaches commonly used for the resection of intracranial chordomas and chondrosarcomas are transsphenoidal, transbasal, cranio-orbitozygomatic, transzygomatic extended middle fossa, transcondylar, and transmaxillary approaches. Chordomas and chondrosarcomas are not sensitive to chemotherapy and there are no approved drugs for their treatment. The present treatment concept is a combination of surgical resection with a maximal excision and preserving patients' quality of life by adjuvant radiotherapy for both chordomas and chondrosarcomas.
Topics: Chondrosarcoma; Chordoma; Humans; Skull Base Neoplasms
PubMed: 32541136
DOI: 10.1159/000509386 -
Acta Psychologica Jul 2023People tend to ignore the probabilistic rules cued by the base-rate information and rely on the heuristic intuition cued by the descriptive information to make...
People tend to ignore the probabilistic rules cued by the base-rate information and rely on the heuristic intuition cued by the descriptive information to make "stereotypical" responses in base-rate problems. Conflict detection studies have shown that reasoners can detect conflicts between heuristic intuition and probabilistic considerations despite ultimately stereotypical responses. However, these studies primarily used extreme base-rate tasks. A critical open question is the extent to which successful conflict detection relies on an extreme base rate. The present study explores this issue by manipulating the base-rate extremity of problems in which the descriptive information and the base-rate information conflict or not. As a result, when reasoners made stereotypical responses in the conflict version of the moderate base-rate task, they took longer to respond, had lower confidence in their responses, and were slower to evaluate their confidence than in the no-conflict version of the task. All three measures indicate that stereotypical reasoners can stably detect conflict in moderate base-rate tasks, which expands the scope of successful conflict detection. Moreover, our response confidence data found a larger detection effect size in the extreme base-rate condition than in the moderate base-rate condition. This suggests that conflict detection is more efficient as the base-rate extremity increases. Implications for the boundary conditions of conflict detection are discussed.
Topics: Humans; Problem Solving; Decision Making; Intuition; Heuristics; Extremities
PubMed: 37327658
DOI: 10.1016/j.actpsy.2023.103960 -
Frontiers in Genome Editing 2021Nuclease-based genome editing strategies hold great promise for the treatment of blood disorders. However, a major drawback of these approaches is the generation of... (Review)
Review
Nuclease-based genome editing strategies hold great promise for the treatment of blood disorders. However, a major drawback of these approaches is the generation of potentially harmful double strand breaks (DSBs). Base editing is a CRISPR-Cas9-based genome editing technology that allows the introduction of point mutations in the DNA without generating DSBs. Two major classes of base editors have been developed: cytidine base editors or CBEs allowing C>T conversions and adenine base editors or ABEs allowing A>G conversions. The scope of base editing tools has been extensively broadened, allowing higher efficiency, specificity, accessibility to previously inaccessible genetic loci and multiplexing, while maintaining a low rate of Insertions and Deletions (InDels). Base editing is a promising therapeutic strategy for genetic diseases caused by point mutations, such as many blood disorders and might be more effective than approaches based on homology-directed repair, which is moderately efficient in hematopoietic stem cells, the target cell population of many gene therapy approaches. In this review, we describe the development and evolution of the base editing system and its potential to correct blood disorders. We also discuss challenges of base editing approaches-including the delivery of base editors and the off-target events-and the advantages and disadvantages of base editing compared to classical genome editing strategies. Finally, we summarize the recent technologies that have further expanded the potential to correct genetic mutations, such as the novel base editing system allowing base transversions and the more versatile prime editing strategy.
PubMed: 34713251
DOI: 10.3389/fgeed.2021.618406 -
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 -
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