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At least 253 records · Page 14Linked to original sources
PubMed2006

Site-specific integration into the human genome: ready for clinical application?

Inserting genetic information at precise locations into the human genome has been the goal of the gene therapy community for almost two decades. Despite their spectacular progress in many fields of mammalian genetics, genome editing and homologous recombination are still too inefficient to be applied to human primary cells and tissues, the targets of any medical application. Site-specific integration, or the insertion of genes at known locations by enzymes that target recognition capacity, has progressed slowly but steadily in recent years, and could very well be the basis of the next generation of gene transfer technology.

Aging↗
PubMed1987

On the politics of madness: a preliminary analysis of the relationship between social roles and psychotherapy.

This study presents a brief account of a theory that argues that diagnostic categories of madness and their prototypes are equivalent to the fulfillment of the roles and role stereotypes of the status groups that tend to receive the diagnoses most often. Two studies provided tentative support for the theory. The results of the first study revealed that clinicians attributed to the stereotypes of various status groups precisely those diagnoses that the groups tend to receive. The second study revealed that undergraduates who were given diagnostic prototypes from the Diagnostic and Statistical Manual of Mental Disorders, 3rd edition (1980) (DSM-III) and were asked to predict the status characteristics of the persons described therein correctly reproduced well known epidemiological data. These results imply an intimate relationship between social and psychiatric taxonomies, and thus raise questions about the meaning of madness in our society.

Adult↗
PubMed1975

A proposed blind routine quality control system for multichannel analyzers.

A blind quality control system using a special type of commercial reference serum is described. As packaged, the product contains six pools of analyzed reference sera with vials identified by coded numbers. The test constituents in the pools cover the range of multichannel analyzers in a random manner, i.e., each pool contains constituents in the low, normal and elevated ranges. As specific pools are not identified, and the analyst is unaware of the expected values for each constituent, results collected for quality control purposes are unbiased, i.e., free of conscious or unconscious editing. Data analysis in the proposed system is by least-squares technics. During an eight-week period, performance was studied using the standard error of the estimate to evaluate precision and the slope of the regression line to evaluate accuracy on the SMA and Mark X instruments. As an empirical comparison, the data are expressed as relative errors and precision and accuracy of analyzer performance evaluated as mean and standard deviation. The proposed regression analysis-based technic has the advantage of simultaneously evaluating linearity, as well as checking accuracy and precision over the total dynamic range of the instrument by use of a series of related serum pools.

Alkaline Phosphatase↗
PubMed1992

[Computer-assisted ENT medical literature search and literature management--a report of experiences].

The increasing number of medical articles calls for a computer-aided system for literature database programs, literature retrieval and bibliography systems. We report an assessment of a dedicated modem line to DIMDI of Cologne (an institute offering a variety of biomedical, psychological and other literature databases), Medline on Silverplatter, Current Contents on disk and the Papyrus bibliography system. The databases with retrieval software are installed on a IBM-compatible PC (386 with an 80MB hard disc) and 4 CD-ROM players. Medline contains bibliographic citations and abstracts of biomedical literature; Current Contents on disk with its weekly update provides citations of articles published very recently; and the Papyrus bibliography system maintains a permanent collection of reference citations. When linked to a word processor, Papyrus can automatically read the manuscript, create a bibliography and produce a new copy of the manuscript in which the citations have been appropriately edited, and the references can be printed in any desired format. Although not without drawbacks, the configuration described here proved to be a valuable, time-saving tool to access citations precisely.

Computer Systems↗
PubMed2025

Precision diagnostic and therapeutic interventions in rare genetic neurodevelopmental disorders.

Neurodevelopmental disorders (NDDs) include a broad spectrum of phenotypes spanning from intellectual disability (ID) to developmental delay (DD) and autism spectrum disorder (ASD). As neurodevelopmental phenotypes are a common presenting feature of an underlying genetic condition, professional medical organizations recommend genetic testing for all individuals with a NDD. When testing is pursued, identified genetic differences can lead to personalized clinical management with early diagnosis supporting the development of surveillance and intervention for co-occurring adverse health outcomes. Despite this, barriers to testing have prevented individuals from receiving a genetics referral and testing. Current therapeutic modalities including small molecule drugs, gene therapies, and antisense oligonucleotide therapies have emerged and shown promise in preclinical trials with therapeutic drugs gaining FDA approval. However, translational challenges are extensive, especially for identifying biomarkers of drug effects in the CNS. In this review, we discuss diagnostic approaches and clinical utility of genetic testing for rare genetic neurodevelopmental disorders, emerging development of individualized therapies, and progress for current therapeutics in addition to challenges with clinical translation and delivery. We will highlight opportunities for early diagnosis and treatment that are steadily gaining ground in favor of optimizing long-term health outcomes and improving quality of life for neurodiverse individuals. IMPACT: The path from genomics to therapeutics for neurodevelopmental disorders continues to present multiple opportunities and challenges. While emerging genome-wide sequencing and gene editing technologies deliver increased diagnostic yields and alternatives to life-long small molecule therapies, clinical translation has been challenging due to inherent cost and genetic heterogeneity. Limited access to genetic testing despite practice guidelines remains a barrier towards precision therapeutics for rare neurodevelopmental disorders, while pre-clinical investigations face obstacles when translating to human subjects. This review will summarize the impact of existing successes in diagnosis and therapeutics for neurodevelopmental disorders while highlighting ongoing challenges and areas of future opportunities.

Humans↗
PubMed2006

Posttraumatic stress disorder in disaster relief workers following direct and indirect trauma exposure to Ground Zero.

The present study compared rates of posttraumatic stress disorder (PTSD) in relief workers at the World Trade Center collapse from two sources: direct exposure to the disaster site and indirect exposure through survivor narratives. Standardized clinical interviews for PTSD were conducted with 109 relief workers 6-8 months after the September 11th terrorist attacks. Rates of acute PTSD from direct and indirect exposure to traumatic stressors were 6.4% and 4.6%, respectively. The findings suggest that indirect exposures can lead to PTSD even when Criterion A1 of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition-Text Revision (DSM-IV-TR; American Psychiatric Association, 2000, p. 463), i.e., "experienced by a family member or other close associate" is not met. Further research is necessary to define precisely the parameters of indirect traumatic exposure that may be linked to the development of PTSD.

Adult↗
PubMed2026

Efficient genome editing in tomato using Cas12i3 variants.

Systematic comparison of Cas12i gene-editing tools in tomato identifies Cas-SF01 as the most efficient variant, achieving editing efficiencies comparable to conventional Cas9 at some genomic sites and providing a compact, highly specific, and versatile tool for studying gene function, engineering fruit metabolism, and developing improved tomato varieties through precision breeding.

Journal Article↗
PubMed2004

Health services use and health care expenditures for children with disabilities.

OBJECTIVE: To examine health care utilization and expenditure patterns for children with disabilities. METHODS: Secondary data analysis was conducted of the 1999 and 2000 editions of the Medical Expenditure Panel Survey (MEPS), a nationally representative survey conducted in 5 rounds by household interview. Two years of MEPS data were combined in this analysis to improve the precision of estimates. Disability was defined by the presence of a limitation in age-appropriate social role activities, such as school or play, or receipt of specialized services through the early intervention or special education programs. The survey sample included 13,792 children younger than 18 years. The overall response rate was 65.5%. RESULTS: Our findings demonstrate that the 7.3% of US children with disabilities used many more services than their counterparts without disabilities in 1999-2000. The largest differences in utilization were for hospital days (464 vs 55 days per 1000), nonphysician professional visits (3.0 vs 0.6), and home health provider days (3.8 vs 0.04). As a result of their greater use, children with disabilities also had much higher health care expenditures (2669 dollars vs 676 dollars) and higher out-of-pocket expenditures (297 dollars vs 189 dollars). We also found that the distributions of total and out-of-pocket expenses were highly skewed, with a small fraction of the disabled population accounting for a large proportion of expenditures: the upper decile accounted for 65% of total health care expenses and 85% of all out-of-pocket expenses for the population with disabilities. Health insurance was found to convey significant protection against financially burdensome expenses. However, even after controlling for insurance status, low-income families experienced greater financial burdens than higher income families. CONCLUSIONS: The skewed distribution of out-of-pocket expenses found in this and earlier studies indicates that the financial burden of childhood disability continues to be shared unevenly by families. Low-income families are especially vulnerable to burdensome out-of-pocket expenses. Additional efforts are needed to protect these high-risk families.

Adolescent↗
PubMed2002

Adjuvant therapy of melanoma.

In 2001, the American Joint Committee on Cancer Melanoma Staging Committee proposed and created a new staging system for melanoma. This new system will become official in 2002, with the publication of the sixth edition of the AJCC Cancer Staging Manual. The new system identifies significant prognostic variables in patients with melanoma and validates them in an analysis of 17,600 patients, making it possible to precisely determine the patient's chance for survival In light of physicians' ability to determine with more precision which patients are at high risk for melanoma recurrence, they face the dilemma of which, if any, surgical adjuvant therapy to choose. Alpha-interferon is the only agent approved for adjuvant therapy of melanoma in the United States, but its questionable benefits and substantial side effects make it hard to justify recommending it to patients. Discussion of trials of high- and low-dose interferon is presented here. The author's group has conducted trials of granulocyte-macrophage colony-stimulating factor (GM-CSF [Leukine]) as surgical adjuvant treatment of patients at high-risk for melanoma recurrence. One of the most important activities of GM-CSF is its ability to activate macrophages and cause them to become cytotoxic for human melanoma cells, at doses low enough to avoid the toxicity associated with other cytokines. The author presents promising trial results, discusses GM-CSF in other malignancies, and includes discussion of tumor vaccines, biochemotherapy, and other agents being studied as adjuvant therapy of melanoma. It is hoped that these newer approaches will result in therapies that are more effective and less toxic than interferon.

Aged↗
PubMed2003

GFT NMR, a new approach to rapidly obtain precise high-dimensional NMR spectral information.

Widely used higher-dimensional Fourier transform (FT) NMR spectroscopy suffers from two major drawbacks: (i) The minimal measurement time of an N-dimensional FT NMR experiment, which is constrained by the need to sample N - 1 indirect dimensions, may exceed by far the measurement time required to achieve sufficient signal-to-noise ratios. (ii) The low resolution in the indirect dimensions severely limits the precision of the indirect chemical shift measurements. To relax on constraints arising from these drawbacks, we present here an acquisition scheme which is based on the phase-sensitive joint sampling of the indirect dimensions spanning a subspace of a conventional NMR experiment. This allows one to very rapidly obtain high-dimensional NMR spectral information. Because the phase-sensitive joint sampling yields subspectra containing "chemical shift multiplets", alternative data processing is required for editing the components of the multiplets. The subspectra are linearly combined using a so-called "G-matrix" and subsequently Fourier-transformed. The chemical shifts are multiply encoded in the resonance lines constituting the shift multiplets. This corresponds to performing statistically independent multiple measurements, and the chemical shifts can thus be obtained with high precision. To indicate that a combined G-matrix and FT is employed, we named the new approach "GFT NMR spectroscopy". GFT NMR opens new avenues to establish high-throughput protein structure determination, to investigate systems with a higher degree of chemical shift degeneracy, and to study dynamic phenomena such as slow folding of biological macromolecules in greater detail.

Fourier Analysis↗
PubMed2026

The mighty microproteins: from versatile cellular regulators to precision medicine therapeutics.

Microproteins, are tiny proteins encoded by small open reading frame (sORF), translation of these non-canonical open reading frames (ncORFs) has been implicated in diverse biological processes and diseases. This review summarizes recent developments in the discovery, biogenesis, and functional characterization of microproteins, and their involvement in various disease, with special focus on their roles in cancer, cardiovascular, metabolic, neurodegenerative and immune-related disorders. We emphasize the regulation of key cellular pathways by microproteins, including mitochondrial homeostasis, apoptosis, metabolic reprogramming, and immune signaling, all of which affect disease initiation and progression. Emerging evidence also supports their potential as disease biomarkers and therapeutic candidates for precision medicine. Finally, the review critically discusses the current challenges including discrepancies in microprotein annotation, the limitations of ribosome profiling and proteogenomic approaches, the gap between computationally predicted and experimentally validated microproteins, and the need for rigorous orthogonal validation by means of CRISPR-based genome editing, ribosome release assays, mutational analysis, high-resolution mass spectrometry, and functional studies. Finally, we review recent development of AI-assisted ORF prediction, single-cell translatomics, spatial proteomics, and integrated multi-omics as emerging technologies reshaping. Microprotein discovery and functional annotation. Finally, we discuss the translational potential of microproteins and highlight the remaining challenges to clinical application, including peptide stability, pharmacokinetics, tissue-specific delivery, immunogenicity, and the need for rigorous preclinical and clinical validation. Together, this review provides an updated and critical overview of the rapidly evolving microprotein field and highlights future research priorities for translating these molecules into clinically useful biomarkers and precision therapeutics.

Microproteins↗
PubMed2025

A six-repeat PPR protein WPR directly binds target RNAs and coordinates chloroplast RNA processing via dual recruitment of MORF1, MORF8b, and CAF2 proteins in rice.

Pentatricopeptide repeat (PPR) proteins are key regulators of organelle RNA metabolism in plants, yet their precise mechanisms in chloroplast RNA processing remain unclear. Here, we identify WPR, a unique P-type PPR protein in rice (Oryza sativa L.), as a critical factor in chloroplast RNA splicing and editing. A ~112-kb chromosomal inversion upstream of WPR causes an albino panicle rachis phenotype (wpr mutant), while complete loss of WPR function leads to seedling lethality. WPR deficiency disrupts the splicing of multiple group II introns (atpF, ndhA, ndhB, petB, rpl2, and rps12) and impairs RNA editing in transcripts such as ndhA, ndhB, ndhG, rps14, and ycf3. Electrophoretic mobility shift assay (EMSA) data confirm that WPR directly binds to precursor mRNAs of atpF, ndhA, petB, rpl2, and rps12. Strikingly, WPR interacts with both RNA editing factors (MORF1, MORF8b) and the splicing factor CAF2, but not with other PPR proteins targeting the same transcripts. Unlike most PPR proteins, WPR contains only six PPR repeats, which is the fewest among all functionally characterized rice PPR proteins. With few informative repeats, WPR likely possesses a broad, low-specificity RNA-binding activity. Moreover, WPR may act on chloroplast RNA maturation by recruiting MORFs and CAF2 rather than other PPR proteins, highlighting a novel regulatory mode in which P-type PPR protein may act as an RNA-binding scaffold to integrate diverse RNA-processing machineries. This study advances the understanding of PPR protein diversity and provides new insights into the molecular mechanisms of chloroplast RNA processing in rice.

Oryza↗
PubMed1995

Accurate and efficient insertional RNA editing in isolated Physarum mitochondria.

RNA editing is a process whereby nucleotide insertion, deletion, or base substitution results in the production of an RNA whose sequence differs from that of its template. The mitochondrial RNAs of Physarum polycephalum are processed specifically at multiple sites by both mono- and dinucleotide insertions, as well as apparent cytidine (C) to uridine (U) changes. The precise mechanism and timing of these processing events are currently unknown. We describe here the development of an isolated mitochondrial system in which exogenously supplied nucleotides can be incorporated into RNAs under defined conditions. The results of S1 nuclease protection, nearest neighbor and RNase T1 fingerprint analyses indicate that the vast majority of these newly synthesized mitochondrial RNAs have been accurately and efficiently processed by both mono- and dinucleotide insertions. This work provides a direct demonstration of faithful nucleotide insertion in a mitochondrial editing system. In contrast, the newly synthesized RNAs are not processed by C to U changes in the isolated mitochondria, suggesting that the base changes observed in Physarum are unlikely to occur via a deletion/insertion mechanism.

Animals↗
PubMed2025

Adapting systems biology to address the complexity of human disease in the single-cell era.

Systems biology aims to achieve holistic insights into the molecular workings of cellular systems through iterative loops of measurement, analysis and perturbation. This framework has had remarkable success in unicellular model organisms, and recent experimental and computational advances - from single-cell and spatial profiling to CRISPR genome editing and machine learning - have raised the exciting possibility of leveraging such strategies to prevent, diagnose and treat human diseases. However, adapting systems-inspired approaches to dissect human disease complexity is challenging, given that discrepancies between the biological features of human tissues and the experimental models typically used to probe function (which we term 'translational distance') can confound insight. Here we review how samples, measurements and analyses can be contextualized within overall multiscale human disease processes to mitigate data and representation gaps. We then examine ways to bridge the translational distance between systems-inspired human discovery loops and model system validation loops to empower precision interventions in the era of single-cell genomics.

Humans↗
PubMed1995

Maternal and child health in Saudi Arabia. Study design and methodology.

Saudi Maternal and Child Health Survey was designed to study the utilisation of maternal health services by ever-married women of child-bearing age, by measuring level of tetanus vaccination coverage; breastfeeding and weaning knowledge, attitude and practices; and by measuring the level of vaccination coverage with BCG, DPT, Poliomyelitis and measles vaccines among children 1-2 years old at the national level. The standard world health organization (WHO) cluster technique was employed. The kingdom was divided into five geographical areas. The sampling frame used was available at the Ministry of Health (MOH) in the form of ascending cumulative frequency tables where the catchment areas of 1625 health centres (HC) constitute primary sampling units (PSUs). Thirty clusters were randomly selected from each of the five geographic areas, and 40 household per cluster were used. The target populations included: (i) the ever-married Saudi females in the child-bearing age (15-49 years), (ii) children less than 5 years old, and (iii) children 1-2 years old. The respondents were interviewed using a questionnaire. The quality of data was assured by pre-coding of data which was edited throughout the field work period. A 4-day workshop was held for the interviewers and supervisors 48 hours prior to commencement of the survey. During the workshop, interviewers were instructed to read the questions precisely, were acquainted with survey methodology in general, pretested the questionnaire, received guide manual, instruction notes, progress sheets and follow-up formats for referring to when needed. The investigators were in the field during the first few days to solve any problem arising.

Adolescent↗
PubMed2005

Utilizing the UMLS for semantic mapping between terminologies.

An algorithm was derived to find candidate mappings between any two terminologies inside the UMLS, making use of synonymy, explicit mapping relations and hierarchical relationships among UMLS concepts. Using an existing set of mappings from SNOMED CT to ICD9CM as our gold standard, we managed to find candidate mappings for 86% of SNOMED CT terms, with recall of 42% and precision of 20%. Among the various methods used, mapping by UMLS synonymy was particularly accurate and could potentially be useful as a quality assurance tool in the creation of mapping sets or in the UMLS editing process. Other strengths and weaknesses of the algorithm are discussed.

Algorithms↗
PubMed2005

Oligonucleotide-mediated gene editing for neuromuscular disorders.

In the last decade, outstanding progress has been made in the development of new approaches to treat neuromuscular disorders and in particular Duchenne muscular dystrophy (DMD). The use of oligonucleotides to induce single base pair alterations in the dystrophin gene and restore gene expression in skeletal muscle has proven to be a feasible alternative approach to dystrophin gene replacement. Oligonucleotide-mediated gene editing for dystrophin has the potential to treat the disorder permanently and effectively. Many hurdles however still need to be overcome before this technology can enter into a clinical setting. Understanding the mechanisms of the repair process is a key for the design of oligonucleotides capable to induce gene repair more efficiently and precisely. The future of this technology will depend, ultimately, on the development of safe delivery systems capable to target a large number of muscles. Furthermore, before using oligonucleotides into a clinical setting, we will need to evaluate issues of toxicity, which will have to be balanced with the severity of the disease and the prognosis of the patient. Finally, the rapid progress that has been made to scale up the production of synthetic oligonucleotides will enable the synthesis from micrograms to milligrams quantities allowing this field to move from the bench to the bedside. This review will describe the basic mechanisms of oligonucleotide-mediated gene editing and will explain the potential, hurdles and substantial results obtained using this technology in the treatment of muscular dystrophies.

DNA Repair↗
PubMed1996

Effects of experimentally achievable improvements in the quality of NMR distance constraints on the accuracy of calculated protein structures.

New methods for collecting cross-relaxation data from proteins and nucleic acids make it possible to improve the accuracy and precision of interproton distance measurements used as input for NMR solution structure determinations. It thus is of interest to determine whether such experimentally achievable improvements in input distance constraints have significant effects on the precision and accuracy of the resulting structures. To answer this question, we have turned to a computational procedure involving the use of data simulated from a known structure, in order to allow unambiguous assessments of accuracy. The approach to improved distances evaluated here is that afforded by magnetization exchange network editing (MENE); MENE pulse sequences break the network of cross-relaxation interactions into regions that are manipulated so as to defeat certain spin-diffusion terms. A target structure was prepared from the X-ray structure of a small protein, turkey ovomucoid third domain (OMTKY3). A normal NOESY spectrum and two varieties of MENE spectra, BD-NOESY and CBD-NOESY, were simulated by means of complete relaxation matrix analysis. These results were used to create different input data sets with the same number of constraints (perfectly accurate distances derived from the target structure, more accurate distances derived from the MENE simulations, and less accurate distances derived from the NOESY simulation), and these, interpreted at different levels of precision, were used as input for solution structure calculations. The results showed that the use of more precise input data measurably improves the local precision and accuracy of calculated structures, but only if the more precise data include the actual target distance. Incorporation of the experimentally achievable, accurate distances with higher precision afforded by the MENE pulse sequences into the set of input distances was found to improve the accuracy of the resulting structures, particularly in terms of side-chain conformation.

Animals↗