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PubMed2000

NLP techniques associated with the OpenGALEN ontology for semi-automatic textual extraction of medical knowledge: abstracting and mapping equivalent linguistic and logical constructs.

This research project presents methodological and theoretical issues related to the inter-relationship between linguistic and conceptual semantics, analysing the results obtained by the application of a NLP parser to a set of radiology reports. Our objective is to define a technique for associating linguistic methods with domain specific ontologies for semi-automatic extraction of intermediate representation (IR) information formats and medical ontological knowledge from clinical texts. We have applied the Edinburgh LTG natural language parser to 2810 clinical narratives describing radiology procedures. In a second step, we have used medical expertise and ontology formalism for identification of semantic structures and abstraction of IR schemas related to the processed texts. These IR schemas are an association of linguistic and conceptual knowledge, based on their semantic contents. This methodology aims to contribute to the elaboration of models relating linguistic and logical constructs based on empirical data analysis. Advance in this field might lead to the development of computational techniques for automatic enrichment of medical ontologies from real clinical environments, using descriptive knowledge implicit in large text corpora sources.

Electronic Data Processing↗

PubMed2025

Design of highly functional genome editors by modelling CRISPR-Cas sequences.

Gene editing has the potential to solve fundamental challenges in agriculture, biotechnology and human health. CRISPR-based gene editors derived from microorganisms, although powerful, often show notable functional tradeoffs when ported into non-native environments, such as human cells1. Artificial-intelligence-enabled design provides a powerful alternative with the potential to bypass evolutionary constraints and generate editors with optimal properties. Here, using large language models2 trained on biological diversity at scale, we demonstrate successful precision editing of the human genome with a programmable gene editor designed with artificial intelligence. To achieve this goal, we curated a dataset of more than 1 million CRISPR operons through systematic mining of 26 terabases of assembled genomes and metagenomes. We demonstrate the capacity of our models by generating 4.8× the number of protein clusters across CRISPR-Cas families found in nature and tailoring single-guide RNA sequences for Cas9-like effector proteins. Several of the generated gene editors show comparable or improved activity and specificity relative to SpCas9, the prototypical gene editing effector, while being 400 mutations away in sequence. Finally, we demonstrate that an artificial-intelligence-generated gene editor, denoted as OpenCRISPR-1, exhibits compatibility with base editing. We release OpenCRISPR-1 to facilitate broad, ethical use across research and commercial applications.

CRISPR-Cas Systems↗

PubMed1989

Pleiotropy and preadaptation in the evolution of human language capacity.

The capacity for spoken language in the human is a genetic trait, but the information communicated by this means is to a large extent culturally determined. Using a gene-culture coevolutionary approach, we model the hypothesis that speech evolved as a channel for the communication of adaptive cultural traits from parent to offspring. The motivation for this paper is a condition obtained previously that initial increase of communication would require at least a two-fold advantage for the transmitted trait. Here, we show that under reasonable assumptions the invasion condition becomes less stringent. In Model 1, we assume that two adaptive cultural traits can be transmitted. A gene which permits communication of the second adaptive trait. In Model 2, we assume that a related function such as greater memory capacity is a prerequisite for speech, and that this function confers an advantage independent of its association with speech. In both models we assume haploid sexual genetics and a simple scheme of vertical transmission. The stability properties of all corner and edge equilibria of the models are analyzed. The two models taken together suggest a possible scenario for the initial stages of the evolution of speech.

Adaptation, Biological↗

PubMed2001

International development of the Quality of Life in Depression Scale (QLDS).

BACKGROUND: The Quality of Life in Depression Scale (QLDS) employs the needs-based model of quality of life (QoL) and was developed in the UK and The Netherlands as an outcome measure for clinical trials. This paper describes the production and psychometric assessment of nine new language versions for Canada (French and English), Denmark, France, Germany, Italy, Morocco, Spain and the US. METHODS: Three adaptation stages were employed; production of conceptually equivalent translations, field-test interviews and assessment of reliability and construct validity by survey of patients with major depression. RESULTS: Few problems were experienced with producing conceptually equivalent translations, except in Morocco. Patients in the field-test interviews found the instrument to have appropriate content and to be easy to complete. Internal consistency and test-retest reliability were excellent for all language versions and scores were found to relate appropriately to measures of depression severity and health status. LIMITATIONS: Further investigation is required of the ability of the measure to assess individuals at the extremes of the QoL continuum. Data collected with the Arabic QLDS should not be combined with those from other countries. CONCLUSIONS: The QLDS is the first instrument designed to assess QoL in depression based on a coherent model of the construct. Each language version has been shown to be well accepted by respondents and to have excellent psychometric properties. As the instrument is now available in a large number of languages, the QLDS is the QoL instrument of choice for inclusion in clinical trials of interventions for depression.

Adult↗

PubMed2001

Simplest random K-satisfiability problem.

We study a simple and exactly solvable model for the generation of random satisfiability problems. These consist of gammaN random boolean constraints which are to be satisfied simultaneously by N logical variables. In statistical-mechanics language, the considered model can be seen as a diluted p-spin model at zero temperature. While such problems become extraordinarily hard to solve by local search methods in a large region of the parameter space, still at least one solution may be superimposed by construction. The statistical properties of the model can be studied exactly by the replica method and each single instance can be analyzed in polynomial time by a simple global solution method. The geometrical and topological structures responsible for dynamic and static phase transitions as well as for the onset of computational complexity in the local search method are thoroughly analyzed. Numerical analysis on very large samples allows for a precise characterization of the critical scaling behavior.

Journal Article↗

PubMed1997

[Intercultural communication in general practice].

What is the reason for possible communication problems between physicians and immigrants from the third world? How is the interaction between the two groups regulated? To answer such questions, 15 doctors and 10 immigrants were interviewed about their experience of the doctor-patient interaction in unstructured open-ended interviews. Culturally based verbal and non-verbal expressions were particularly difficult to interpret, being based on different thought models and language. Owing to the world wide generalisation of the doctor-patient roles the gap between the two "partners" in the communication has been to some extent bridged. Largely independent of the doctors' will, the immigrants assigned considerable authority to the doctors. Thus the power of the doctor is based on the institutionalisation of the more universal doctor-patient role.

Communication↗

PubMed1992

GOFCOX: a computer program for the goodness-of-fit analysis of the Cox proportional hazards model.

GOFCOX is a user-friendly FORTRAN program for assessing the adequacy of the Cox proportional hazards model. The underlying methodology is based on the comparison of the maximum partial likelihood estimator and a weighted parameter estimator. The latter is the root to an estimation equation that assigns varying weights to the individual contributions to the partial likelihood score function. The weighted and unweighted parameter estimators have the same expectation under the Cox model, but tend to differ when the model is inappropriate. The GOFCOX program computes a rich class of weighted parameter estimators and corresponding goodness-of-fit test statistics. The program runs on both mainframe computers and microcomputers. The running time is minimal even for large data sets. A simple example is provided to illustrate the features of the program.

Computers, Mainframe↗

PubMed2001

Reliable short-term memory in the trion model: toward a cortical language and grammar.

It has previously been shown that Hebb learning in a single column in the trion model of cortical organization occurs by selection. Motivated by von Neumann's solution for obtaining reliability and by models of circulating cortical activity, we introduce Hebb intercolumnar couplings to achieve dramatic enhancements in reliability in the firing of connected columns. In order for these enhancements to occur, specific temporal phase differences must exist between the same inherent spatial-temporal memory patterns in connected columns. We then generalize the criteria of large enhancements in the global firing of the entire connected columnar network to investigate the case when different inherent memory patterns are in the columns. The spatial rotations as well as the temporal phases now are crucial. Only certain combinations of inherent memory patterns meet these criteria with the symmetry properties playing a major role. The columnar order of these memory patterns not in the same symmetry family can be extremely important. This yields the first higher-level architecture of a cortical language and grammar within the trion model. The implications of this result with regard to an innate human language and grammar are discussed.

Cerebral Cortex↗

PubMed1984

Computer programs as theories in biology.

Complex theories in biology may be developed, refined, and tested by the use of computer programmed simulations. The computer is recognized as a powerful tool for theory development; it is, in fact, the only means of thoroughly testing and examining a large and intricate theory. A program as a text is a statement of a theory and when run on the computer it is model of that theory. As the program's behavior is then the major argument for the credibility of a large and complex theory, the program itself is the only irrefutable statement of the theory. Bur programs written in the currently available programming languages tend to be incomprehensible. We argue that the program should be the definitive statement of the theory. In addition, the program plus a series of abstractions is a vehicle for effective communication of complex theories in biology. Several techniques of computer science are borrowed, for the purpose of developing a methodology for abstraction and a language for representing abstractions. The arguments are fully illustrated with a recently published biological theory.

Communication↗

PubMed2000

A centralised telephone service for tobacco cessation: the California experience.

OBJECTIVE: To provide an overview of the California Smokers' Helpline, an increasingly popular telephone program for tobacco cessation in California since 1992. As many states, regions, and nations are contemplating various telephone programs as part of large scale anti-tobacco campaigns, this paper presents a practical model. DESIGN: The Helpline provides Californians with free cessation services that include counselling, self help quit kits, and cessation related information. Services are provided in six spoken languages plus a line for the hearing impaired. The program is promoted statewide by media campaigns, health care providers, local tobacco control programs, and the public school system. SETTING: The Helpline is centrally operated through the University of California, San Diego and provides services statewide via telephone. RESULTS: The Helpline has served over 100 000 tobacco users and has become the chief cessation resource for the Comprehensive Tobacco Control Program in California. Media was the most important referral source for Helpline callers (50%), followed by health care providers (20%). About one third of the callers were ethnic minorities and 17% were 24 years old or younger. Compared to California smokers in general, the callers were more dependent on nicotine and more likely to live with other smokers, but they were also more likely to have tried to quit recently and were more ready to try again. Two randomised trials have demonstrated the efficacy of the Helpline's counselling protocol. CONCLUSION: A centralised helpline operation can be an accessible and effective service for tobacco users and should be included in any large scale, comprehensive tobacco control program.

Adolescent↗

PubMed1991

Finite dose percutaneous drug absorption: a BASIC program for the solution of the diffusion equation.

A BASIC program to obtain the solution for the diffusion equation describing the finite dose percutaneous absorption pharmacokinetics is shown. Drug amount in the solution matrix, Av, that in the skin which is regarded as a simple diffusion membrane. As, and the drug flux from the skin which is provided by the local circulation per unit area, J, and the blood drug concentration. C, expressed as functions of time are obtained using Fourier series. Usually, a small number (less than 10) of series is enough to obtain the accurate values for Av, As, J, and C. It is also shown that the solution of the diffusion equation reported previously for the specific case where both the diffusion coefficient of a drug through the vehicle and skin-capillary clearance are very large is expressed as a limit.

Administration, Cutaneous↗

PubMed1978

Speech development in hearing-impaired children.

Many hearing-impaired children are unable to speak intelligibly. Research indicates, however, that patterns of errors typically found in the speech of such children could be largely avoided by systematic teaching. The purpose of this paper is to present and discuss a model for the progressive development of speech skills to the levels of automaticity required for fluent spoken language.

Child↗

PubMed1994

Emergence of visual-graphic symbol combinations by youth with moderate or severe mental retardation.

Research and practice on augmentative communication for persons with moderate or severe mental retardation have primarily targeted the acquisition and use of single symbols. Symbol combinations, however, provide insight into how augmented communicators use individual symbols to build more complex communications. In Study 1, untaught symbol combinations produced during natural communication interactions by 7 subjects with mental retardation were examined for their semantic, ordering, and generalization patterns. The symbol combinations largely resembled those produced by young speaking language learners, suggesting that the augmented communicators were following typical patterns of communication in generating their symbol combinations. In Study 2, we examined the symbol combinations modeled for subjects by their partners. The structure of the modeled combinations did not resemble the children's productions, indicating that the children could not have relied on simple rote imitation for their combination production. These results suggest that augmented communicators with mental retardation may use their symbols as speaking children use oral words in the development of complex communications.

Adolescent↗

PubMed1998

Progress in modeling and simulation.

For the modeling of systems, the computers are more and more used while the other "media" (including the human intellect) carrying the models are abandoned. For the modeling of knowledges, i.e. of more or less general concepts (possibly used to model systems composed of instances of such concepts), the object-oriented programming is nowadays widely used. For the modeling of processes existing and developing in the time, computer simulation is used, the results of which are often presented by means of animation (graphical pictures moving and changing in time). Unfortunately, the object-oriented programming tools are commonly not designed to be of a great use for simulation while the programming tools for simulation do not enable their users to apply the advantages of the object-oriented programming. Nevertheless, there are exclusions enabling to use general concepts represented at a computer, for constructing simulation models and for their easy modification. They are described in the present paper, together with true definitions of modeling, simulation and object-oriented programming (including cases that do not satisfy the definitions but are dangerous to introduce misunderstanding), an outline of their applications and of their further development. In relation to the fact that computing systems are being introduced to be control components into a large spectrum of (technological, social and biological) systems, the attention is oriented to models of systems containing modeling components.

Computer Simulation↗

PubMed1996

Variation in the application of natural processes: language-dependent constraints in the phonological acquisition of bilingual children.

This paper studies phonological processes and constraints on early phonological and lexical development, as well as the strategies employed by a young Spanish-, Portuguese-, and Hebrew-speaking child-Nurit (the author's niece)-in the construction of her early lexicon. Nurit's linguistic development is compared to that of another Spanish-, Portuguese-, and Hebrew-speaking child-Noam (the author's son). Noam and Nurit's linguistic development is contrasted to that of Berman's (1977) English- and Hebrew-speaking daughter (Shelli). The simultaneous acquisition of similar (closely related languages) such as Spanish and Portuguese versus that of nonrelated languages such as English and Hebrew yields different results: Children acquiring similar languages seem to prefer maintenance as a strategy for the construction of their early lexicon, while children exposed to nonrelated languages appear to prefer reduction to a large extent (Faingold, 1990). The Spanish- and Portuguese-speaking children's high accuracy stems from a wider choice of target words, where the diachronic development of two closely related languages provides a simplified model lexicon to the child.

Child Language↗

PubMed1997

Context-free evolutionary grammars and the structural language of nucleic acids.

This paper introduces and investigates a generative mechanism based on some operations inspired by the large-scale mutations in genomes (deletion, inversion, transposition, duplication). Basic questions regarding these devices and their generated languages are investigated: generative capacity, closure properties, decidability. We also briefly discuss a few problems concerning our model with respect to some structural features of the nucleic acids.

Evolution, Molecular↗

PubMed2026

Evidence supporting the role of GIGYF2 in synapse development and autism.

Autism spectrum disorder (ASD) is a heterogeneous condition in which genetically defined subtypes offered insights into underlying biological mechanisms and potential targeted treatments. Here, we investigate the clinical and pathogenic significance of GIGYF2 variants in ASD through an integrated approach combining clinical genetics, conditional knockout (cKO) mouse models, neurobiology, and molecular studies. Through targeted sequencing, large-scale genomic data analysis of neurodevelopmental disorder cohorts, and international collaborations, we identified ten affected individuals from eight families harboring de novo or dominantly inherited likely gene-disruptive (LGD) variants and 13 affected individuals from 13 families with de novo missense variants in GIGYF2. Clinical characterization of 16 probands with GIGYF2 variants revealed common features, including ASD, language problems, intellectual disability, and anxiety. In a Gigyf2 cKO mouse model, we observed pronounced autistic-like behaviors, cognitive deficits, and anxiety-like behaviors, mirroring phenotypes observed in affected individuals. Mechanistically, Gigyf2 deficiency disrupted synaptic homeostasis, as evidenced by altered spine density and miniature excitatory postsynaptic currents, and impaired IGF-1R/mTOR signaling, along with dysregulation of synapse-related genes such as Nrp2. Pharmacological inhibition of mTOR with rapamycin or Torin1, as well as Nrp2 knockdown rescued synaptic defects in Gigyf2 KO neurons. These findings define a novel ASD subtype associated with GIGYF2 variants and establish GIGYF2 as a key regulator of synaptic development and function, implicating GIGYF2 dysfunction in ASD pathogenesis and highlighting the IGF-1R/mTOR pathway as a potential therapeutic target for GIGYF2-related ASD subtype.

Journal Article↗

PubMed2000

Structural basis of carbohydrate recognition by lectin II from Ulex europaeus, a protein with a promiscuous carbohydrate-binding site.

Protein-carbohydrate interactions are the language of choice for inter- cellular communication. The legume lectins form a large family of homologous proteins that exhibit a wide variety of carbohydrate specificities. The legume lectin family is therefore highly suitable as a model system to study the structural principles of protein-carbohydrate recognition. Until now, structural data are only available for two specificity families: Man/Glc and Gal/GalNAc. No structural data are available for any of the fucose or chitobiose specific lectins. The crystal structure of Ulex europaeus (UEA-II) is the first of a legume lectin belonging to the chitobiose specificity group. The complexes with N-acetylglucosamine, galactose and fucosylgalactose show a promiscuous primary binding site capable of accommodating both N-acetylglucos amine or galactose in the primary binding site. The hydrogen bonding network in these complexes can be considered suboptimal, in agreement with the low affinities of these sugars. In the complexes with chitobiose, lactose and fucosyllactose this suboptimal hydrogen bonding network is compensated by extensive hydrophobic interactions in a Glc/GlcNAc binding subsite. UEA-II thus forms the first example of a legume lectin with a promiscuous binding site and illustrates the importance of hydrophobic interactions in protein-carbohydrate complexes. Together with other known legume lectin crystal structures, it shows how different specificities can be grafted upon a conserved structural framework.

Amino Acid Sequence↗