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PubMed2026

Foundation model enables interpretable open and error-tolerant searching for mass spectrometry-based proteomics.

MOTIVATION: Mass spectrometry-based proteomics allows studying all proteins of a sample on a molecular level. However, mass spectra are noisy and contain complex patterns, making them inherently challenging to analyze with algorithmic approaches. In terms of the protein sequence landscape, most recent bottom-up MS-based proteomics studies consider either a diverse pool of post-translational modifications, employ large databases-as in metaproteomics or proteogenomics, study multiple isoforms of proteins, include unspecific cleavage sites or even combinations thereof. All this makes peptide and protein identifications challenging. RESULTS: Here, we present a foundation model, called yHydra, that jointly embeds spectra and peptides. This allows us to implement various downstream tasks and search modes in Euclidean space. We implement an open search which allows querying multiple ten-thousands of spectra against millions of peptides. Furthermore, we implement an error-tolerant search for identifying additional proteoforms that are not included in off-the-shelf reference proteomes. Our foundation model provides meaningful embeddings, as we interpret learned peptide embeddings in comparison to the peptide's physico-chemical properties. Hydra's open search, assigns delta masses to each identification which allows to unrestrictedly characterize post-translational modifications. The error-tolerant mode of yHydra can be used as post-processing to existing search engines or as a standalone. yHydra is evaluated on several real life data sets for the identification of modified peptide sequences and shows up to 25% increase in peptide identification at constant false discovery rate compared to the current state-of-the-art. AVAILABILITY AND IMPLEMENTATION: Code is available on Gitlab: https://gitlab.com/dacs-hpi/yHydra, and https://gitlab.com/dacs-hpi/yHydra_train.

Proteomics↗

PubMed2026

Causal circuit tracing reveals distinct computational architectures in single-cell foundation models: inhibitory dominance, biological coherence, and cross-model convergence.

MOTIVATION: Sparse autoencoders (SAEs) decompose foundation-model activations into interpretable features, but the model-internal causal interactions between those features (i.e. what ablating one feature does to the others, as distinct from the biological causal structure of the underlying cells)-and how those model-internal relationships relate to biological structure-are uncharacterized in single-cell foundation models. RESULTS: We introduce model-internal causal circuit tracing-zeroing one SAE feature at a source layer and measuring the resulting change in all downstream SAE features, for each of 120 source features-and apply it to Geneformer V2-316M and scGPT whole-human across four conditions (96 892 ablation-derived edges, 80 191 forward passes). On annotation-selected source features, edges share GO/KEGG/Reactome/STRING/TRRUST ontology terms at 50.9%-68.5%, a 2.9-6.2× enrichment over a configuration-preserving permutation null (P<.002); on 20 randomly sampled source features this attenuates to 21.5%-26.3%-still 2.5-3.1× above null-quantifying the annotation-selection contribution. Inhibitory dominance (fraction of ablation edges with d<0, i.e. source activation supports downstream target) is 65.5%-89.4%. scGPT produces larger raw per-edge effects (mean |d|=1.40 versus 1.05); after feature-share normalization, Geneformer is stronger (paired gene-pair ratio 0.64 on 33 301 shared pairs). Cross-model consensus yields 1142 architecture-invariant domain pairs (ordered pairs of GO biological-process categories "A→B" each connected by at least one ablation edge in both models; 10.6× enrichment over permutation null; P<.001). Circuit edge magnitude explains <1% of the variance in marginal driver-gene coexpression on the same cells (R2=0.010, n=31 176): the graph encodes structure beyond bivariate correlation. Against a matched-cell-type ENCODE ChIP-seq prior, circuit-predicted transcription factor (TF)→target pairs are enriched 2.06× (Fisher OR 5.84), markedly higher than 1.12× against TRRUST; direct ChIP-seq-supported target pairs show 10-30× larger CRISPRi sign-bias-corrected excess than indirect pairs. Gene-level CRISPRi validation on Replogle K562 and the noncancer RPE1 arm (and a true primary-T-cell control from Shifrut E, Carnevale J, Tobin V et al. Genome-wide CRISPR screens in primary human T cells reveal key regulators of immune function. Cell 2018; 175: 1958-71.e15) after sign-bias correction shows excess over baseline of +0.03 and +0.35 percentage points on K562 and RPE1, respectively (baseline already 52%-56% from sign marginals); effect-magnitude Spearman correlations ρ≈0. Bootstrap and per-cell-type stability (N∈{50,100,200}; B cell, CD4 + T, macrophage) give Pearson r≥0.97 on shared edges with 100% sign agreement; edge Jaccard grows monotonically with sample size. The circuit graph is therefore highly reproducible as an effect-size map, cell type specific in edge identity, consistent with coexpression encoding, and weakly but detectably enriched for ChIP-seq-supported direct regulatory edges. AVAILABILITY AND IMPLEMENTATION: https://github.com/Biodyn-AI/bio-sae-circuits (Python). Archival DOI: 10.5281/zenodo.19,633,166 (Zenodo).

Humans↗

PubMed2005

Patients' views on interpersonal continuity in primary care: a sense of security based on four core foundations.

BACKGROUND: A deep and comprehensive understanding of what patients value about having a personal doctor in primary care is lacking. OBJECTIVES: To acquire a comprehensive understanding of the core values of having a personal doctor in a continuing doctor-patient relationship in primary care among long-term, chronically ill patients. METHOD: In this qualitative study, 14 chronically ill patients at three primary health care centres were strategically selected. The centres were selected to include patients with experiences from both long-term and short-term doctors. The patients were asked about their views on having a personal doctor in a continuing doctor-patient relationship in primary care compared with having different short-term doctors. Sixteen health care professionals were interviewed about what chronically ill patients convey to them about having a personal doctor in contrast to seeing different short-term locum doctors. The in-depth interviews were transcribed verbatim and analysed by qualitative content analysis. RESULTS: The core category, i.e. a universal concept that many patients used to describe the impact of having access to a personal doctor, was a sense of security. This was based on four main categories or core foundations which were: feelings of coherence, confidence in care, a trusting relationship and accessibility. In turn, the four main categories emerged from two to four of subcategories. CONCLUSION: The foundations that underpin the value of personal care from the patients' perspective could be based on categories found in this study.

Adult↗

PubMed2000

The EFQM excellence model: European and Dutch experiences with the EFQM approach in health care. European Foundation for Quality Management.

One way to meet the challenges in creating a high performance organization in health care is the approach of the European Foundation for Quality Management (EFQM). The Foundation is in the tradition of the American Malcolm Baldrige Award and was initiated by the European Commission and 14 European multi-national organizations in 1988. The essence of the approach is the EFQM Model, which can be used as a self-assessment instrument on all levels of a health care organization and as an auditing instrument for the Quality Award. In 1999 the EFQM Model was revised but its principles remained the same. In The Netherlands many health care organizations apply the EFQM Model. In addition to improvement projects, peer review of professional practices, accreditation and certification, the EFQM Approach is used mainly as a framework for quality management and as a conceptualization for organizational excellence. The Dutch National Institute for Quality, the Instituut Nederlandse Kwaliteit, delivers training and supports self-assessment and runs the Dutch quality award programme. Two specific guidelines for health care organizations, 'Positioning and Improving' and 'Self-Assessment', have been developed and are used frequently. To illustrate the EFQM approach in The Netherlands, the improvement project of the Jellinek Centre is described. The Jellinek Centre conducted internal and external assessments and received in 1996, as the first health care organization, the Dutch Quality Prize.

Academies and Institutes↗

PubMed1985

Veatch's new foundation for medical ethics.

Robert M. Veatch proposes a "triple contract theory" as a new foundation for medical ethics. His criticisms of unilateral "physician ethics" are sound, but uncertainty as to whether he is proposing merely imaginary or real contracts vitiates his constructive arguments. If the former, he is recommending a minor heuristic device for thinking about ethics, not a foundation. If the latter, his proposal is utterly impractical and a medical covenant will have to be developed another way.

Bioethical Issues↗

PubMed1993

The experiential foundations of shamanic healing.

An experience-centered approach reveals empirical foundations for shamanic healing. This article is based on data derived from surveys of Chinese, Japanese, Caucasian-American, and African-American populations and participant observation of over thirty Asian shamans. Respondents reported anomalous events such as apparitions, extrasensory perceptions, contact with the dead, precognitive dreams, clairvoyance, and out-of-body experiences. Based on folk reasoning, these episodes support belief in spirits, souls, and life after death. Shamanic healers have a far greater propensity to experience anomalous events than general populations and to use their beliefs arising from these episodes to produce ceremonies that change clients' perceptions of their illnesses. Although the foundations supporting shamanism differ from those sustaining Western medicine, both traditions provide experiences that convince clients that specific procedural methods alleviate illness.

Black or African American↗

PubMedDate not supplied

Constructing a team model: creating a foundation for evidence-based teams.

Teams are the fundamental element of work in the contemporary clinical setting. As interdisciplinary teams become an essential component of the evidence-based framework for clinical practice, their formalization, integration, and synthesis within the practice framework will become increasingly mandatory. Outlined here is a contextual model for team action that is formalized as the organizational leadership continuously addresses the structural and process components of team dynamics in a continuous and cybernetic frame that assures all of the elements of effective teamwork. The theoretical foundations for team modeling are explicated, the elements of the systems approach to team process are outlined, and a necessary synthesis of team processes is described and established as a foundation for evidence-based clinical practice.

Attitude of Health Personnel↗

PubMed1987

Evolutionary idealism: a philosophical foundation for holistic nursing theory.

The philosophical tradition of evolutionary idealism is explored as an appropriate metaphysical foundation for holistic nursing science. Some implications of this tradition for theory development, testing, and practice are identified. It is suggested that evolutionary idealism can form an appropriate philosophical foundation for nursing theory development.

Biological Evolution↗

PubMed2003

Foundations for offshore wind turbines.

An important engineering challenge of today, and a vital one for the future, is to develop and harvest alternative sources of energy. This is a firm priority in the UK, with the government setting a target of 10% of electricity from renewable sources by 2010. A component central to this commitment will be to harvest electrical power from the vast energy reserves offshore, through wind turbines or current or wave power generators. The most mature of these technologies is that of wind, as much technology transfer can be gained from onshore experience. Onshore wind farms, although supplying 'green energy', tend to provoke some objections on aesthetic grounds. These objections can be countered by locating the turbines offshore, where it will also be possible to install larger capacity turbines, thus maximizing the potential of each wind farm location. This paper explores some civil-engineering problems encountered for offshore wind turbines. A critical component is the connection of the structure to the ground, and in particular how the load applied to the structure is transferred safely to the surrounding soil. We review previous work on the design of offshore foundations, and then present some simple design calculations for sizing foundations and structures appropriate to the wind-turbine problem. We examine the deficiencies in the current design approaches, and the research currently under way to overcome these deficiencies. Designs must be improved so that these alternative energy sources can compete economically with traditional energy suppliers.

Journal Article↗

PubMed2006

Development of a new sensor based on micro-electro-mechanical systems for objective in vivo measurement of the cutaneous temperature: application to foundations.

BACKGROUND/AIMS: The purpose of this work was to develop a new sensor for objective in vivo measurement of the cutaneous temperature based on micro-electro-mechanical systems (MEMS), and to compare these performances with those of a classical thermocouple. Research on this new sensor was carried out to allow the quantification of the thermal properties of the made-up skin. METHODS: Sixteen female subjects divided into two different age groups (18-35 and >50 years old) were recruited for this study. Several zones of the face and forearms were made up at random with foundations containing or not a thermoregulator raw material. The quantity of foundation applied on the skin was standardized and measurements were carried out first before make-up, and then 10 s and 5 min after make-up. The new sensor and the thermocouple were used successively on each zone. The cutaneous temperature was expressed in degrees celsius. RESULTS/CONCLUSION: The two systems are similar in terms of repeatability and reproducibility, with some differences in sensibility. The data measured by the MEMS sensor appear lower than those measured by the thermocouple. After make-up, the MEMS sensor detects a progressive increase of the temperature in time whereas the thermocouple detects a decrease. We found the same evolution on the face but in a more attenuated way. These results tend to show that the devices do not measure the same phenomenon. The thermocouple appears more sensitive to the thermal response of the made-up surface whereas the MEMS sensor appears more sensitive to the heat transfers in the interface between the skin and make-up.

Adult↗

PubMed1987

Foundational studies in nursing.

The essential nature of foundational studies in nursing, which are usually called meta-theories or conceptual frameworks, is explored. There are three approaches to this type of study, namely foundationalism, language critique and philosophical analysis. The work of Orem, King and Rogers is briefly analysed as an example of each of these approaches.

Humans↗

PubMed2004

Pre-registration house officer training: a role for nurses in the new Foundation Programme?

PURPOSE: To explore senior nurses' views of pre-registration house officer (PRHO) training, including the scope for their contribution to the new Foundation Programme. DESIGN: Data reported here are drawn from a larger, national project, which aimed to identify a curriculum for the PRHO year. The project was based in the Education Development Unit, Scottish Council for Postgraduate Medical and Dental Education (SCPMDE), Dundee. As part of the project, 40 semistructured interviews, each lasting about 1 hour, were held with senior nurses. Interviews were fully transcribed and coded in the qualitative software NVivo for further analysis. Codes were studied for emergent themes and categories. PARTICIPANTS: Senior nurses (10 from each of the 4 postgraduate regions of Scotland), from diverse specialties. RESULTS: Data suggest considerable cross- regional/specialty consistency. Key emergent themes concerned the process of training as much as the educational outcomes. The nurses focused on the development of outcomes such as communication and teamworking in addition to clinical and practical skills. They guided the PRHOs informally, but were concerned that their own extended roles were detracting from this. DISCUSSION: Nurses are gaining increasingly advanced professional, clinical and practical skills. Traditionally, experienced nurses guide and support PRHOs, at least informally. Data collected suggested there may be scope for capitalising on their expertise, including formalising aspects of their contribution to the proposed PRHO Foundation Programme. However, this is a potentially sensitive area and more interprofessional dialogue is needed.

Clinical Competence↗

PubMed1989

(Mis)understanding Cleveland: foundational issues and the sexual abuse of children.

The Cleveland case led to the widespread condemnation of a new system for the diagnosis, initial treatment, and management of child sexual abuse. The Butler-Sloss Report identifies what went wrong as resulting from poor organisational links among agencies and poor interpersonal skills among professionals. Without denying that these faults occurred, this paper claims that what happened in Cleveland did so primarily because those making policy ignored two foundational issues inherent in the problem of child abuse: the status of the child in society and hence the State's justification in intervening on her behalf, and the status of abuse and the abuser and the consequences of their medicalisation. Analysis of these foundational issues suggests what additional steps will need to be taken if we are to deal effectively with sexually abused children and their families.

Child↗

PubMed2007

Shifts from competition to facilitation between a foundation tree and a pioneer shrub across spatial and temporal scales in a semiarid woodland.

* Theoretical and empirical research has supported the hypothesis that plant-plant interactions change from competition to facilitation with increasing abiotic stress. However, the consistency of such changes has been questioned in arid and semiarid ecosystems. * During a drought in the semiarid south-western USA, we used observations and a field experiment to examine the interactions between juveniles of a foundation tree (Pinyon pine, Pinus edulis) and a common shrub (Apache plume, Fallugia paradoxa) in replicated areas of high and low stress. * The presence of F. paradoxa reduced P. edulis performance at low-stress sites, but had the opposite effect at high-stress sites. However, the intensity of the interactions depended on temporal variation in climate and age of P. edulis. Both above- and below-ground factors contributed to competition, while only above-ground factors contributed to facilitation. * These results support the hypothesis that interactions can change from competition to facilitation as abiotic stress increases in semiarid environments. A shift from competition to facilitation may be important for the recovery of P. edulis and other foundation species that have experienced large-scale mortality during recent droughts.

Adaptation, Physiological↗

PubMed1981

The National Science Foundation looks to the future.

Great advances have been made in fundamental scientific research in recent years. The new knowledge gathered, in addition to deepening our understanding of the physical universe, contributes a range of abilities and opportunities to society that would not otherwise be available. Much research that may be called applied because it addresses needs of society is quite fundamental in character, and support of such research at the National Science Foundation is to be handled in tandem by the research directorates. Other areas that require a refocusing of support are engineering science and education, at all levels, in science and engineering. Increasing our strength in these areas is essential to achieve our national economic, social, and political goals. Steps are being taken by the National Science Foundation to make its structure better able to deal with engineering and applied research and to provide greater mutual reinforcement between applied and basic research.

Cell Biology↗

PubMed1983

Thermodynamics of living matter: physical foundations of biology.

All major functions of life are exerted by reversible conformational changes of living matter, the genetically coded, giant molecules of proteins, polynucleotides, and biological membranes. Only thermodynamics can answer the questions why these reversible actions occur, why they are inevitable, and what the physical foundations may be on which biology rests. Classical Gibbs-Helmholtz thermodynamics was found to be inapplicable to the interpretation of reactions in living matter, because copious flows of heat without exchange of work obscure the subtle bond-forming or bond-breaking energy transformations that are driving the actions of living matter. An alternative thermodynamic formulation that is universally applicable was developed and applied to numerical examples: formation of a diatomic molecule from the elements, and two conformational changes, a protein folding and the winding of a polynucleotide helix. The subtle energy transformations, bond-forming or bond-breaking, that were causing the two reactions of living matter to proceed in vitro forward or in reverse have been identified as the thermal work function delta Wto(T) and the chemical bond energy delta Ho0. Since the chemical bond energies and the heat capacities delta CoP(T) between reaction temperature and the absolute zero, unchangeable attributes of matter, were the only ingredients used for the treatment, the complexity of the reactions has been reduced--as far as effects and ultimate causes are concerned--to the simplicity of low temperature physics, a solid physical foundation for all biological and medical sciences.

Animals↗

PubMed1995

American Heart Association-Bugher Foundation Centers for Molecular Biology in the Cardiovascular System.

BACKGROUND: The American Heart Association (AHA) and the Henrietta B. and Frederick H. Bugher Foundation in 1985 entered into a partnership to establish a group of Centers for Molecular Biology in the Cardiovascular System. The goal was to recruit and train young scientists with medical training to apply molecular and cellular biology knowledge and techniques to cardiovascular problems. METHODS AND RESULTS: Six Centers have been awarded (three in 1986 and three in 1991), and a total of 110 trainees have been involved as of June 30, 1994. Of these trainees, 77 were recruited and trained by the 1986 Centers. As of June 1994, 88% of these trainees remained in academic medicine and 54% progressed to higher academic ranks; 79% published papers in science and 66% in molecular biology; and 36% obtained extramural funding for their work. On this basis, the 1986 trainees appear to be well on their way to becoming successful academic cardiologists. CONCLUSIONS: The AHA-Bugher Foundation Center program has produced a cadre of cardiovascular scientists who are applying molecular biology knowledge to both basic and clinical problems.

Awards and Prizes↗

PubMedDate not supplied

Support of programs for the communicatively disadvantaged child: role of the private foundation.

In comparison to its support of life-threatening diseases, the Federal government has given little support to preventing and alleviating communicative disorders. The very fact that they are not life threatening, means that communicative disorders can remain an uncomfortable, costly, and debilitating factor throughout the lives of millions of children and adults. In view of the magnitude of the problem and the lack of Federal support, responsible leaders are going to have to turn to the general public for support. Foundations, corporations and individuals can provide support for training and organizing services. Such support may well provide them with an opportunity to assist in an area which has touched their families or them personally. Research, training and service programs for the communicatively disadvantaged child are urged to seek financial support from private foundations.

Academies and Institutes↗