The conceptual foundations of innate immunity: Taking stock 30 years later.

While largely neglected over decades during which adaptive immunity captured most of the attention, innate immune mechanisms have now become central to our understanding of immunology. Innate immunity provides the first barrier to infection in vertebrates, and it is the sole mechanism of host defense in invertebrates and plants. Innate immunity also plays a critical role in maintaining homeostasis, shaping the microbiota, and in disease contexts such as cancer, neurodegeneration, metabolic syndromes, and aging. The emergence of the field of innate immunity has led to an expanded view of the immune system, which is no longer restricted to vertebrates and instead concerns all metazoans, plants, and even prokaryotes. The study of innate immunity has given rise to new concepts and language. Here, we review the history and definition of the core concepts of innate immunity, discussing their value and fruitfulness in the long run.

Early-emerging combinatorial thought: Human infants flexibly combine kind and quantity concepts.

Combinatorial thought, or the ability to combine a finite set of concepts into a myriad of complex ideas and knowledge structures, is the key to the productivity of the human mind and underlies communication, science, technology, and art. Despite the importance of combinatorial thought for human cognition and culture, its developmental origins remain unknown. To address this, we tested whether 12-mo-old infants (N = 60), who cannot yet speak and only understand a handful of words, can combine quantity and kind concepts activated by verbal input. We proceeded in two steps: first, we taught infants two novel labels denoting quantity (e.g., "mize" for 1 item; "padu" for 2 items, Experiment 1). Then, we assessed whether they could combine quantity and kind concepts upon hearing complex expressions comprising their labels (e.g., "padu duck", Experiments 2-3). At test, infants viewed four different sets of objects (e.g., 1 duck, 2 ducks, 1 ball, 2 balls) while being presented with the target phrase (e.g., "padu duck") naming one of them (e.g., 2 ducks). They successfully retrieved and combined on-line the labeled concepts, as evidenced by increased looking to the named sets but not to distractor sets. Our results suggest that combinatorial processes for building complex representations are available by the end of the first year of life. The infant mind seems geared to integrate concepts in novel productive ways. This ability may be a precondition for deciphering the ambient language(s) and building abstract models of experience that enable fast and flexible learning.

MEG Evidence That Modality-Independent Conceptual Representations Contain Semantic and Visual Features.

The semantic knowledge stored in our brains can be accessed from different stimulus modalities. For example, a picture of a cat and the word "cat" both engage similar conceptual representations. While existing research has found evidence for modality-independent representations, their content remains unknown. Modality-independent representations could be semantic, or they might also contain perceptual features. We developed a novel approach combining word/picture cross-condition decoding with neural network classifiers that learned latent modality-independent representations from MEG data (25 human participants, 15 females, 10 males). We then compared these representations to models representing semantic, sensory, and orthographic features. Results show that modality-independent representations correlate both with semantic and visual representations. There was no evidence that these results were due to picture-specific visual features or orthographic features automatically activated by the stimuli presented in the experiment. These findings support the notion that modality-independent concepts contain both perceptual and semantic representations.

Minimal representations of possibility at age 3.

Young children do not always consider alternative possibilities when planning. Suppose a prize is hidden in a single occluded container and another prize is hidden in an occluded pair. If given a chance to choose one container and receive its contents, choosing the singleton maximizes expected reward because each member of the pair might be empty. Yet, 3-y-olds choose a member of the pair almost half the time. Why don't they maximize expected reward? Three studies provide evidence that 3-y-olds do not deploy possibility concepts like MIGHT, which would let them represent that each container in the pair might and might not contain a prize. Rather, they build an overly specific model of the situation that correctly specifies that the singleton holds a prize while inappropriately specifying which member of the pair holds a prize and which is empty. So, when asked to choose a container, they see two equally good options. This predicts approximately 50% choice of the singleton, observed in studies 1 and 3. But when asked to throw away a container so that they can receive the remaining contents (study 2), they mostly throw away a member of the pair. The full pattern of data is expected if children construct overly specific models. We discuss whether 3-year-olds lack possibility concepts or whether performance demands prevent deployment of them in our tasks.

Experiential grounding of abstract concepts: Processing of abstract mental state concepts engages brain regions involved in mentalizing, automatic speech, and lip movements.

concepts like mental state concepts lack a physical referent, which can be directly perceived. Classical theories therefore claim that abstract concepts require amodal representations detached from experiential brain systems. However, grounded cognition approaches suggest an involvement of modal experiential brain regions in the processing of abstract concepts. In the present functional magnetic resonance imaging study, we investigated the relation of the processing of abstract mental state concepts to modal experiential brain systems in a fine-grained fashion. Participants performed lexical decisions on abstract mental state as well as on verbal association concepts as control category. Experiential brain systems related to the processing of mental states, generating verbal associations, automatic speech as well as hand and lip movements were determined by corresponding localizer tasks. Processing of abstract mental state concepts neuroanatomically overlapped with activity patterns associated with processing of mental states, generating verbal associations, automatic speech and lip movements. Hence, mental state concepts activate the mentalizing brain network, complemented by perceptual-motor brain regions involved in simulation of visual or action features associated with social interactions, linguistic brain regions as well as face-motor brain regions recruited for articulation. The present results provide compelling evidence for the rich grounding of abstract mental state concepts in experiential brain systems related to mentalizing, verbal communication and mouth action.

Oligometastatic non-small cell lung cancer: Impact of local and contemporary systemic treatment approaches on clinical outcome.

Oligometastatic (OMD) non-small cell lung cancer (NSCLC) is a distinct but heterogeneous entity. Current guidelines recommend systemic therapy and consolidation with local ablative therapy (LAT). However, evidence regarding the optimal choice of multimodal treatment approaches is lacking, in particular with respect to the integration of immunotherapy. This real-world study identified 218 patients with OMD NSCLC (2004-2023, prespecified criteria: ≤5 metastases in ≤2 organ systems) from three major German comprehensive cancer centers. Most patients had one (72.5%) or two (17.4%) metastatic lesions in a single (89.9%) organ system. Overall survival (OS) was significantly longer with a single metastatic lesion (HR 0.54, p = .003), and female gender (HR 0.4, p < .001). Median OS of the full cohort was 27.8 months, with 29% survival at 5 years. Patients who had completed LAT to all NSCLC sites, typically excluding patients with early progression, had a median OS of 34.4 months (37.7% 5-year OS rate) with a median recurrence-free survival (RFS) of 10.9 months (13.3% at 5 years). In those patients, systemic treatment as part of first-line therapy was associated with doubling of RFS (12.3 vs. 6.4 months, p < .001). Despite limited follow-up of patients receiving chemo-immunotherapy (EU approval 2018/2019), RFS was greatly improved by adding checkpoint inhibitors to chemotherapy (HR 0.44, p = .008, 2-year RFS 51.4% vs. 15.1%). In conclusion, patients with OMD NSCLC benefitted from multimodality approaches integrating systemic therapy and local ablation of all cancer sites. A substantial proportion of patients achieved extended OS, suggesting a potential for cure that can be further augmented with the addition of immunotherapy.

Delocalization-ratio analysis of 3-center bonding in position-space for closo-boranes and related systems: Approaching the styx picture and beyond.

Closo-boron hydrides BnHn 2- (n = 5-12) are a conceptually well understood class of compounds. For these and a few related prototype compounds, both the local and the global picture of 3-center bonding are extracted from position-space quantities based on the electron density and the pair density. For this purpose, three-center delocalization indices between quantum theory of atoms in molecules (QTAIM) atoms in position space are used to develop a consistent set of local bond and triangle, and global cluster delocalization ratios (DRs), which are quantitatively compared with conceptual Γ values derived from the styx code for each cluster. Combination of the cluster DRs with associated effective numbers of skeletal electron sharing (SES) for selected cluster surface edges, triangles, or the whole cluster yields effective styx type values describing the trend and even the size of the conceptual styx codes for closo-boranes BnHn 2- and related systems with increasing cluster size n reasonably well. For nonuniform cluster topologies, the different vertex degrees are shown to cause systematic 3-center wise bond delocalization effects for the associated edges and triangles of different average vertex degrees. Extension of DR analysis beyond the styx type triangular cluster-surface bonding corresponds to a triangulation of multicentric bonding. The cluster-wise results keep indicating consistency with the mixed 2- and 3-center bonding approach. The successfully established chemical meaning of the local edge, triangle, and global cluster DRs and their associated SES values constitutes the basis for systematic investigations of mixed 2- and 3-center bonding scenarios in particular in intermetallic and related (endohedral) cluster compounds in the future.

Twenty years of big plant genera.

In 2004, David Frodin published a landmark review of the history and concepts of big plant genera. Two decades of taxonomic activity have taken place since, coinciding with a revolution in phylogenetics and taxonomic bioinformatics. Here we use data from the World Flora Online (WFO) to provide an updated list of big (more than 500 species) and megadiverse (more than 1000 species) flowering plant genera and highlight changes since 2004. The number of big genera has increased from 57 to 86; today one of every four plant species is classified as a member of a big genus, with 14% in just 28 megadiverse genera. Most (71%) of the growth in big genera since 2000 is the result of new species description, not generic re-circumscription. More than 15% of all currently accepted flowering plant species described in the last two decades are in big genera, suggesting that groups previously considered intractable are now being actively studied taxonomically. Despite this rapid growth in big genera, they remain a significant yet understudied proportion of plant diversity. They represent a significant proportion of global plant diversity and should remain a priority not only for taxonomy but for understanding global diversity patterns and plant evolution in general.

tDCS of right-hemispheric Wernicke's area homologue affects contextual learning of novel lexicon.

Numerous studies have shown robust evidence of the right hemisphere's involvement in the language function, for instance in the processing of intonation, grammar, word meanings, metaphors, etc. However, its role in lexicon acquisition remains obscure. We applied transcranial direct current stimulation (tDCS) over the right-hemispheric homologue of Wernicke's area to assess its putative involvement in the processing of different types of novel semantics. After receiving 15 min of anodal, cathodal, or sham (placebo) tDCS, three groups of healthy participants learnt novel concrete and abstract words in the context of short stories. Learning outcomes were assessed using a battery of tests immediately after this contextual learning session and 24 h later. As a result, an inhibitory effect of cathodal tDCS and a facilitatory effect of anodal tDCS were found for abstract word acquisition only. We also found a significant drop in task performance on the second day of the assessment for both word types in all the stimulation groups, suggesting no significant influence of tDCS on the post-learning consolidation of new memory traces. The results suggest an involvement of Wernicke's right-hemispheric counterpart in initial encoding (but not consolidation) of abstract semantics, which may be explained either by the right hemispheres direct role in processing lexical semantics or by an indirect impact of tDCS on contralateral (left-hemispheric) cortical areas through cross-callosal connections.

Acute kidney injury in diabetes mellitus: Epidemiology, diagnostic, and therapeutic concepts.

Acute kidney injury (AKI) and diabetes mellitus (DM) are public health problems that cause a high socioeconomic burden worldwide. In recent years, the landscape of AKI etiology has shifted: Emerging evidence has demonstrated that DM is an independent risk factor for the onset of AKI, while an alternative perspective considers AKI as a bona fide complication of DM. Therefore, it is necessary to systematically characterize the features of AKI in DM. In this review, we summarized the epidemiology of AKI in DM. While focusing on circulation- and tissue-specific microenvironment changes after DM, we described the active cellular and molecular mechanisms of increased kidney susceptibility to AKI under DM stress. We also reviewed the current diagnostic and therapeutic strategies for AKI in DM recommended in the clinic. Updated recognition of the epidemiology, pathophysiology, diagnosis, and medications of AKI in DM is believed to reveal a path to mitigate the frequency of AKI and DM comorbidity that will ultimately improve the quality of life in DM patients.

Quantification of the Donor-Acceptor Character of Ligands by the Effective Fragment Orbitals.

Metal-ligand interactions are at the heart of transition metal complexes. The Dewar-Chat-Duncanson model is often invoked, whereby the metal-ligand bonding is decomposed into the simultaneous ligand→metal electron donation and the metal→ligand back-donation. The separate quantification of both effects is not a trivial task, neither from experimental nor computational exercises. In this work we present the effective fragment orbitals (EFOs) and their occupations as a general procedure beyond the Kohn-Sham density functional theory (KS-DFT) framework for the identification and quantification of donor-acceptor interactions, using solely the wavefunction of the complex. Using a common Fe(II) octahedral complex framework, we quantify the σ-donor, π-donor, and π-acceptor character for a large and chemically diverse set of ligands, by introducing the respective descriptors σd, πd, and πa. We also explore the effect of the metal size, coordination number, and spin state on the donor/acceptor features. The spin-state is shown to be the most critical effect, inducing a systematic decrease of the sigma donation and π-backdonation going from low spin to high spin. Finally, we illustrate the ability of the EFOs to rationalize the Tolman electronic parameter and the trans influence in planar square complexes in terms of these new descriptors.

Academic training increases grounding of scientific concepts in experiential brain systems.

Scientific concepts typically transcendent our sensory experiences. Traditional approaches to science education therefore assume a shift towards amodal or verbal knowledge representations during academic training. Grounded cognition approaches, in contrast, predict a maintenance of grounding of the concepts in experiential brain networks or even an increase. To test these competing approaches, the present study investigated the semantic content of scientific psychological concepts and identified the corresponding neural circuits using functional magnetic resonance imaging (fMRI) in undergraduate psychology students (beginners) and in graduated psychologists (advanced learners). During fMRI scanning, participants were presented with words denoting scientific psychological concepts within a lexical decision task (e.g. "conditioning", "habituation"). The individual semantic property content of each concept was related to brain activity during abstract concept processing. In both beginners and advanced learners, visual and motor properties activated brain regions also involved in perception and action, while mental state properties increased activity in brain regions also recruited by emotional-social scene observation. Only in advanced learners, social constellation properties elicited brain activity overlapping with emotional-social scene observation. In line with grounded cognition approaches, the present results highlight the importance of experiential information for constituting the meaning of abstract scientific concepts during the course of academic training.

Comparing Loneliness, Social Inactivity, and Social Isolation: Associations with Health-Related Quality of Life and Mortality among Home-Dwelling Older Adults.

INTRODUCTION: Loneliness, social inactivity, and social isolation are intertwined concepts. When assessed separately, they indicate poor well-being, adverse health effects, and increased mortality. Studies exploring overlapping and comparing the prognosis of these concepts are scarce. We investigated (1) overlapping of concepts of loneliness, social inactivity, and social isolation, (2) characteristics of groups: group 0 (not lonely, socially inactive, or socially isolated), group 1 (lonely), group 2 (not lonely but socially inactive and/or socially isolated), and (3) the health-related quality of life (HRQoL), psychological well-being (PWB), and 3.6-year mortality of these groups. METHODS: The home-dwelling older adults (n = 989; 75 y+) of the Helsinki Aging Study in 2019-2022 completing all required questionnaires were assessed. Group 0 included 494, group 1 included 280, and group 2 included 215 participants. Variables studied were demographics, diagnoses, mobility, physical functioning (Barthel index), and cognition (Mini-Mental State Examination). Outcomes were HRQoL (15D) and PWB. Mortality was retrieved from central registers. RESULTS: Half of the sample was lonely, socially inactive, or socially isolated, but only 2% were simultaneously lonely, socially inactive, and socially isolated. Of lonely participants, 38% were also socially inactive and/or socially isolated. The lonely participants were significantly more often widowed or lived alone and had the lowest HRQoL and poorest PWB compared with the other groups. After adjustments (age, sex, Charlson Comorbidity Index), mortality did not statistically differ between the groups. CONCLUSION: Loneliness is an independent determinant of poor HRQoL and PWB, and it should be considered separately from social inactivity and social isolation.

Thresholds of becoming: an exploration of threshold concepts as a means to support professional identity formation in competency-based curricula.

Inherent in every clinical preceptor's role is the ability to understand the learning needs of individual trainees, enabling them to meet their potential. Competency-based medical education frameworks have been developed to this end, but efforts to identify behaviours and activities that define competence are based on mapping knowledge, skills and ability, which can be difficult to integrate into a comprehensive picture of who the trainee is becoming. Professional identity formation, in contrast, prioritizes attention to who trainees are becoming, but provision of detailed guidance to preceptors on how to best support this form of development is challenging. The tension that results limits our ability to optimally support learners as strengths in competency development may mask professional identity development gaps and vice versa. To address this tension, this paper examines how the theory of threshold concepts - troublesome ideas that, once appreciated, fundamentally change how you understand and approach a particular activity - can shine light on professional identity formation and its relationship with developing competence. The recognition and identification of threshold concepts is offered as a means to improve our ability to identify, discuss and support behaviours and actions that impact the learner's capacity to act competently as they develop their identity at various stages of training.

Many preschoolers do not distinguish the possible from the impossible in a marble-catching task.

Do preschoolers differentiate events that might and might not happen from events that cannot happen? The current study modified Redshaw & Suddendorf's "Y-shaped tube task" to test how the ability to distinguish mere possibilities from impossibilities emerges over ontogenesis. In the Y-shaped tube task, the experimenter holds a ball above a tube shaped like an upside-down "Y" and asks a participant to catch it. A participant who identifies the two possible paths the ball can take should cover both exits at the bottom of the Y. But children might cover both exits without identifying both possibilities. For example, there are two good places to put hands, so they might just put one hand in each place. This does not require checking whether there is a path from the entrance to each exit. If children cover both exits because they have identified two possible paths for the ball, then they should differentiate exits where it is possible for the ball to come out from impossible exits, where there is no path from the entrance to the exit. In total, 24 36-month-olds and 24 48-month-olds were tested. Less than 20% of 36-month-olds and only about half of 48-month-olds distinguished between possible and impossible exits. Children who do not distinguish the possible from the impossible might not be evaluating possibilities at all. Results converge with existing literature suggesting that action planning that is sensitive to incompatible possibilities often emerges after the fourth birthday.

The influence of language on the formation of number concepts: Evidence from preschool children who are bilingual in English and Arabic.

We asked whether grammatical number marking has specific influence on the formation of early number concepts. In particular, does comprehension of dual case marking support young children's understanding of cardinality? We assessed number knowledge in 77 3-year-old Arabic-English bilingual children using the Give-a-Number task in both languages. Given recent concerns around the administration and scoring of the Give-a-Number task, we used two complementary approaches: one based on conceptual levels and the other based on overall test scores. We also tested comprehension of dual case marking in Arabic and number sequence knowledge in both languages. Regression analyses showed that dual case comprehension exerts a strong influence on cardinality tested in Arabic independent of age, general language skills, and number sequence knowledge. No such influence was found for cardinality tested in English, indicating a language-specific effect. Further analyses tested for transfer of cardinality knowledge between languages. These revealed, in addition to the findings outlined above, a powerful cross-linguistic transfer effect. Our findings are consistent with a model in which the direct effect of dual case marking is language specific, but concepts, once acquired, may be represented abstractly and transferred between languages.

Mental association of time and valence.

Five experiments investigated the association between time and valence. In the first experiment, participants classified temporal expressions (e.g., past, future) and positively or negatively connotated words (e.g., glorious, nasty) based on temporal reference or valence. They responded slower and made more errors in the mismatched condition (positive/past mapped to one hand, negative/future to the other) compared with the matched condition (positive/future to one hand, negative/past to the other hand). Experiment 2 confirmed the generalization of the match effect to nonspatial responses, while Experiment 3 found no reversal of this effect for left-handers. Overall, the results of the three experiments indicate a robust match effect, associating the past with negative valence and the future with positive valence. Experiment 4 involved rating the valence of time-related words, showing higher ratings for future-related words. Additionally, Experiment 5 employed latent semantic analysis and revealed that linguistic experiences are unlikely to be the source of this time-valence association. An interactive activation model offers a quantitative explanation of the match effect, potentially arising from a favorable perception of the future over the past.

Can we get human nature right?

Few questions in science are as controversial as human nature. At stake is whether our basic concepts and emotions are all learned from experience, or whether some are innate. Here, I demonstrate that reasoning about innateness is biased by the basic workings of the human mind. Psychological science suggests that newborns possess core concepts of "object" and "number." Laypeople, however, believe that newborns are devoid of such notions but that they can recognize emotions. Moreover, people presume that concepts are learned, whereas emotions (along with sensations and actions) are innate. I trace these beliefs to two tacit psychological principles: intuitive dualism and essentialism. Essentialism guides tacit reasoning about biological inheritance and suggests that innate traits reside in the body; per intuitive dualism, however, the mind seems ethereal, distinct from the body. It thus follows that, in our intuitive psychology, concepts (which people falsely consider as disembodied) must be learned, whereas emotions, sensations, and emotions (which are considered embodied) are likely innate; these predictions are in line with the experimental results. These conclusions do not speak to the question of whether concepts and emotions are innate, but they suggest caution in its scientific evaluation.

(Re)integrating radioactive materials and waste into a global sustainable development context.

The 17 Sustainable Development Goals (SDGs) of the United Nations, established in 2015, aim to achieve global sustainability by 2030 through the improvement of environmental, social, and economic parameters. However, unlike earlier concepts such as the Agenda 21 of 1992, the SDGs overlook radioactive waste management and related challenges of radiation itself. First, we investigate the historic consideration and unexplained disappearance of radioactive waste in earlier sustainability concepts. Then, we propose amending seven SDGs to address this gap. For SDGs 6 (Clean Water and Sanitation), 14 (Life Below Water), and 15 (Life on Land), new or revised indicators should monitor the release of hazardous materials. SDGs 9 (Industry, Innovation and Infrastructure), 16 (Peace, Justice and Strong Institutions), and 17 (Partnerships for the Goals) require additional targets and indicators to integrate international cooperation and social implications of nuclear facilities' operation. Redefining "hazardous waste" in SDG 12 (Responsible Consumption and Production) and "environmentally sound technologies" in SDG 17 is necessary to encompass radioactive waste. Implementing these changes demands statistical efforts, but the existing monitoring infrastructure, particularly in Europe and North America, can facilitate this. As 2030 approaches, it is crucial to reintroduce radioactive waste management into sustainability agendas, whether within the SDGs themselves or in a subsequent framework.

Exploring health and disease concepts in healthcare practice: an empirical philosophy of medicine study.

In line with recent proposals for experimental philosophy and philosophy of science in practice, we propose that the philosophy of medicine could benefit from incorporating empirical research, just as bioethics has. In this paper, we therefore take first steps towards the development of an empirical philosophy of medicine, that includes investigating practical and moral dimensions. This qualitative study gives insight into the views and experiences of a group of various medical professionals and patient representatives regarding the conceptualization of health and disease concepts in practice and the possible problems that surround them. This includes clinical, epistemological, and ethical issues. We have conducted qualitative interviews with a broad range of participants (n = 17), working in various health-related disciplines, fields and organizations. From the interviews, we highlight several different practical functions of definitions of health and disease. Furthermore, we discuss 5 types of problematic situations that emerged from the interviews and analyze the underlying conceptual issues. By providing theoretical frameworks and conceptual tools, and by suggesting conceptual changes or adaptations, philosophers might be able to help solve some of these problems. This empirical-philosophical study contributes to a more pragmatic way of understanding the relevance of conceptualizing health and disease by connecting the participants' views and experiences to the theoretical debate. Going back and forth between theory and practice will likely result in a more complex but hopefully also better and more fruitful understanding of health and disease concepts.