The synthesis of higher-order mechanically interlocked molecules is challenging when targeting so-called improbable rotaxanes-statistically disfavored architectures whose ring and axle components lack mutual recognition. This challenge becomes more severe when the rings are racemic or stereolabile, as any successful assembly will inevitably produce a stereoisomeric mixture rather than a well-defined product. Herein, we demonstrate a post-interlocking ring editing strategy using covalent organic pillar COP-1 as the ring component. Nanotubular COP-1 is assembled by dynamic covalent imine condensation of two inherently chiral yet stereolabile macrocyclic building blocks that exhibit negligible binding towards long n-alkyl threads. Preorganization within COP-1 renders the duplex scaffold stereostable, enabling its chiral resolution and switching on ring-axle recognition. Using the resolved COP-1, a threading-followed-by-stoppering protocol furnishes enantiopure [2]rotaxanes. Subsequent imine hydrolysis edits the interlocked COP-1 duplex into its two parent macrocycles, converting each [2]rotaxane into the corresponding improbable [3]rotaxane. The mechanical bond preserves the stereochemical configuration inherited from COP-1, without loss of enantiopurity. This post-interlocking ring editing strategy circumvents the statistical limitations of direct multiring interlocking, providing a programmable route to stereodefined improbable rotaxanes and design principles for higher-order chiral mechanically interlocked architectures.
The original conditions from which primitive life emerged on the early Earth were likely to be dilute mixtures of organic compounds in aqueous solutions. A significant challenge for origins of life research is to discover the reactions that allowed such mixtures to become increasingly complex with products such as polymers that had structural and functional properties related to biology. The chances are low that potential reactants could find one another in dilute solutions composed of thousands of different molecular species. To improve the probability of such encounters, we have investigated a novel condition that both concentrates and organizes potential reactants and encapsulates polymeric products to form protocells. The condition involves a source of freshwater that falls as rainfall precipitation on land masses such as volcanic islands. The water dissolves exogenously and endogenously available organic compounds and feeds into hydrothermal fields where the solutions undergo cycles of evaporation and rehydration, a process easily observed today. Most researchers would agree that monomers such as amino acids and nucleotides would be present in the mixture, but less attention has been paid to the self-assembly of amphiphilic compounds that are also essential components of widely studied protocells. Here, we hypothesize how a closely related medium--multilamellar lipid-polymer (LP) matrices exposed to wet-dry cycles--can act as a progenitor and drive three essential processes: concentration of monomers, polymerization by synthesis of ester and peptide bonds, and promotion of interactions between peptides and nucleotide oligomers. We propose that such matrices represent "combinatorial engines" that can generate otherwise improbable functional complexes. After characterizing the sources of organics, the geochemical settings, and energetic environments in which such an LP progenitor can assemble, we present a conceptual model system that informs both chemical and computational experimental approaches to test this hypothesis.
Ventricular tachycardia (VT) is typically associated with wide QRS complexes; therefore, narrow QRS tachycardia in pacemaker-dependent patients represents a diagnostic challenge. We report a 79-year-old man with permanent atrial fibrillation and complete atrioventricular block who presented with a regular narrow QRS tachycardia. Device interrogation confirmed ventricular pacing dependence. Electrophysiological studies demonstrated scar-related VT arising from the basal interventricular septum adjacent to the left bundle branch. The tachycardia was characterized by fragmented potentials and slow conduction channels and was entrainable with a short postpacing return cycle, supporting a reentrant mechanism. Targeted ablation rendered VT noninducible. No recurrent arrhythmic events occurred during follow-up. VT may present with a narrow QRS morphology in pacemaker-dependent patients when reentrant circuits are located near the His-Purkinje system. Recognition of this uncommon mechanism and advanced electrophysiological mapping are essential for accurate diagnosis and targeted ablation.
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Children often deny the possibility of unusual and improbable events and immoral actions. Three preregistered experiments on 5- and 6-year-old children (N = 154, 47% female, 53% male, tested across three sites in Canada with varied ethnic compositions between March and September 2025) find that children better recognize that improbable events are possible when the events include agents who could plausibly be involved in them and who might want to produce them. In Experiments 1 and 2, children affirmed possibility more when unusual events were described as involving thematically related agents rather than unrelated or indefinite ones. Children also affirmed possibility more for actions that could be voluntarily chosen than for incidents that might happen involuntarily. In Experiment 3, children affirmed possibility more when improbable events involved agents with relevant motives and locations, but this did not affect children's judgments about the possibility of acting immorally. These findings suggest that children often deny the possibility of improbable events because they fail to recall relevant knowledge useful for envisaging the circumstances behind the events. Young children often say it is impossible for people to do unusual things. For instance, they deny that a person in real life could have a pet zebra. The research reported here shows, though, that children are more likely to say unusual events can happen if they are asked about events that involve people who could plausibly be involved in the events, and who might even want the events to happen. For example, they often say a pet zebra is possible if asked about a zookeeper having one. Specifying a related person may help children imagine how unusual events could occur. Reminding children about zookeepers may help them think about where and how a person could get a pet zebra.
Background. The diagnosis of immediate drug allergy (DA) relies on a combination of skin tests (ST), drug provocation tests (DPT), specific IgE levels (sIgE) and/or basophil activation tests (BAT). We aimed to compare BAT results with those of other allergy tests in patients with suspected immediate DA to a heterogeneous group of drugs, aiming to assess its diagnostic value. Methods. Patients who underwent BAT for suspected immediate DA at our hospital from January 2018 to December 2023 were included. Each case (suspected drug) was classified based on diagnostic tests performed - probable vs. improbable allergy (assessed by ST and/or sIgE only) or confirmed vs. excluded allergy (assessed by DPT). Inter-method agreement was assessed with Cohen's kappa index (κ). Results. Eighty-five patients were included: 51 female (60.0%), median age 53.0 years [interquartile range (IQR) = 33.0, Q1-Q3=31.0-64.0]. Median time elapsed since index reaction was 1.0 year [IQR=3.0, Q1-Q3 = 1.0-3.0]. We identified 112 suspected drugs: out of 16 cases with positive BAT (14.3%), 6 were probable (37.5%) and 1 confirmed allergy (6.3%). From 89 drugs with negative BAT (79.5%), 41 were improbable (46.1%) and 5 excluded allergy (5.6%). Seven agents had an inconclusive BAT (6.3%). A slight agreement (κ = 0.201) between BAT and other studies was observed when combining probable/improbable and confirmed/excluded results (n = 76). When limiting these findings to confirmed/excluded results (n=6), we found a perfect agreement (κ = 1).  Conclusions. We assessed BAT performance in a larger sample than those from previous studies. Slight agreement between methods increased to a perfect agreement when limiting to confirmed cases. Larger studies are needed to establish BAT's diagnostic value.
Children often say that possible events are impossible, and only gradually come to see these events as possible. For instance, they often deny that people could do unusual things, like own a pet peacock, or immoral things, like stealing or lying. These possibility denials are surprising. For instance, children have first-hand experience with the very moral violations they say are impossible. In two experiments (total N = 220), we provide evidence that children's possibility denials can nonetheless be taken at face value and do not merely arise from quirks in how children understand questions about possibility. We do this by showing that these denials also arise in children's judgments of actuality-their judgments about what has actually happened and about which assertions of actual events could be true. In Experiment 1, children aged 4-7 judged whether ordinary, immoral, and improbable events could happen or had ever happened. With both judgments, children mostly responded affirmatively to ordinary events, often responded negatively for immoral events, and mostly responded negatively to improbable ones. In Experiment 2, children aged 5-7 judged if assertions of the three kinds of events could be true, and the same pattern emerged again. Together, these findings show that children's denials of immoral and conceptually improbable events extend beyond their judgments about what is possible and match their inferences about what is actual. These correspondences across judgments suggest that children drew on a single procedure, or set of procedures, for assessing possibility. SUMMARY: We show that children judge unexpected events as both impossible and nonactual. Four- to seven-year-olds judged if events could happen, if events had ever happened, and if assertions about events could be true. For all judgments, children often responded negatively to immoral events, and mostly responded negatively to conceptually improbable ones. Children's possibility denials can be taken at face value, and do not reflect quirks in how they respond to questions about possibility.
Understanding broadly neutralizing antibody (bnAb) lineage development in rhesus macaques (RMs) infected with simian-human immunodeficiency virus (SHIV) may inform HIV-1 vaccine designs. We analyzed HIV-1 envelope (Env)-antibody coevolution in 18 RMs infected with SHIV.BG505 (subtype A) and found conserved patterns of antibody recognition and Env escape, including in three animals that developed V3-glycan-reactive bnAbs. From one RM with V3-glycan-targeted plasma Abs that neutralized heterologous HIV-1 strains, we isolated 203 members of a single clonal antibody lineage designated DH1030. DH1030 antibodies demonstrated genetic, functional, and structural similarities with the human V3-glycan bnAb lineage DH270, which was isolated from an individual with subtype C HIV-1 CH848 infection. Human-DH270 and macaque-DH1030 bnAbs shared early improbable mutations in the heavy chain complementarity determining region 2 that were critical for bnAb development. These convergent patterns of antibody evolution, accumulation of key improbable mutations, and mode of epitope recognition were shared across primate species and distinct HIV-1 subtypes, findings that may be leveraged in HIV-1 vaccine designs. Furthermore, our data highlight the value of SHIV-infected macaques as an outbred model system to explore conserved molecular pathways of bnAb development after infection and vaccination.
Harmonic expectation is an important mediator of musical experience. EEG research has identified event-related potential (ERP) components associated with expectation, including the early (right) anterior negativity (E(R)AN), which is theorized to index harmonic surprisal with reference to long-term memory of the statistical structure of music. However, the role of top-down influences on harmonic predictions remains underexplored. One specific influence concerns how a given harmony can be interpreted in different ways, depending on its syntactic role in a musical context. We present data from a novel paradigm that cues listeners to the syntactic structure of the stimuli (but not whether they contain improbable events). Our main result revealed larger E(R)AN amplitudes for improbable chords when listeners knew that additional context would follow a surprising harmony; P3a and P600 amplitudes were also larger in such cases. Using the theoretical framework of predictive coding, we propose that, in such cases, listeners assign higher precision to their predictions, leading to larger prediction errors as indexed by the E(R)AN, P3a, and P600 ERP components, and that prior context alone does not fully explain how unpredictable events are processed. Musical surprisal arises from a dynamic interplay between bottom-up cues and a listener's top-down anticipation within specific syntactic contexts.
Understanding broadly neutralizing antibody (bnAb) lineage development in rhesus macaques (RMs) infected with Simian-HIV (SHIV) may inform HIV-1 vaccine designs. We analyzed HIV-1 envelope-antibody coevolution in 18 RMs infected by SHIV.BG505 (subtype A) and found highly conserved patterns of antibody recognition and Env escape, including in three animals that developed V3-glycan bnAbs. From one RM with V3-glycan targeted plasma breadth, we isolated 203 members of a single clonal Ab lineage designated DH1030. DH1030 Abs demonstrated striking genetic, functional and structural similarities with the human V3-glycan bnAb lineage DH270, which was isolated from an individual with subtype C HIV-1 CH848 infection. Notably, human-DH270 and macaque-DH1030 bnAbs shared early improbable mutations in HCDR2 that were critical for bnAb development. Thus, key improbable mutations and convergent patterns of antibody evolution and epitope recognition were shared across primate species and distinct HIV-1 subtypes, findings that may be leveraged in new HIV-1 vaccine designs. Broadly neutralizing antibodies targeting HIV-1 envelope surface protein develop via a common maturation pathway across primate phylogeny.
In-depth qualitative studies concerning exceptionally gifted mediums are very useful for investigating the occurrence of anomalous information reception, however, there is a dearth of studies with recorded evidence. To investigate the occurrence of anomalous information reception in a recorded session with Chico Xavier, one of the 20th century's leading mediums. Analysis of a 54-minute recording containing the reading of a mediumistic letter, two poems attributed to deceased Portuguese poets, and a dialogue in which Chico Xavier describes 18 deceased personalities. Following the identification of the verifiable information, an exhaustive investigation was carried out to assess the accuracy of the items of information and the likelihood of the medium having had prior access thereto. For the poems, a linguistic-literary, comparative analysis examined convergences and divergences of metre, style and themes between the alleged mediumistic texts and the original works of the authors. The poems analysed show features consistent with the claimed authorship, substantiating this attribution based on textual and comparative criteria. A total of 30 people were identified, with 65 verifiable items of information produced, of which 87.7% were classified as "Correct" and 30.8% as "Highly Improbable" or "Improbable" to have been accessed through conventional means. Conventional explanations are unlikely or highly unlikely for a considerable proportion of the items, particularly those related to Isabel Ramos. Her case is conspicuous, not only for its high degree of accuracy but also for having arisen spontaneously and for being someone who was unknown to the participants, characterising a drop-in case. Considering the complementary, diverse and highly assertive nature of the communications, the survival hypothesis offers the simplest and most parsimonious explanation for what occurred in this meeting.
Humans comprehend language rapidly, with active prediction of upcoming words as a key mechanism. Studies using sentences have documented facilitations in behavior and brain activity (N400) when people encounter predictable words, and brain responses (anterior positivity) specific to prediction violations. However, it has been challenging to investigate prediction formation mechanisms, given the complex, incremental context provided by sentences. Here, we examined prediction by measuring EEG in a simple word stem completion task. Participants saw three initial letters (e.g., bro___) varying in constraint/entropy of possible completions and were asked to generate a word completion. They then saw a target that was either a probable completion (brother), an improbable completion (bronze), or a pseudoword (*brom). In Experiment 1, participants self-reported whether the target matched their prediction; in Experiment 2 they made a lexical decision to the target and then typed in their prediction. Consistent with findings from sentences, N400s were reduced for probable completions, primarily driven by a greater proportion of match responses with highly facilitated N400 amplitudes. No anterior positivity was found to improbable words in Experiment 1, but it was present in Experiment 2. Given these task differences, the anterior positivity may therefore reflect engagement of processes to manage activation of lexico-semantic information when there is competition, as from a strong prediction. Crucially, neural responses following the word stem (i.e., during prediction formation) showed a sustained centro-posterior positivity that was graded with entropy (more negative for high-entropy stems). This effect reveals that prediction-formation processes are sensitive to the distribution of possible completions based on the context.
Invasive marine crustaceans present ecological and socio-economic challenges, particularly where high fecundity, behavioural plasticity, and environmental tolerance limit the effectiveness of conventional control measures. The Atlantic blue crab, Callinectes sapidus, has expanded across the Mediterranean, where it exerts strong predatory pressure on native species and aquaculture resources, yet management efforts rely largely on traditional baited trapping. Drawing on extensive evidence from the global management of the European green crab, Carcinus maenas, we evaluate why conventional trapping has failed to achieve sustained population suppression in invasive brachyuran crabs. We synthesise lessons from green crab control to identify common biological and operational constraints, including rapid compensatory population responses, bycatch, and limited behavioural selectivity. We then examine the potential of semiochemical-based strategies-incorporating olfactory cues-within an integrated pest management (IPM) framework. Semiochemical-enhanced approaches offer the capacity to directly exploit species-specific sensory ecology, improve trap selectivity, and reduce non-target impacts, addressing fundamental limitations of existing methods. We argue that prioritising such IPM, rather than further optimisation of traditional trapping alone, represents the most realistic pathway for long-term mitigation of C. sapidus in the Mediterranean. While eradication remains improbable, strategically deployed semiochemical-based control could substantially enhance suppression efficiency and inform broader invasive species management.
Evolution is often understood through genetic mutations driving changes in an organism's fitness, but there is potential to extend this understanding beyond the genetics. We propose that natural products─complex molecules central to Earth's biochemistry─can be used to uncover evolutionary mechanisms beyond genes. By applying assembly theory (AT), which views selection as a process not limited to biological systems, we can map and measure evolutionary forces in these molecules. AT enables the exploration of the assembly space of natural products, demonstrating how the principles of evolution apply to these complex chemical structures, selecting vastly improbable and complex molecules from a vast space of possibilities. By comparing natural products with a broader molecular database, we can assess the degree of evolutionary contingency, providing insight into how molecular novelty emerges and persists. This approach not only quantifies evolutionary selection at the molecular level but also offers a new avenue for drug discovery by exploring the molecular assembly spaces of natural products. Our method provides a fresh perspective on measuring the evolutionary processes both shaping and being read out by the molecular imprint of selection.
Epilepsy may cause sudden death. More scenarios are possible: sudden unexpected death in epilepsy (SUDEP), cardiac and non-cardiac mechanisms of death. This study presents the case history of a 57-year-old person known for epilepsy who experienced a final tonic-clonic seizures with ictal cardiorespiratory arrest shortly after hospital admission. The present study aimed to determine 1) the cause of death and possible mechanisms; and 2) reference values for immunoassays at 36.8-hour postmortem interval. A full medico-legal autopsy was performed. Postmortem findings and a large panel of investigations are provided: anatomic pathology, pericardial chemistry investigations, forensic serology and toxicology. Immunoassays including sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) with Western blotting for vinculin and enzyme-linked immunosorbent for cardiac TnT, vinculin and desmin were used to assess the postmortem interval. Cause of death, mechanisms and medico-legal causality are debated. Autopsy findings and relevant investigations did not reveal a single identifiable cause of death incompatible with life. Even more, SUDEP appears improbable and status epilepticus not documented. An ictogenic cause of death with autogenous and cardiac mechanisms involvement, enhanced by concomitant conditioning factors, a severe metabolic acidosis, respiratory failure with impaired ventilation and extensive myocardial fibrosis appears more probable. SDS-PAGE with Western Blot was able to detect the native molecular band 117 kD of vinculin and three molecular products of degradation at 90 kD, 87 kD, 84 kD at 36,8-hour postmortem interval and therefore confirmed the postmortem interval, while ELISA detected cardiac TnT (178.85 pg/mL), vinculin (570.96 pg/mL) and desmin (565.77 pg/mL) in the skeletal muscle. This case highlights the important role played by medico-legal autopsy in death investigation in epilepsy. If for legal purpose causality is required, causes of death and conditioning factors are to be extensively investigated and connected. ELISA delivered benchmarks references at 36.8-hour postmortem interval and provided to be a valuable immunoassay method in estimation of postmortem interval.
This study employed the magnetic field-mediated/gum arabic to prepare low-salt myofibrillar protein (MP) gel and simulated the oral processing of interactions between MP and mucin on the perception of saltiness. The results indicated that the amalgamation of magnetic fields and gum arabic effectively promoted the release of sodium ions, enhanced the apparent viscosity of MP, and increased its binding affinity with mucin. Consequently, this resulted in the prolongation in the retention time of MP on the tongue surface and ultimately improved the perception of saltiness. Besides, spontaneous endothermic interactions occurred between MP and mucin, which primarily dominated by hydrophobic interactions that induced changes in the structure of MP, such as the occurrence of disulfide bonds. However, it was improbable that there would be direct bonds between mucin and MP. In summary, magnetic field-mediated/gum arabic promoted sodium ions to interact with taste receptors to generate stronger salty taste signals.
Numerous unidentified white blobs were discovered along Ship Cove Beach, Newfoundland, Canada, in September 2024. Fueled by national and international media coverage and public speculation, this incident raised concerns about potential health, safety, and environmental impacts. A comprehensive forensic analysis was conducted using physicochemical characterization, spectroscopy, mass spectrometry, and elemental analysis to determine the composition, nature, and possible origin of the material. The chemical fingerprinting results indicate the following: (1) the sample is unlikely to be petroleum-derived or contaminated by petroleum products; (2) biodiesel is improbable due to the absence of significant fatty acid methyl esters; (3) the material does not appear to be silicone-based or chlorinated (e.g., silicone sealants or chlorinated vinyl compounds); (4) the presence of aldehydes, fatty acids, and plant-derived sterols-coupled with the absence of cholesterol-suggests a plant oil-based origin; (5) high molecular weight compounds and thermal transformation behavior point to the presence of polymeric materials; and (6) the substance is neither flammable, combustible, corrosive, oxidizing, nor radioactive. These findings contribute to understanding the nature of the spill and highlight the utility of multidisciplinary forensic approaches in environmental incident response.
Current assessments of brain permeability rely predominantly on drug delivery to contrast-enhancing tumor regions. However, substantial portions of central nervous system (CNS) tumors reside within non-enhancing brain (NEB), where drug concentrations frequently remain subtherapeutic. This collaborative Adult Brain Tumor Consortium and Food and Drug Administration workshop aimed to identify criteria for defining NEB permeability to accomplish 2 critical objectives: (1) allocate clinical trial resources toward agents achieving therapeutic NEB concentrations and (2) minimize systemic toxicity when CNS benefit is improbable. The workshop systematically evaluated permeability assessment modalities, including drug physicochemical properties, in vitro blood-brain barrier models, and penetration into cerebrospinal fluid and normal rodent brain. Methodological approaches to determine requisite NEB drug concentrations and approaches to measuring NEB pharmacokinetics and pharmacodynamics were examined. This culminated in developing the Non-Enhancing Brain Permeability Index (NEBPI), which assigns therapeutic agents to 3 categories: sufficiently permeable, insufficiently permeable, or impermeable. The NEBPI provides a standardized framework to assist investigators and regulatory agencies to evaluate NEB penetration before human efficacy studies are initiated for agents that require direct tumor contact. Assessing NEB drug penetration is critical to improving outcomes in CNS tumors and reducing the incidence of brain metastases in systemic malignancies.
AP-1 transcription factors are a network of cellular regulators that combine in different dimer pairs to control a range of pathways involved in differentiation, growth, and cell death. They dimerize via leucine zipper coiled-coil domains that are preceded by a basic DNA binding domain. Depending on which AP-1 transcription factors dimerize, different DNA sequences will be recognized resulting in differential gene expression. The affinity of AP-1 transcription factors for each other dictates which dimers form. The relative concentration of AP-1 transcription factors varies with tissue type and environment, adding another layer of control to this integral network of cellular regulation. The development of artificial intelligence (AI)-based protein structure prediction methods gives us a new technique to investigate or predict how dimerization affects combinatorial control. All versions of AlphaFold2 and AlphaFold3 are AI/deep learning programs that predict 3D structures of proteins from an amino acid sequence and multiple sequence alignments of homologous proteins. To fully realize the potential of AI for structural biology, it is essential to understand its current capabilities and limitations. In this study, we used the classical example of an AP-1 dimer: Fos and Jun, and an array of over 2000 experimentally tested human leucine zippers to interrogate how AlphaFold models leucine zipper domains and if AlphaFold can be used to differentiate between probable and improbable dimer interfaces. We found that AlphaFold predicts highly confident leucine zipper dimers, even for dimer pairs such as the FosB homodimer, for which electrostatics are known to prevent their formation in vivo. This is an important case study concerning high-confidence but low-accuracy protein structure prediction.