Biology and Life Sciences

Abstract: Exercise affects psychological, neural, immune, and hormonal processes, but evidence linking these responses to health varies across domains. This critical narrative review synthesizes evidence from human intervention studies, recent meta-analytic syntheses and selected mechanistic experiments identified through structured literature searches conducted up to 25 October 2026. Psychological trials support benefits for depressive symptoms and sleep in certain populations, although uncertainty remains regarding comparators, durability, and treatment components. Neural studies show some structural and functional change, although pooled effects on hippocampal volume are small, and circulating neurotrophic factors do not reliably indicate their cerebral origin or cognitive benefit. Immune experiments support cytokine signaling and leukocyte redistribution, with qualified evidence for vaccine and respiratory-illness responses. Hormonal studies show that acute cortisol responses and longer-term stress regulation depend on protocol, sampling time, and participant context, with selective rather than generalized training effects. Across domains, clinical improvement, physiological responsiveness, and causal mediation are distinct findings. We integrate these findings within a response and recovery framework that specifies domain-specific measures, temporal sequence, competing explanations, and conditions that would weaken a proposed mechanism. Domain-specific health benefits must be interpreted relative to the population studied and the comparator. Coordinated longitudinal studies are needed before psychological, neural, immune, or hormonal measures can inform individualized exercise prescription.

Abstract: Ubiquitin-pathway enzymes and chromatin-associated co-regulators set the half-life, activity and processing of a large fraction of the regulatory proteome, yet few small molecules are known to alter their transcription in primary human cells. Here the response of four such genes to Metadichol, a nanoemulsion of long-chain policosanol alcohols, was measured in human peripheral blood mononuclear cells by quantitative real-time PCR across five concentrations spanning six orders of magnitude. All four genes responded. At 1 pg/mL every gene was significantly induced, with PPIL4 reaching 7.39-fold, UBE3A 6.57-fold, USP7 5.65-fold and BCOR 4.93-fold. The concentration–response was strongly non-monotonic: induction peaked at 1 pg/mL and declined at nanogram concentrations, where the BCOR and PPIL4 responses were no longer significant. At the lowest concentration tested, 0.1 pg/mL, the genes separated into two opposing groups, with BCOR and PPIL4 up-regulated while UBE3A and USP7 were suppressed to 0.42- and 0.62-fold. Pairwise correlation across the dose series resolved the same two groupings quantitatively: UBE3A with USP7 and BCOR with PPIL4. USP7 was the only gene significantly changed at every concentration tested. Because USP7 and UBE3A encode a deubiquitinase and an E3 ligase whose reported substrates include sirtuins, MYC, steroid receptors, clock proteins and NF-κB subunits, a transcript-level change in these two genes offers a route by which a single upstream event could propagate across many downstream proteins. The findings are transcript-level and do not establish changes in protein abundance or enzymatic activity, which remain to be tested.

Abstract: Transferrin, an iron-transporting human serum protein, has recently emerged as a versatile carrier for drug delivery to tumors or for transport across the blood-brain barrier. Conjugating hTf-binding peptides to therapeutic agents is a promising strategy for targeted drug delivery. Therefore, we screened high-affinity human serum transferrin (hTf)-binding peptides using phage display technology to identify candidate binders, established quantitative criteria for bio-panning assessment and binding-affinity constants from experimentally quantified phage titers rather than clonal sequencing to support objective evaluation, and used structural bioinformatics docking approaches to characterize the molecular interactions between the phage display-derived dodecapeptides and transferrin. These methods linked screening, quantification, and docking to candidate identification and interaction characterization, enabling identification of hTf-binding peptides as a robust platform for transferrin receptor-mediated targeted drug design and clinical translation of targeted therapeutics.

Abstract: Background. Hyperbolic embedding of Hi-C matrices into a Poincaré disc recovers the full TAD hierarchy from a single embedding. Two questions remain open: whether the hierarchy is method-independent, and whether the radial coordinate acquires new biological meaning upon neoplastic transformation.Results. Using the isogenic MCF10A/MCF7 pair at 40 kb (chr17, chr1, chr19), we show that (i) the Poincaré hierarchy is stable across lines and chromosomes (loss 1.4–2.9; six levels; ~16.7% of loci per level); (ii) concordance with an independent tree-based method (OnTAD) is level- and line-dependent: negligible for small TADs in MCF10A (ARI = 0.001, within noise) but detectable in MCF7 (ARI = 0.022, 16 SD above chance), and consistently detectable for large TADs (ARI = 0.047 for Lv.5–6, 36–48 SD above chance); (iii) mean TAD size increases monotonically from Lv.1 to Lv.6 (Spearman ρ = +0.39 to +0.70), quantitatively confirming scale encoding; (iv) boundaries are partially conserved between MCF10A and MCF7 (Jaccard 0.20–0.59), with reorganization concentrated at the largest domains; and (v) in MCF7 the radial coordinate correlates with the A/B compartment eigenvector (ρ = −0.43 chr17, −0.41 chr1), a coupling that is weak or unstable in MCF10A; (vi) a dimensionless hierarchy-shift metric—the median radius difference Δ r̃—is positive on all three chromosomes (chr17 +0.020, chr1 +0.013, chr19 +0.047, all p < 0.001 by permutation test) and is reproduced at the gene level (ΔTH_gene > 0, all p < 0.05), indicating a redistribution of the hierarchy toward the periphery rather than a simple expansion of large domains.Conclusions. The Poincaré hierarchy is scale-encoding and shows scale- and line-dependent concordance with an independent method, and it acquires a compartmental signature in the transformed state. These results extend the Poincaré framework toward comparative, method-agnostic analysis of 3D chromatin organization.

Abstract: Genetic evaluation of therapeutic targets can clarify disease-pathway relevance and developmental compatibility in inflammatory bowel disease (IBD). We performed two-sample drug-target Mendelian randomization using cis-pQTL instruments for IL12B and ITGB7, evaluating IBD, Crohn disease, ulcerative colitis, and childhood total-body bone mineral density (BMD), with pediatric total-body-less-head BMD replication. Four IL12B and two ITGB7 instruments were retained. Higher genetically proxied IL12B abundance was associated with IBD (OR, 1.341; 95% CI, 1.280–1.405), Crohn disease (OR, 1.357; 95% CI, 1.278–1.441), and ulcerative colitis (OR, 1.339; 95% CI, 1.262–1.420), whereas ITGB7 showed no convincing disease association. Neither target showed convincing evidence of a major effect on childhood BMD; replication was inconclusive, with lower precision for ITGB7. Primary colocalization showed no supportive evidence of a shared causal signal; IL12B–IBD strongly favored distinct signals (H3 = 0.999995; H4 = 5.07 × 10⁻⁶). Exploratory fine-mapping suggested possible sharing with a secondary IBD component, but this finding was prior-sensitive and limited by LD-reference reliability. Bayesian analyses were compatible with small IL12B BMD effects, whereas ITGB7 remained less precise. Overall, these findings support IL12B-related pathway relevance while informing developmental compatibility rather than drug efficacy or clinical safety.

Abstract: Ischemic stroke rapidly disrupts neuronal and synaptic integrity through excitotoxicity, oxidative stress, and inflammation, yet no effective neuroprotective therapy exists. Remote ischemic conditioning (RIC) is linked to systemic protective responses, but the molecular mechanisms by which circulating blood cells (BCs) contribute to RIC-mediated neuroprotection remain poorly understood. To address this gap, we examined whether RIC is associated with changes in BC properties and whether these changes correspond to alterations in the composition and function of their secretome. RIC-treated donor BCs exhibited biochemical features consistent with reduced hemo-lysis, maintained stable glutathione levels during incubation, and showed increased catalase activity, suggesting improved redox resilience. Secretomes from RIC-treated BCs showed elevated levels of the exosome-associated tetraspanin markers CD9 and CD81. Quantitative proteomics identified 680 proteins, of which 40 were differentially abundant (DAPs) between tolerant (TS) and non-tolerant secretomes (NTS). Most DAPs were downregulated in TS. GO enrichment analysis did not identify any significantly enriched terms after FDR correction. Because no GO term passed multiple testing cor-rection, GO results were not interpreted further. Functionally, TS treatment reduced infarct volume from 62.5% to 41.6%, improved neurological scores, and significantly decreased neuronal pyknosis, degeneration, and loss in the penumbra. TS also improved systemic redox balance, lowering oxidized glutathione, reducing the oxidative stress index from 3.5% to 1.9%, and diminishing the oxidative burden, as reflected in lymphocyte DNA damage, to near-control levels. Together, these findings indicate that TS derived from RIC treated donors exhibits neuroprotective potential in an experimental stroke model and is associated with dis-tinct proteomic signatures. The results are exploratory and do not establish a definitive mechanism or therapeutic readiness.

Abstract: Immunohistochemistry preserves the spatial relationship between molecular signals and tissue architecture, but its biological interpretation is less straightforward than its visual appearance suggests. Antibody binding in a fixed section establishes neither the accessibility of an epitope in living tissue nor the functional activity of the recognised protein. Membrane localisation, nuclear retention, staining intensity and cellular distribution are distinct measurements, each supporting different conclusions. Gastric adenocarcinoma provides an informative example because several clinically validated assays interrogate these properties within the same specimen. This critical narrative review examines the effects of fixation and antigen retrieval, membrane organisation and protein trafficking, cellular attribution, quantitative signal generation and spatial sampling on the interpretation of immunohistochemical findings. Building on established methodological literature, it proposes a measurement-to-claim framework that identifies the evidentiary gap between a histochemical observation and the biological conclusion drawn from it. The framework is intended neither as a new diagnostic score nor as an alternative to validated clinical thresholds. Its proposed contribution is to match specific interpretative uncertainties to complementary methods capable of addressing them. Applications extend beyond gastric pathology to receptor biology, developmental histology, neuroscience and quantitative tissue imaging. Its practical value remains to be tested experimentally. The central argument is that a reproducible stain becomes biologically informative only when the conclusion attributed to it is proportionate to the measurement performed.

Abstract: The essay critically analyzes the role of physical and functional contacts between lipid droplets and mitochondria (MLCs) in maintaining cellular lipid and redox homeostasis and in the pathogenesis of metabolic and neurodegenerative diseases. The molecular architecture of MLCs, including the involvement of PLIN5, Mfn2, FATP4, Rab8a, SNAP23, CIDE proteins, and seipin, as well as the mechanisms of fatty acid transport into mitochondria for β-oxidation, are reviewed. Based on data from cellular and animal models, it has been shown that dysregulation of MLCs accompanies obesity, type 2 diabetes, MASLD, cardiovascular, and neurodegenerative disorders. The central thesis is that MLC disruption is not only a marker of lipotoxicity, but also a causally significant early driver of metabolic dysfunction; accordingly, stabilization or restoration of these contacts may be a promising therapeutic strategy. At the same time, the counterargument about the adaptive nature of MLC and the tissue specificity of their regulation is critically reviewed. The need for clinical validation of MLC modulators, improvement of contact imaging methods, and longitudinal studies to establish cause-and-effect relationships is emphasized.

Abstract: Many Pseudomonas species produce pyoverdines, fluorescent siderophores that comprise a conserved dihydroxyquinoline chromophore, a strain-specific peptide chain, and a small acyl side chain. Their exceptional affinity for Fe(III), and the more-recent discovery that they also bind some other metals, has prompted diverse biotechnological applications. These applications span iron biofertilisation and biocontrol, bioremediation and metal scavenging, infection imaging, Trojan horse antibiotic delivery, direct antibacterial activity, and tumour targeting. To support these and other applications, we establish a robust catalogue of structurally distinct pyoverdines, consolidating published lists with manual literature searches and resolving duplicate and conflicting structural assignments. We identify 83 pyoverdines with discrete peptide chains, ranging from 6 to 14 residues (median 8), together with five chromophore variants and six acyl side chains. Each peptide contains two oxidatively modified iron-binding residues, most often ornithine-derived hydroxamates, although 26.3% are threo-hydroxylated amino acids. Peptide composition is strongly biased towards small and polar residues, with just a few amino acid families accounting for an overwhelming majority of residues, and with L-stereochemistry slightly favoured (60.8%). We conclude that pyoverdines are tightly constrained in chelation chemistry yet highly plastic in recognition, and hope that our catalogue will provide a useful parts list for engineering tailored products.

Abstract: Survivin (BIRC5), a core component of the chromosomal passenger complex (CPC), is essential for faithful mitosis and frequently overexpressed in human cancers. Despite extensive investigation of its mitotic and cell survival functions, its relationship with cellular senescence remains poorly understood. We investigated Survivin in therapy- and stress-induced senescence models and examined the consequences of transient Survivin depletion by RNA interference. Camptothecin treatment of HCT116 wt and A549 cells and oxidative stress in WI-38 fibroblasts induced characteristic morphological changes, increased senescence-associated β-galactosidase activity and reduced DNA synthesis. In HCT116 wt and A549 cells, senescence induction was accompanied by changes in cell-cycle regulatory proteins and altered immunofluorescence patterns of cell-cycle and chromatin-associated proteins. Survivin-targeting siRNA promoted pronounced senescence-associated morphological changes and increased β-galactosidase activity in HCT116 wt cells, whereas A549 cells exhibited a less pronounced response. These phenotypic differences were accompanied by changes in p53, p21 and CDK1 protein levels during the observation period. However, transient Survivin depletion does not establish whether the observed changes represent stable or irreversible senescence. Together, our findings support a cell-context-dependent association between Survivin perturbation and senescence-associated phenotypes, extending its biological significance beyond mitosis and highlighting cellular senescence as a potential outcome relevant to Survivin-targeted anticancer strategies.

Abstract: Ex vivo expansion is needed to produce human myogenic cell products, but culture can alter the molecular states that govern engraftment and regeneration. This critical narrative review reappraised 28 primary reports of tissue-derived human myogenic cells, yielding 39 question-specific records. We separated production yield, administered dose, donor persistence, human fiber contribution, later regenerative activity, and recipient function. In documented adult donor sources, transient p38 mitogen-activated protein kinase inhibition and extracellular matrix culture increased histological graft output at matched final doses. SETD7 inhibition increased cell production and postgraft reporter signal, although the administered human dose was unreported. Brief Notch-ligand exposure changed myogenic markers without a detected gain in human fiber output. Population selection, senolytic removal, delivery geometry, and recipient support also altered selected outcomes. Expanded preparations retained later graft activity in some studies, but durable adult-source functional recovery remained insufficiently tested. The evidence supports a product-level framework that links molecular state to defined graft endpoints while evaluating dose, spatial delivery, host context, and indication-specific function separately.

Abstract: Analytical standardization of Brucella molecular assays requires reference materials with assigned values and defined uncertainty. We produced and characterized intralaboratory a candidate genomic DNA reference material from Brucella abortus RB51 for PCR-based detection of Brucella spp., and evaluated its preliminary use in fluorescence-based and colorimetric LAMP assays. DNA was extracted, assessed by qPCR and dPCR, and diluted to two levels. Homogeneity and stability were evaluated by duplex qPCR targeting ctrA and nikR, whereas property values were assigned by duplex dPCR. qPCR efficiencies were 95.3% for ctrA and 92.1% for nikR. The material fulfilled the homogeneity criterion, with relative homogeneity uncertainties between 0.37% and 1.41%. Assigned values (levels 1 and 2) were 32 989 ± 5 475 and 285 ± 47 copies/µL for ctrA, and 29 722 ± 3 263 and 286 ± 42 copies/µL for nikR. Short-term stability at 4 °C was supported for 8 weeks and was included in the uncertainty budget. ctrA-based LAMP assays were optimized at 67 °C for 45 min and amplified reproducibly in both formats. Amplification was consistent from 2411 to 6.34 copies/µL. This material provides a metrologically characterized tool for quality control, method verification, and optimization of PCR- and LAMP-based assays for Brucella spp.

Abstract: Background/Objectives: DNA methylation episignatures can inform variant interpretation, but the strength of evidence provided by a negative result depends on sensitivity and its uncertainty. We examined how published cohort sizes and independent performance data constrain benign evidence strength. Methods: We calculated sample-size ceilings for 57 episignatures under perfect observed sensitivity and assumed specificity. We reanalysed published classifier calls for 14 signatures using conservative likelihood-ratio bounds and mapped these to Bayesian ACMG/AMP evidence bands. Clinical relevance was assessed in a published referral cohort after excluding replicate records. Results: The sample-size ceilings were strong for three signatures, moderate for 22, supporting for 24 and below supporting for eight. In the independent dataset, nine signatures reached supporting benign strength and five fell below it; none reached moderate. Positive results reached strong pathogenic strength for six signatures. Of 2,399 primary clinical records, 713 had a negative result reported with high confidence and a recorded sequence variant. Among 712 records with parseable gene lists, 460 (64.6%) involved no gene represented in the analysed groups. The performance estimates concern independently implemented classifiers and cannot be transferred directly to a clinical platform. Conclusions: Negative episignature results require calibration for the relevant classifier and patient group. Reports should state the validation population, uncertainty and limits of applicability, and distinguish an uninformative result from one that supplies supporting benign evidence.

Abstract: Background/Objective. Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most prevalent chronic liver condition often linked to metabolic disor-ders such as obesity, type 2 diabetes, and dyslipidemia. MASLD can progress to more severe conditions like metabolic dysfunction-associated steatohepatitis, cirrhosis, and hepatocellular carcinoma. While lifestyle changes are currently the main therapeutic strategy, emerging evidence suggests that dietary micronutrients, such as vitamin B6 (VB6), could play an important role in the development and progression of MASLD through their involvement in one-carbon (1C) metabolism. Methods: This study inves-tigated the impact of dietary VB6 levels on the progression of MASLD using a modified high-fat diet (HFD)-induced mouse model. Thirty-two male C57BL/6J mice were ran-domly assigned to either an AIN-93G-based control diet or an HFD containing varying levels of dietary VB6 for eight weeks. At the end of the dietary intervention, physical parameters, clinical markers, hepatic and fecal metabolites, and gut morphology were evaluated. Results: Our findings demonstrated that dietary VB6 deficiency significantly affected hepatic B6 levels, lipid accumulation, and key metabolites involved in the 1C metabolic pathway. Notably, HFD-fed animals receiving low VB6 levels exhibited re-duced plasma triglyceride levels, increased hepatic triglyceride content, and alterations in homocysteine and glycine levels, suggesting disruptions in both lipid and 1C metab-olism. Interestingly, fecal glycerol and 3-hydroxyisovalerate levels were elevated in HFD-fed groups compared with those in the control group. Conclusions: These findings suggest that dietary VB6 plays a crucial role in regulating MASLD progression, particu-larly in the context of diet-induced MASLD, providing insights into potential dietary interventions for disease management.

Abstract: Background: Expression quantitative trait loci (eQTLs) carry a disproportionate share of autoimmune disease heritability, yet whether genetic regulation differs across inflammatory diseases within one cell type is unknown. Cross-disease comparison of monocyte eQTLs has not been performed with harmonized processing and power-calibrated specificity, and the ten-fold range of cohort sample sizes makes naive comparisons vulnerable to false specificity.Methods: We harmonized monocyte cis-eQTL summary statistics from five public resources spanning healthy, lupus-enriched, influenza-stimulated, and inflammatory bowel disease contexts; quantified power and false specificity by simulation; and decomposed effect sharing with multivariate adaptive shrinkage (mashR) and a variance-based specificity index.Results: In simulation, naive per-condition significance calls misclassify 72.6% of truly shared eQTLs as disease-specific; cross-condition borrowing reduces this to 13.0%, and a high-confidence specificity criterion to 0.005%. A three-condition pilot run (1,671,712 gene–variant pairs) passed all quality-control gates, and the full-scale seven-condition run (3,277,117 pairs) confirmed the patterns at scale across the healthy, SLE-cohort, and influenza axes: data-driven covariance structures dominated the fitted mixture (combined weight 0.9471), 2,737,644 pairs (83.5% of the strong set) remained significant under the joint model, and 16.87% of pairs were high-confidence specific under the tested-mask-aware criterion (16.90% after adjudication-layer MHC exclusion), within the pre-registered 20% ceiling under both configurations and in all 18 cells of the adjudication sensitivity grid, with MHC-region and 17q21.31 genes top-ranked. Magnitude sharing was highest within studies (within-study mean 0.859 versus cross-study mean 0.345; Randolph non-infected versus influenza-exposed 0.953, Perez classical versus non-classical 0.899). Pre-registered arbitration diagnostics (PCA and hierarchical clustering of the posterior mean matrix) grouped conditions by study of origin rather than by health-versus-disease status; under the pre-registered scenario-C rule, cross-cohort disease-specificity claims therefore contract to within-study paired contrasts. In the paired Randolph cohort—the single design in which disease state is unconfounded with cohort—influenza exposure and infection left the monocyte eQTL landscape nearly intact: sign concordance between the non-infected and infected states was 99.7% among jointly significant pairs, magnitude sharing was 0.89–0.95, and effect amplitudes were attenuated with infection (median posterior-effect ratio, non-infected over infected, 1.31), while 71,107 pairs (2.2% of the strong set) were high-confidence specific to the influenza axis. Conclusions: This study establishes and validates a power-calibrated framework for cross-disease regulatory genetics at full scale. Because disease context is confounded with cohort, ancestry, and platform in the current design and the pre-registered discriminating diagnostics show study-of-origin grouping, cross-cohort disease-specificity claims contract to within-study paired contrasts under the pre-registered rule. Within the one paired disease-state design available, influenza exposure and infection produce graded amplitude modulation on an almost completely shared regulatory backbone rather than wholesale regulatory rewiring; whether healthy-reference maps systematically miss disease-context regulation beyond such amplitude effects cannot be decomposed from cohort effects here. Disease-stratified heritability partitioning and locus-level nomination are pre-registered and in progress.

Abstract: Extreme endurance exercise offers a field setting for characterizing urinary cellular responses across sexes. This prospective observational study examined paired baseline and immediate post-race urine from 16 women and 16 men completing a 150 km ultramarathon. Automated fluorescence flow-cytometric counts were assessed alongside physicochemical and reagent-strip outputs. Between-sex tests compared individual acute changes; post hoc Bonferroni adjustment retained the original eight-comparison family. Median erythrocyte changes were +1.70 cells/µL in women and +0.60 cells/µL in men, with a between-group distributional difference retained after adjustment (p = 0.032). Corresponding squamous-cell changes were +0.85 and +0.30 cells/µL; this nominal difference did not meet the adjusted threshold (p = 0.056). Leukocyte, bacterial, pH and specific-gravity changes showed no significant between-group contrast. Recorded protein, ketone and male-only 24 h observations provided descriptive context. The findings identify an endpoint-specific urinary phenotype, with the erythrocyte association providing the clearest statistical signal. They establish a focused empirical target for source-specific replication and mechanistic investigation; anatomical origin and clinical significance require additional assessment.

Abstract: RNA viruses often generate a defective RNA (D-RNA) species that has internal deletion(s) and recombined fragment(s), which are believed to occur during viral replication. Such subviral RNA fragments sometimes exert overt effects on their parental viral replication or pathogenicity and are called defective-interfering RNA (DI-RNA). This study reports a rare example in which a D-RNA acquired a novel function that determines the hypovirulent phenotype of the host fungus, Fusarium boothii Ep-BL13, a causal agent of Fusarium head blight. The parental Fusarium boothii large flexivirus 1 (FbLFV1) is a tymo-like virus with a 13 kb (+)ssRNA genome encoding a single large ORF, and the D-RNA has an approximately 10 kb internal deletion in the ORF with an in-frame connection. Partial virus curing revealed a clear association between viral infection (FbLFV1 + D-RNA) and inhibition of colony growth and the pathogenicity of the host F. boothii. These traits were further confirmed in a fungal strain expressing the D-RNA ORF, specifically under FbLFV1 infection. Moreover, FbLFV1 and D-RNA infection decreased the host fungal production of the mycotoxin deoxynivalenol. Overall, FbLFV1 produced a D-RNA in F. boothii in nature, which carries the rearranged gene (D-RNA ORF) with a virulence-determining function, representing a rare example of gain-of-function by a D-RNA.

Abstract: Origin-of-life research has largely focused on how the components of life arose and became integrated. Biological persistence, the continued existence of a living system actively maintained by the system itself, is assumed to follow once chemistry is sufficiently complex. We argue that persistence is a distinct explanandum and identify two conceptual obstacles that have kept it out of view. Molecular Darwinitis applies biological categories such as survival, fitness and selection to chemical systems before biological organization exists. The Category Jump treats extreme improbability as a substitute for mechanism, and Darwinian vocabulary, we argue, keeps this jump hidden. What remains is the Soft Problem of Life: how matter acquired conatus, the capacity to maintain and restore the conditions of its own existence. We propose that conatus emerged gradually from a measurable persistence bias, name its still-unidentified source aliqon, and argue that primitive restoration plausibly preceded replication. The framework yields testable predictions and suggests a shift in emphasis: from asking only how life’s components arose to asking how chemistry became persistent.

Abstract: Molecular sequencing has refined lymphoma classification while exposing a fundamental interpretative limitation: a mutation detected in lymphoid tissue cannot necessarily be attributed to the malignant clone. Clonal haematopoiesis may contribute genetically altered infiltrating cells, establish ancestral mutations shared by malignant and non-malignant lineages, or coexist independently with lymphoma. These relationships create two opposing attribution errors: assigning a non-malignant variant to the lymphoma and excluding a genuinely ancestral lymphoma-associated alteration because it is also detectable in blood. Recent investigations substantiate both biological possibilities, although their prevalence and diagnostic consequences in routine practice remain uncertain. This critical narrative review examines the evidentiary boundaries separating variant detection, cellular localisation, clonal ancestry, pathogenic involvement and clinical utility. Particular attention is given to compartment-resolved sequencing, molecular clonality, precursor-like lymphoid proliferations and emerging prognostic associations. A claim-specific framework of evidentiary sufficiency is proposed to distinguish conclusions supported by existing methods from those requiring further validation, with additional investigation reserved for potentially consequential diagnostic uncertainty. The central contention is that detecting an alteration establishes its presence, whereas attributing it to lymphoma requires independent evidence of cellular ownership and biological significance.

Abstract: Body-weight-supported locomotor training has been studied for three decades, yet its clinical outcomes remain inconsistent. The standard interpretation of this inconsistency is that the right dosage, timing, or patient subgroup has not been found. We propose a different reading: the inconsistency may reflect a conceptual underspecification in how loading is understood. Two interpretations of body-weight support coexist in the literature—loading as task difficulty (unloading makes the task easier) and loading as control strategy (unloading changes which neural circuits can participate in the solution). These two interpretations generate different predictions, imply different training protocols, and have rarely been distinguished empirically. We review evidence from spinal reflex physiology, body-weight-supported treadmill training trials, and developmental motor control, and argue that the strategy interpretation is better supported but has not been directly tested against the difficulty interpretation. Three testable predictions are offered that could distinguish the two. The framework has direct implications for the sequencing of load in rehabilitation and for the interpretation of load-dependent training failure.