Biology and Life Sciences

Abstract: Clinical hypnosis can relieve pain and anxiety, yet its cerebral and systemic physiological mechanisms remain unclear. Portable optical imaging offers a means to investigate both, provided systemic vascular changes are distinguished from cortical activity. We tested whether time-domain diffuse optical tomography (TD-DOT), which provides separate superficial and model-assigned intracranial estimates, withstands a challenge from each recording’s own scalp field. In processed continuous-wave near-infrared spectroscopy (NIRS) hypnosis recordings (26 participants), low-frequency oxyhaemoglobin variability decreased by 21.8% (P = 0.0067), whereas a network effect did not survive global-signal regression. In a time-domain NIRS auditory cohort (49 participants, two visits), withheld short channels matched reconstructed scalp more closely than intracranial estimates (t(48) = 16.5). In the auditory cohort, scalp-only injection reproduced an apparent intracranial HbR phase lead, whereas attenuated 0.02–0.07-Hz HbO/HbT transfer differed from the specified leakage null (P < 10⁻⁶). In three exploratory hypnosis sessions (novice, intermediate and experienced participants), heart-rate fluctuations at 0.04–0.15 Hz were lower than during induction in all nine phase comparisons, and directly measured forehead pulsatility increased in two participants. These findings support leakage-aware optical monitoring during hypnosis, while intracranial source identity and hypnosis-specific effects require independent validation.

Abstract: Approximately 900,000 individuals worldwide experience a traumatic spinal cord injury (SCI) each year, with roughly 15.4 million people estimated by the World Health Organization to be living with SCI. The effects of SCI on the lives of affected individuals and their families can be profound. In addition to partial or complete loss of sensory and/or motor function below the level of the lesion, a high proportion of patients with spinal cord injuries experience: neuropathic pain, spasticity, bladder and bowel dysfunction, autonomic dysreflexia, adrenal insufficiency, infertility, or sexual dysfunction due to their injury. The disabilities associated with SCI result from both direct physical injury to neurons and glia and from secondary damage caused by a complex cascade of biochemical processes involving multiple cell types. These processes present many potential targets for intervening in outcomes and reducing disability. This review will summarize the complex pathophysiology of traumatic spinal cord lesions and describe the main strategies and agents being investigated for reducing disability and enhancing recovery after spinal cord injury and the note status of related clinical trials. The goal is to provide a framework for moving forward to develop better treatments for this life-changing condition.

Abstract:

Gradient-based, performance-optimizing updates of artificial neural network (ANN) representations quantitatively predict plasticity measured in primate inferior temporal (IT) cortex after object training (Sörensen, DiCarlo & Kar, 2026). But the leading biologically motivated alternatives to backpropagation, notably feedback alignment and predictive coding, approximate gradient descent in several regimes, so it is unclear whether representational-change measurements can identify which rule produced them. We study this identifiability question exactly in the two-layer linear network. We show that backpropagation (BP), feedback alignment (FA), and predictive coding (PC) all produce first-layer updates of the form ΔW1=ηME with a shared error matrix \(E\) and a rule-specific preconditioner \(M\), and that the three rules have exactly the same reachable set of single-episode updates \(\Delta : \operatorname{rank}(\Delta) \leq 0\): when the readout, task error, and step size are unobserved, no single-episode measurement at any precision can reject any of the three rules (whereas with all three observed, single episodes generically do identify). For PC we derive the exact identity \(\Delta W_1^{PC} = (I + W_2^{\top} W_2)^{-1} \Delta W_1^{BP}\), giving relative deviation at most \(s_{\max}^2/(1+s_{\max}^2)\) in the largest readout singular value \(s_{\max}\), and we formalize the resulting non-identifiability regime under bounded measurement noise. Across an isotropic task ensemble, the update covariance has eigenvalues \(d\omega^2 s_i^2\) (BP) and \(d\omega^2 s_i^2/(1+s_i^2)^2\) (PC) on the readout's right singular vectors, while FA produces a rank-\(o\) covariance on a readout-independent random subspace. Two negative results follow: the PC covariance is exactly the BP covariance of a shrunken readout, so second moments alone cannot separate PC from BP; and, as our nonlinear-network simulations confirm, ranked covariance spectra confound the rules further. A readout-referenced projection statistic separates BP from PC deterministically (given two distinct readout singular values) and FA generically (almost surely over a nondegenerate random feedback draw, at the population level; finite-sample power is quantified by simulation), and we give a heuristic sample-complexity estimate for it. In a small nonlinear (tanh) network, the PC–BP collapse is confirmed at the level of probe-set representations, but the separation of rules from representation-only second moments partially degrades: BP separates from the local-rule family by spectral slope, while PC and FA are not separated by shape, quantifying what is lost when moving from weight space to measurable representations. All lemmas, theorems, and propositions are proved, except the sample-complexity estimate, which is a labeled heuristic; all empirical findings are simulations, plus one small trained-network check (a linear network trained by each rule on an MNIST subset, CPU, seconds), reproducible from the attached code. No neural data are analyzed, and no claim about cortex is made; we close with a proposed protocol for applying these tests to models trained in the framework of Sörensen et al. (2026).

Abstract: Glutamate excitotoxicity, a hallmark of acute brain injury, causes intracellular calcium overload and disrupts cation homeostasis. Although selective neuronal vulnerability is well established, the coordinated multi-ion mechanisms underlying resistance or death in distinct subpopulations, and the role of neuron–glia interactions, remain poorly understood. Using synchronous multi-channel fluorescence imaging in primary hippocampal cultures, we assessed coupled dynamics of cytosolic [Ca²⁺]i, [Na⁺]i, [K⁺]i, and pHᵢ in neurons and astrocytes exposed to toxic glutamate concentration (100 μM). Based on post-washout [Ca²⁺]ᵢ recovery, neurons were divided into fast-return, slow-return, and no-return groups. Vulnerable no-return neurons showed irreversible Ca²⁺ overload and persistent K⁺ loss, and contained the highest proportion of cells expressing calcium-permeable AMPA receptors and GluK1-containing kainate receptors. GABAergic neurons were mainly found in the slow-return and no-return groups. Fast-return neurons exhibited a two-step [Na⁺]i rise during glutamate application and washout, coinciding with a sharp [Ca²⁺]i decline, and marked cytosolic acidification; however, pHᵢ and [Na⁺]i did not recover even 40 min after washout. Their [K⁺]i recovered almost immediately and correlated inversely with [Ca²⁺]i, while [Na⁺]i correlated inversely with pHᵢ. Astrocytes rapidly cleared Ca²⁺ and stabilized pH despite sustained Na⁺ accumulation; their [K⁺]i also recovered quickly and correlated inversely with [Ca²⁺]i. GABABR agonist baclofen shifted neurons toward the slow-return group, whereas the A₁ adenosine agonist N⁶-cyclohexyladenosine abolished irreversible calcium collapse and expanded the fast-return pool. These findings clarify mechanisms of selective neuronal resilience to excitotoxicity and support Gᵢ-receptor activation as a strategy to preserve ion homeostasis.

Abstract: The future of developmental population neuroscience lies in transforming the path to brain individuality into personalized, context‑sensitive, and actionable predictions.

Abstract: This review asks whether female and male animals differ in neuroinflammatory measurements in Parkinson’s disease models and whether the findings establish different responses to disease induction. We searched APA PsycNET, PubMed, Scopus, Web of Science and SciELO, initially covering publications from January 2014 to December 31, 2024. Update searches ran from May 12 to May 31, 2025. Eligible studies used neurotoxin, pesticide or genetic models in rodents or nonhuman primates and included both sexes and control groups. We assessed risk of bias with the Systematic Review Centre for Laboratory Animal Experimentation (SYRCLE) tool. Findings were tabulated and compared descriptively, accounting for shared cohorts and distinguishing differences in measured values from interactions involving sex. Variation in methods and measurements, incomplete numerical data and uncertain independence prevented pooling. Eighteen publications represented 17 study units, all in rodents. No nonhuman primate studies were eligible. A total number of unique animals could not be established. Among mice that underwent sham surgery without dutasteride, striatal glial fibrillary acidic protein fluorescence increased after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in males; no increase was detected in females. An interaction between sex and MPTP exposure supported different responses. Microglial density and branching after rotenone varied with sex and genotype. Female mice overexpressing \(\alpha\)-synuclein had higher plasma interleukin 5 than males at 4 and 18 months. After a 6-hydroxydopamine lesion, male rats given a control oligonucleotide had more cells expressing inducible nitric oxide synthase per section in the substantia nigra pars compacta than females given the same treatment. These last two comparisons did not establish different responses to disease induction. Many findings relied on separate analyses within each sex. Unclear risk of bias, sparse replication and variation in assays and conditions limited interpretation. Some glial and inflammatory measurements differed between sexes under particular experimental conditions. The evidence does not establish generally greater neuroinflammation in either sex. Comparable independent experiments and direct assessment of cellular function are needed to clarify the biological significance of these differences.

Abstract: This article reviews reported coupling properties of astrocytes in neural circuits, functional structures, and molecular mechanisms linked to astrocytic specialized domains and spatiotemporal specificity of Ca2+ signaling. We propose a model in which astrocytes act as a bridging mechanism from microcircuit specialization to functional connectivity of brain regions and nuclei, addressing which signals are involved, how integration is achieved, and how these processes contribute to long-term memory and brain–body dimension of consciousness. The model posits that during consciousness and cognition astrocytes and their functional structures bridge neuronal encoding of multimodal embodied perception, integrate and transmit this information, and generate lagged, low-frequency Ca2+ waves that correspond to current state of consciousness or cognition. Through a relatively global signal, astrocytes shape the dynamics of cortical connectome and act at the level of brain dynamics as a downstream bridging router for memory, thereby shaping inertial circuits of consciousness over extended timescales. At the microenvironmental level, region-specific astrocytes and their subtypes shape neural circuits through metabolic coupling based on layer-specific spatial transcriptomes, thereby reversibly shaping cellular and synaptic basis of long-term memory. Through their broad receptor repertoire, astrocytes also serve as both terminal integrators of perceptual information and a neurochemical basis for information integration. At the circuit level, syncytium-based global Ca2+ waves form a global signal that locally and specifically influences cortical activity while globally regulating it, thereby coordinating cortical connectivity and spatial transcriptional profiles associated with consciousness. In embodied consciousness, astrocytes bridge bidirectional communication between consciousness as brain–body synchrony and bodily rhythms such as blood flow and respiration via neurovascular coupling and global signals.

Abstract: Alcohol use disorder involves persistent changes in motivation that a uniform increase or decrease in dopamine activity cannot explain. This narrative review examines how alcohol alters ventral tegmental dopamine circuits through membrane conductances, excitatory and inhibitory inputs, and synaptic plasticity. We propose that repeated exposure can reduce baseline dopamine output while preserving or enhancing responses to alcohol and its cues. Baseline output is defined as a prespecified measurement before an event; recruitment is the event-evoked increment above that baseline. Evidence for individual adaptations is distinguished from the unproven prediction that their joint change within a defined projection contributes to renewed seeking. Withdrawal-related reward deficits, stress recruitment, receptor-specific inhibitory signaling, and selective synaptic recovery provide complementary mechanisms. Projection identity, sex, hormonal state, and dopamine release and clearance at terminals help explain differences across studies. Regional rescue experiments strengthen causal inference, but most mechanisms have not been linked selectively to relief-driven drinking or recurrence. For prevention research, these findings identify candidate processes that may support progression to persistent use and vulnerability after cessation; they do not establish clinical preventive efficacy. Priorities include longitudinal measurements within defined circuits, independent tests of reward and relief motivation, and selective physiological rescue with appropriate behavioral controls. The practical contribution is a framework for evaluating when a dopamine adaptation is a cause of vulnerability, a compensatory response, or a marker of exposure.

Abstract: (1) Background: Social evaluation engages neural systems involved in stress and social information processing, with responses potentially depending on valence and evaluator characteristics. We investigated how valence and evaluator sex are reflected in functional connectivity (FC) within a meta-analytically derived stress network in women. (2) Methods: Sixty-three healthy women underwent functional magnetic resonance imaging while receiving praise, criticism, and neutral statements from unfamiliar male and female evaluators. Task-based FC was examined within the stress network. (3) Results: Participants reported less positive affect during criticism and more positive affect during praise, with both effects more pronounced for male than female evaluators. Stress-network FC differed by valence and evaluator sex. Both praise and criticism were associated with greater left insula-–right inferior frontal gyrus FC than neutral statements, while criticism was associated with greater left superior temporal gyrus–right amygdala FC than praise and neutral statements. Furthermore, evaluator sex modulated valence-dependent FC across several FCs involving prefrontal, striatal, medial temporal, thalamic, and posterior midline regions. Post-hoc comparisons revealed evaluator-sex differences in FC during criticism and praise, as well as opposing valence-dependent FC patterns between male and female evaluators. Exploratory analyses showed that associations between FC and self-related positive affect also depended on valence and evaluator sex. (4) Conclusions: Stress-network FC during the perception of praise and criticism delivered by strangers depended on evaluator sex. Importantly, stress-network involvement was not restricted to criticism, indicating that praise may also engage stress-related neural processes depending on social context, particularly when voiced by a male.

Abstract: Intellectual disability (ID) characterizes numerous neurodevelopmental disorders, many of which also show increased obesity and metabolic comorbidities. Traditionally investigated independently, their coexistence suggests potentially shared pathogenic mechanisms, whose molecular and neural bases remain poorly understood. Down syndrome (DS), caused by trisomy 21, offers a genetically defined model for examining how altered gene dosage may affect cognition, feeding behavior, and energy homeostasis. Understanding these relationships could illuminate both the heterogeneous DS phenotype and metabolic vulnerability across ID-associated disorders. The locus coeruleus (LC), a major noradrenergic nucleus, regulates learning, memory, and energy balance. LC abnormalities have been reported in individuals with DS and corresponding mouse models, suggesting a potential contribution to both cognitive and metabolic phenotypes. Among chromosome 21 genes, dual-specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) is a compelling candidate. DYRK1A influences pancreatic β-cell mass and metabolic pathways while regulating neuronal development, synaptic function, and cognitive processes. Moreover, DYRK1A has been implicated in LC alterations in DS, although their functional consequences have primarily been investigated in cognition. Here, we review evidence connecting intellectual disability, obesity, LC function, and chromosome 21 gene dosage. We propose that DYRK1A-dependent changes in LC-noradrenergic signaling may contribute to cognitive impairment and potentially modify metabolic regulation in DS. Rather than assuming a single established causal pathway, this framework highlights a testable interaction between genetic dosage, neural circuitry, and environmental challenges that could explain divergent outcomes across physiological domains. Importantly, current experimental evidence more strongly supports a cognitive contribution than a direct causal role in metabolic and energy balance dysfunction.

Abstract: Alcohol use disorder (AUD) involves persistent changes in stress-responsive and motivational circuits, but the relationships among neuropeptide signaling, neuroimmune responses, and sex-dependent behavioral effects remain incompletely defined. This focused narrative review critically evaluates experimental evidence concerning neuropeptide Y (NPY) and its Y1 receptor (Y1R), corticotropin-releasing factor (CRF), and inflammatory signaling in the central amygdala (CeA) and bed nucleus of the stria terminalis (BNST), alongside selected glucagon-like peptide-1 receptor (GLP-1R) studies relevant to translation. Literature was identified through targeted database searches and reference tracking, with emphasis on causal manipulations, anatomical specificity, behavioral models, and clinical endpoints. The evidence supports distinct effects of manipulating CeA Y1R-expressing projections and activating Y1 receptors, and indicates that NPY can regulate inhibitory inputs to BNST CRF neurons. Inflammasome-related findings are region-, exposure-, and model-dependent; direct causal links to defined extended amygdala neuropeptide circuits remain to be established. Sex-specific findings require adequately powered interaction tests rather than comparisons of significance within each sex. GLP-1R studies provide therapeutic context but do not establish a common mechanism in the extended amygdala. Future experiments should distinguish parallel pathways from circuit convergence and molecular mediation using cell-specific perturbations, physiological readouts, and behavioral rescue.

Abstract: Hybrid brain–computer interfaces (hBCIs) combine EEG with optical and peripheral channels and are increasingly worn outside the laboratory for passive state characterization. Activity below 0.5 Hz is largely excluded from such systems, though brain–body coupling is reported to occur there. This review asks what can be rigorously measured in that range. Some of the analytical conventions imported from faster bands assume a stable characteristic frequency that slow signals often lack. We argue that the absence of periodicity does not preclude rigorous tracking and state characterization. Analyses are organized into three tiers by the temporal assumption each makes: stable frequency, recurrence without stable frequency, and neither, with admissibility often established by test for a given recording rather than assumed from a band label. We review candidate channels by generator character, wearability and required stillness. We set out the estimators available without phase, including directional ones. We also specify hardware-related acquisition requirements for two possible approaches to analyze the infraslow band, band-limited envelopes and DC-coupled potentials. In the absence of population norms, we propose individual referencing and identify the reporting minimum a slow-band result requires.

Abstract: Hypothalamic tanycytes have traditionally been viewed as metabolic sensors, structural components of hypothalamic barriers, and transporters of circulating signals. However, accumulating evidence indicates that they also translate metabolic, hormonal, and inflammatory inputs into bioactive signals that coordinate communication with neurons, glia, blood vessels, and cerebrospinal fluid. Here, we introduce the term tanykines to describe bioactive molecules whose extracellular availability depends on their regulated generation, release, processing, or bioactivation by tanycytes and that modify tanycyte function or other target cells. We propose a mechanism-based taxonomy comprising: (i) primary tanykines, directly generated and released by tanycytes, including ATP, lactate, β-hydroxybutyrate, prostaglandin E₂, and VEGF-A; (ii) secondary processed tanykines, generated extracellularly from a primary tanykine, exemplified by ATP-derived adenosine; and (iii) bioactivated tanykines, produced through tanycyte-dependent transformation of a transported precursor, exemplified by T4-to-T3 conversion. We further distinguish established, probable, and candidate or disputed tanykines according to tanycytic origin, regulated extracellular availability, target-cell identity, mechanism of action, and physiological causality. This framework separates tanykines from molecules merely sensed, transported, or expressed by tanycytes and reframes these cells as context-dependent signal generators coordinating metabolic and neuroendocrine homeostasis.

Abstract: Errors in scientific code pose a significant risk to the accuracy of research. Yet, formal code review remains uncommon in academia. This is a particular challenge for interdisciplinary fields, such as mental health research, which increasingly rely on computational approaches. This paper presents a pragmatic experience-based framework for code review procedures in mental health research. In order to facilitate practical implementation, it includes a structured checklist for identifying common coding issues, from data handling errors to flawed statistical analyses. We discuss barriers to introducing code review and how to overcome them, revisit best practices from software engineering, and highlight the emerging role of large language models in automating aspects of code review. We argue that, despite perceived costs, code review significantly enhances the reliability of research results and fosters a culture of transparency and continuous learning. Our proposal provides an adaptable model for integrating code review into research workflows, helping mitigate errors before publication and strengthening trust in scientific results.

Abstract: Functional near-infrared spectroscopy (fNIRS) is almost absent from the foundation-model literature. On OpenNeuro, the largest open BIDS-structured neuroimaging repository, fNIRS accounts for 1.0% of participants and 1.6% of datasets, against 28.6 times more participants for EEG. We ask why, and what a first fNIRS foundation model would require. The paper is a review and a roadmap: its contribution is an inventory, a synthesis of evidence from adjacent modalities, and a set of requirements, not new model results.We argue that the barrier is not primarily data structure. The fNIRS data standards already require sensor positions to be recorded, so the laborious step of reconstructing where each sensor sat, which dominates the equivalent EEG models, is largely unnecessary here. The barrier is corpus scale, compounded by the absence of any clinical archive comparable to the Temple University Hospital EEG corpus, and by the recency of NIRS-BIDS, published in 2025 against 2019 for EEG. Because no single fNIRS corpus is large enough, aggregation across heterogeneous montages is the most plausible route to pretraining scale, which makes montage-agnostic architecture a precondition rather than an optimization.Reviewing four EEG foundation models that solve montage heterogeneity, we find that the two available ablations of both components rank spatial aggregation above the choice of positional encoding. Several models without a unifying spatial abstraction fall to near-chance under stringent cross-montage evaluation, mainly when encoders are frozen or tested on layouts they were not trained on. In hemodynamic and multimodal work, the one foundation model borrowed from another domain gave no uplift on fNIRS, while joint pretraining with EEG did. In the one available ablation, though, that benefit tracked the mutual information between modalities and, at the larger shot counts, fell below fNIRS-only pretraining at the lowest level tested. From functional magnetic resonance imaging (fMRI) we take a direction fNIRS has not yet followed: recent work there has moved from signal reconstruction toward latent prediction, because the signal is noisy and off-the-shelf evaluation matters. That rationale may be particularly relevant to fNIRS, where some of the systemic physiological confounds, particularly the Mayer wave, overlap the band in which the hemodynamic signal is analyzed. We chart the nine fNIRS-relevant works we located. We identify three especially consequential properties of fNIRS with no electrophysiological counterpart (source–detector geometry, chromophore choice and hemodynamic timescale) and set out eight requirements for a first fNIRS foundation model, on which work is under way in our laboratory.

Abstract: More than 30 years after the discovery of the genetic cause of spinocerebellar ataxia type 1 (SCA1), selective Purkinje cell vulnerability remains a defining feature of disease pathogenesis. Increasing evidence also implicates glial cells, including oligodendroglia, astroglia, and microglia, as important contributors to neurodegeneration in SCA1 and other ataxias. In this review, we summarize current evidence for the mechanisms through which glia contribute to SCA1 progression and pathology. Early oligodendroglial dys-function leads to cell-autonomous myelination deficits and non-cell-autonomous im-pairments in Purkinje cell axonal health. Astroglial dysfunction, particularly in Berg-mann glia, disrupts glutamate homeostasis and is associated with aberrant activation of NF-κβ, JNK, and Wnt/β-catenin signaling pathways. Although microglial involvement in SCA1 remains less well understood, microglial activation appears to be regionally re-stricted to the cerebellum and inferior olive. Studies of microglial depletion have yielded partial and, in some cases, conflicting functional outcomes. Notably, dysregulated Wnt/β-catenin signaling across all three glial subtypes may represent a unifying mechanism. Together, these findings identify glia as active, region-specific contributors to SCA1 pathogenesis and highlight underexplored opportunities for mechanistic and therapeutic investigation in polyglutamine diseases.

Abstract: Many plants used traditionally to aid memory have been put forward as neuroprotective candidates against dementia. This mini review weighs the preclinical and clinical evidence for six of them (Centella asiatica, Ginkgo biloba, Salvia species, Withania somnifera, Bacopa monnieri and Semecarpus anacardium), briefly describes five more, and considers their relevance to Bangladesh. Sources were PubMed, Google Scholar and Semantic Scholar, with a targeted update in 2026. In cells and rodents, the same mechanisms recur cholinergic modulation, antioxidant and anti-inflammatory activity, and protection against amyloid-beta toxicity. Human evidence is thin. Two large ginkgo trials did not prevent dementia, while small trials of sage, ashwagandha and Bacopa point to modest cognitive gains. Centella and Semecarpus have no controlled human data. Before any clinical recommendation, the field needs standardised extracts, safety assessment, and adequately powered trials in people at the earliest stages of Alzheimer's disease.

Abstract: Cisplatin-induced hearing loss (CIHL) is a debilitating side effect in cancer patients undergoing chemotherapy. So far, epigenetic studies in the inner ear have largely focused on developmental biology to regenerate hair cells. In post-mitotic hair cells, on the other hand, DNA methylation regulates transcriptomic response to external stimuli. Adult mammalian hair cells are locked in the G0 phase, and passive demethylation via DNA replication does not occur under normal physiological conditions. However, external stimuli such as cisplatin can aberrantly upregulate DNMT methyltransferases (DNMTs), resulting in promoter methylation and silencing protective genes. From this angle, DNMTs modulation is an attractive therapeutic strategy to protect hearing during chemotherapy. Recent studies suggest that non-nucleoside inhibitors such as RG108 and natural polyphenolic compounds downregulate DNMTs, and at the same time, protect auditory cells. These compounds function via the inhibition of the DNMT catalytic site but can also act through downregulating DNMT1 and DNMT3A/B at mRNA and protein levels. Polyphenols are also antioxidants, decreasing reactive oxygen species, thereby increasing cell survival. Furthermore, it is suggested that upregulating TET-mediated active demethylation can be another angle to modify DNA methylation in cancer and CIHL models. However, functional DNA methylation should be distinguished from non-functional, passenger DNA methylation to elucidate the compounds’ otoprotective effects. In addition, the candidate compounds should not interfere with cisplatin’s antitumor effect. In this review, we investigate the relationship between DNA methylation and CIHL in the post-mitotic inner ear and evaluate the therapeutic potential of candidate DNMT inhibitors.

Abstract: In the papers we reviewed, the two modelling lineages of sleep rarely meet. Mechanistic models simulate inputs such as light or caffeine with other people’s parameters; most learned models estimate or forecast the state and take no input. We define a sleep world model: a probabilistic model of one person’s sleep in which dated events, the sleeper’s actions and assigned interventions drive a latent SleepState of physiological and mental leaves, sleep-regulation models can inform the transition as priors, and instruments and the sleeper observe the night through separate observation models. Of the 62 learned models among the papers placed on our map, 56 only estimate or forecast. Few placed papers score a model’s predicted sleep contrast against an assigned one; in a nap study given in fixed order, a two-process model with parameters fixed beforehand overestimated slow-wave activity after the nap. No paper reviewed compares, on sleep data, a learned transition with and without a mechanistic prior. Assigned emotional or cognitive manipulations shift recorded sleep onset by minutes at group level, but an influence of a mental leaf on one person’s transitions is not shown, and every dose–response relation found is a group average. We propose a capability ladder, an evidence ladder that reserves “effect” for contrasts between inputs assigned at random or otherwise independently of the state, a minimum data protocol, six benchmark tasks and a staged roadmap. Until a person-fitted model’s predicted contrast is scored against that person’s replicated, randomised contrast, its simulated branches remain scenarios.

Abstract: Background: We previously reported a familial balanced translocation t(8;20)(p12;q11.23) segregating with early-onset, non-progressive, mild cerebellar ataxia. The association between the translocation and the phenotype remains elusive, even though the chromosome 20 breakpoint disrupts the DLGAP4 gene. Objectives: In this project, we aim to revisit the breakpoint region on chromosome 8 for any genes, transcripts, or mechanisms affected by the rearrangement and assess their potential contribution to the cerebellar ataxia phenotype. Results: The chromosome 8 breakpoint disrupts a previously uncharacterized conjoined transcript, PURG-TEX15, expressed in the adult human brain, particularly in Purkinje cell dendrites in the cerebellum, which are important for motor coordination. PURG-TEX15 encodes a stable protein localized to the nucleus and cytoplasm, where it presents as distinct, dense perinuclear foci. In addition, the translocation generates a fusion transcript, PURG::DLGAP4, encoding a stable protein with slightly altered properties compared with wild-type PURG. Methods: We assessed the molecular consequences of the rearrangement on the disrupted novel transcript, PURG-TEX15, at the bioinformatic, RNA, and protein level using material from human and mouse brain. Conclusions: We identify PURG-TEX15, a previously unrecognized protein-coding conjoined transcript expressed in Purkinje cells, disrupted by a balanced translocation, t(8;20), associated with familial cerebellar ataxia. The translocation alters multiple neuronal transcripts through gene disruption and fusion transcript formation. The breakpoints span PURG-TEX15 and the brain-specific isoform of DLGAP4, generating a potentially functional PURG::DLGAP4 fusion protein. This supports a model in which PURG-TEX15 disruption plays a central role in cerebellar ataxia pathogenesis, either alone or in combination with the PURG::DLGAP4 fusion protein and/or DLGAP4 truncation. More broadly, this work highlights the biological significance of chimeric transcripts in the nervous system and implicates their dysregulation as an underrecognized mechanism in neurodevelopmental and neurological disorders. The study also shows the complexity of genome reorganization by balanced structural variants.