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The HTT1a protein initiates HTT aggregation in a knock-in mouse model of Huntington's disease
No full textThe mutation that causes Huntington's disease is a CAG repeat expansion in exon 1 of the huntingtin gene (HTT) that leads to an abnormally long polyglutamine tract in the huntingtin protein (HTT). Mutant CAG repeats are unstable and increase in size in specific neurons and brain regions with age, a phenomenon that constitutes the first step in the pathogenesis of the disease. In the presence of an expanded CAG repeat, cryptic polyA sites in intron 1 of the HTT pre-mRNA can become activated leading to the polyadenylation of a prematurely terminated transcript, HTT1a. This encodes the HTT1a protein, which is known to be very aggregation-prone and highly pathogenic. Given that the longer the CAG repeat the more HTT1a is generated, could the production of HTT1a be the mechanism through which somatic CAG repeat expansion exerts its pathogenic consequences? Resolving this issue is very important for the design of therapeutic approaches to lower huntingtin levels. We have used a CRISPR-Cas9 approach to prevent the production of HTT1a in a knock-in mouse model of Huntington's disease. All potential cryptic polyA sites were deleted from Htt intron 1 in HdhQ150 mice and colonies were established that were heterozygous for the intron 1 deletion on a mutant allele (HdhQ150ΔI) and heterozygous for the deletion on a wild-type allele (WTΔI). The CAG repeat sizes in the HdhQ150 and HdhQ150ΔI colonies were well-matched at approximately 195 CAGs. As predicted, the deletion of the cryptic polyA sites from Htt intron 1 prevented the generation of the Htt1a transcript in the HdhQ150ΔI mice. However, very low levels of the HTT1a protein were detected, which resulted from a Htt readthrough product of exon 1 and exon 2, that had retained the deleted intron and terminated at a cryptic polyA site in intron 2. HdhQ150, HdhQ150ΔI, wild-type and WTΔI mice were studied until 17 months of age. Immunohistochemical and homogeneous time resolved fluorescence analysis showed that HTT aggregation in both HdhQ150 and HdhQ150ΔI brains contained HTT1a, but the dramatic decrease in soluble HTT1a levels in HdhQ150ΔI brains delayed the appearance of aggregated HTT1a by several months. Although this delay in aggregate pathology only partially reversed transcriptional dysregulation, the biomarkers NEFL and BRP39 (YKL40) remained at wild-type levels in HdhQ150ΔI mice at 17 months of age. These data demonstrate that the production of HTT1a initiates HTT aggregation and that it is important to target HTT1a in huntingtin-lowering therapeutic strategies
Sepsis and the immunometabolic inflammatory response
No full textSepsis is a life-threatening syndrome characterised by dysregulated immunity, inflammation and metabolic disruption. Despite improved care, it remains a major cause of morbidity and mortality, highlighting the need for improved mechanistic insight. Immunometabolism has emerged as a framework for understanding sepsis pathophysiology. Conventional prognostic tools reflect downstream organ injury but not the metabolic states of immune cells. Emerging technologies now enable high-resolution profiling of immunometabolic changes and integrating these approaches may yield metabolic biomarkers capable of tracking immune function and refining diagnostics. This review summarises current knowledge of leukocyte metabolic dysfunction in sepsis and highlights how immunometabolic profiling can inform patient monitoring and advance biomarker-driven precision medicine
The impact of language proficiency on task-dependent neural activity and functional connectivity: insights from deafness
No full textOur study investigates how language proficiency impacts cognitive processing in the brain. We focused on congenitally and early deaf adults, where individual differences in language access during development significantly influence language proficiency and cognitive function. This variability in language backgrounds and skills allows us to explore the influence of early language experience on the large-scale brain networks that support cognition. We used functional MRI in a group of deaf adults with diverse language backgrounds and a control group of hearing participants. We hypothesized that differences in language skills would modulate neural responses and functional connectivity in task-related networks during the execution of demanding working memory and planning tasks. Our study revealed that differences in language proficiency, independently of language modality (signed or spoken), are positively correlated with neural activity and functional connectivity within the task-positive network during working memory in deaf adults. Furthermore, compared to hearing participants, the deaf group showed distinct patterns of neural activity and connectivity in task-dependent regions in the working memory experiment. Our findings emphasize the profound impact of early environmental experiences on brain responses during cognitive processing. Specifically, they highlight the role of language proficiency in shaping and supporting higher-order cognition
Deciphering epileptic dynamics through neurovascular coupling: Insights from a neuro-astrocytic-arteriolar computational modeling approach
No full textEpilepsy is a common neurological disorder whose pathogenesis involves dysfunction in neurovascular coupling. However, current models still lack sufficient realism and diversity. This study investigates the pathological mechanisms of epilepsy based on the physiological process of neurovascular coupling. Our mathematical model incorporates neurons, astrocytes, and arterioles. It employs an extended Hodgkin–Huxley-type model for neuronal dynamics and a model of radius variation in smooth muscle driven by the filament sliding mechanism. Key elements such as BK and KIR potassium channels, along with signaling molecules including O2, Ca2+and NO, are integrated to simulate neuro-hemodynamic responses. The results reveal six distinct transitional firing patterns in neurons under a suitable external stimulation, along with bifurcation phenomena underlying the low-voltage fast oscillation state, tonic spiking, and bursting. Both qualitative and quantitative simulations demonstrate that neuronal activation triggers oscillatory calcium waves in astrocytes, leading to the release of vasodilators and ultimately inducing arteriole dilation. Furthermore, the study delineates the asymptotic behaviors of ionic concentration changes under conditions of ischemia, hypoxia, and astrocytic dysfunction. This multi-pathway synergistic neurovascular coupling framework provides a more comprehensive understanding of epileptic pathology
Association between isolated single umbilical artery and neurodevelopmental disorders: population-based study
No full textObjective:
A single umbilical artery (SUA) is associated with a risk of adverse perinatal outcome. Around 11% of fetuses with SUA present with an associated major anomaly, including those of the central nervous system. However, studies on the associations between SUA and childhood neurodevelopmental disorders (NDD), such as intellectual disability (ID), attention deficit hyperactivity disorder (ADHD), autism spectrum disorder, epilepsy, impaired hearing and impaired vision, are limited. We aimed to evaluate the risk of NDD in children presenting with an isolated SUA (iSUA) at birth and the possible impact of sex, and to examine the extent to which gestational age at birth and birth weight mediate the effect of iSUA on NDD. / /
Methods:
This was a historical national cohort study linking data from the Medical Birth Registry of Norway with other mandatory national registries. We included all singleton live births in Norway between 1 January 1999 and 31 December 2013, and follow-up of the study cohort was concluded on 31 December 2019. We included all newborns diagnosed with iSUA. Data regarding NDD diagnosis were obtained from the Norwegian National Insurance Scheme and the Norwegian Patient Registry. We used multilevel logistic regression to calculate odds ratios (ORs) with 95% CIs, and performed sex-stratified analyses. A causal mediation analysis of the relationship between iSUA and NDD with preterm birth (live birth < 37 weeks' gestation) and small-for-gestational age (SGA) (birth weight < 5th percentile) was performed. / /
Results:
The cohort of 858 397 singleton live births included 3532 cases diagnosed with iSUA (0.41%), of which 1802 (51.3%) were male, 253 (7.2%) were born preterm and 249 (7.0%) were SGA. iSUA was associated with increased odds of subsequent ID (OR, 1.56 (95% CI, 1.09–2.23)) and ADHD (OR, 1.22 (95% CI, 1.02–1.47)), but there was no observed association with other NDD. In sex-stratified analyses, the associations with iSUA were observed in females but not in males. Preterm birth and SGA were each found to mediate < 10% of the total effect of iSUA on ID. / /
Conclusion:
iSUA was weakly associated with ID and ADHD, but not with other NDD. These associations were influenced by sex and were mediated by < 10% by preterm birth or SGA. The absence of associations of iSUA with other NDD is reassuring, and this finding is useful in the counseling of expectant parents of fetuses with iSUA. © 2026 International Society of Ultrasound in Obstetrics and Gynecology
Medicines matter: the expanding role of the perioperative pharmacist
No full textThis narrative vignette examines how perioperative pharmacists can prevent medicationrelated harm during surgical care. We present a case of a 78-year-old man with multiple conditions including atrial fibrillation, type 1 diabetes mellitus, heart failure and long-term steroid dependence undergoing robotic surgery for rectal cancer. Post-operatively, he developed persistent hyperglycaemia and tachycardia, progressing to acute heart failure with pulmonary oedema. When we reviewed the case, we found several medication management failures: inadequate steroid replacement, inappropriate insulin management, failure to restart betablockers and excessive fluid administration. This case shows why medication errors remain a leading cause of avoidable perioperative harm. As surgical patients get older and present with more complex conditions and medications, the risks multiply. While medicines reconciliation works well in acute care, perioperative settings face unique challenges. In practice, we find inconsistent application of medication safety protocols. We propose a proactive model where perioperative pharmacists engage early in the surgical pathway. Rather than waiting until after admission, they would perform medicines reconciliation and optimisation during preassessment. This allows for the creation of personalised medication plans that address drug interactions, dose adjustments and formulation changes needed for surgery. From 2026, pharmacy graduates will enter the workforce as independent prescribers. This positions perioperative pharmacists perfectly to enhance surgical safety through collaborative practice. As surgical demand increases and patients become more complex, integrating pharmacists as core providers is not just an opportunity; it is a necessity
A material perspective on pupils’ experience during museum education as a space for historical consciousness
No full textThis article investigates pupils’ experience with historical objects during an educational visit to a history museum and how this can foster the development of historical consciousness. It is investigated from the pupils’ perspective, which is done by using a theoretical frame consisting of a relational ontological understanding of the pupil, a cultural pedagogical understanding of historical consciousness and an understanding of the experience with museum materiality as an oscillation between meaning effect and presence effects. The article draws on data from 287 pupils (aged 12–16 years) visiting Rosenborg Castle. This was collected through a material and collaborative ethnographic approach, employing qualitative cartographic observations, dialogical sticky note exercises and qualitative photo-elicited surveys, in collaboration with 10 museum professionals all affiliated with museum education from Rosenborg Castle, The Workers Museum, National Museum of Denmark, Museum of Copenhagen and Skoletjenesten. The article offers insights into the richness and complexity of pupils’ material experiences and historical consciousness during museum education. It concludes by highlighting that the material forces, discursive forces, bodily forces and historical consciousness all exist in a state of flux
Etiology of Severe Microcephaly in Infants: A Multinational Surveillance Study
No full textBACKGROUND AND OBJECTIVES: Severe microcephaly, or head circumference at least 3 standard deviations below the mean for age and sex, is a rare condition with diverse etiology, making diagnosis challenging. Following the 2015 to 2016 Zika virus outbreak, surveillance studies in Australia, Canada, New Zealand, and the United Kingdom and Ireland were conducted to monitor severe microcephaly. We describe the etiology, clinical features, and diagnostic investigations of severe microcephaly among children aged younger than 1 year. METHODS: We pooled reports of patients with severe microcephaly detected through 4 national active surveillance studies, through the International Network of Paediatric Surveillance Units. Incident cases were reported voluntarily between June 2016 and October 2018 by networks of pediatricians totaling more than 8000 members. Etiology was categorized as genetic (confirmed/suspected), acquired (infection, ischemia/hypoxia, prenatal alcohol exposure, placental insufficiency), or unknown. Anonymized data were pooled and analyzed using descriptive statistics. RESULTS: Overall, the cases of 118 patients with severe microcephaly were analyzed, including 59 from the United Kingdom and Ireland, 34 from Canada, and 25 from Australia (n < 5 cases from New Zealand were not analyzed). Median age at diagnosis was 17 days (IQR 1-119), and mean head circumference-for-age Z-score was -4.0 (SD 1.1). Genetic causes were determined for 50% (n = 59) vs 18% acquired (n = 21) and 32% unknown (n = 38). Common investigations included brain magnetic resonance imaging (70%), DNA microarray (69%), brain ultrasonography (53%), and cytomegalovirus screening (48%). CONCLUSIONS: At least one-half of severe microcephaly cases are attributable to genetic causes. One-third had unknown etiology, highlighting a need for a systematic approach to diagnostic investigation, including genomic sequencing and brain imaging for all children with severe microcephaly
Unpacking early risks for peer victimization: A network analysis of early temperament and polygenic risk scores
No full textBACKGROUND: Children who show difficult temperament are at risk of peer victimisation, which in turn associates with numerous negative outcomes later in life. We used network analysis to examine whether specific aspects of difficult temperament contributed to these associations, and whether the links were moderated by variations in genetic liability for ADHD, schizophrenia, and depression. METHODS: In 3354 mother-child dyads (51.8% female), we examined in three steps: (i) the network structure of difficult temperament as indexed by adaptability, intensity, and mood (age 2), (ii) its item-level associations with peer victimisation (ages 8, 10, and 13), and (iii) moderation of these associations by polygenic risk scores (PRS) for ADHD, schizophrenia, and depression. RESULTS: Indicators of difficult temperament formed a coherent network that was associated with peer victimisation. Regarding PRS moderation, for those high in PRS (top 10%) for ADHD and schizophrenia, indicators of temperamental intensity and mood were associated with peer victimisation, respectively. For those high in PRS for depression, however, aspects of temperament were no longer associated with peer victimisation. Finally, the network results for those in the general population across all PRS (bottom 90%) largely resembled the model estimated using the full sample. CONCLUSION: The findings highlight specific temperamental behaviours as risk factors for peer victimisation; additionally, children high in PRS for neurodevelopmental disorders may be at especially high-risk for this outcome early in development