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Transient neurones match the spontaneous and sensory driven activities to shape cortical circuits: a landmark collaborative review published in Science from Professor Zoltán Molnár, Professor Patrick Kanold and Professor Heiko Luhmann.
Transferability of European-derived Alzheimer's disease polygenic risk scores across multiancestry populations.
A polygenic score (PGS) for Alzheimer's disease (AD) was derived recently from data on genome-wide significant loci in European ancestry populations. We applied this PGS to populations in 17 European countries and observed a consistent association with the AD risk, age at onset and cerebrospinal fluid levels of AD biomarkers, independently of apolipoprotein E locus (APOE). This PGS was also associated with the AD risk in many other populations of diverse ancestries. A cross-ancestry polygenic risk score improved the association with the AD risk in most of the multiancestry populations tested when the APOE region was included. Finally, we found that the PGS/polygenic risk score captured AD-specific information because the association weakened as the diagnosis was broadened. In conclusion, a simple PGS captures the AD-specific genetic information that is common to populations of different ancestries, although studies of more diverse populations are still needed to better characterize the genetics of AD.
The effect of fire on the carbon fluxes and productivity of Brazilian woodland savannas
The effects of altered fire regimes within open ecosystems are poorly understood and can have serious consequences on functioning and conservation across savanna ecoregions worldwide. In South American savannas like the Cerrado, there is a gap of knowledge relating to carbon cycling in the presence of fire, meaning the impacts of altered fire regimes on the carbon fluxes and budgets are virtually unknown. We thus investigate vegetation carbon flux dynamics within the Cerrado making use of an experimental fire and carbon monitoring research project at the Estação Ecológica da Serra das Araras, Brazil. We present a thorough carbon budget of woodland-type savannas (cerrado sensu stricto), and investigate how annual (every year), biennial (every two years), and triennial (every three years) controlled fire frequencies have influenced net primary productivity and respiration fluxes. Six years of experimental fire had noticeable effects on the vegetation structure and carbon dynamics, reducing woody cover and productivity in favour of grass-dominated carbon balances. Woody NPP increased by 35 % in the unburnt plots from 2017 to 2019 to 2021–2023, but decreased by 75 %, 33 % and 20 % in the triennial, biennial and annual fire frequencies. By 2023, burnt plots revealed around three times higher herbaceous NPP than unburnt plots. Fluxes corresponding to different ecosystem components (canopy, stems, roots, herbs) showed varying patterns of change across the gradient of experimental fire frequencies, indicating other fire regime properties distinctively affect each vegetation segment. Fire intensity and severity appear to be linked with patterns in woody stems and the herbaceous layer. Our results indicate periodically burnt cerrado sensu stricto vegetation experiences different carbon dynamics than unburnt vegetation. Burning is revealed as a strategy that can successfully limit woody encroachment and help conserve open ecosystem structure in the Cerrado. Our study highlights the importance of long-term monitoring efforts in investigating the effects of management interventions and environmental shifts on ecosystem functioning.
Can Southeast Asia's Tigers Break Free? The Connectivity, Constraints, and Recovery of the Region's Remaining Tiger Populations
Southeast Asia's tigers (Panthera tigris) stand at the cross-roads of recovery and ruin. While few populations remain, evidence of growth and dispersal in key sites necessitates an evaluation of broad-scale recovery potential via habitat connectivity. We employ spatially-synoptic modeling (movement from all source points to all potential destinations) to assess tiger population connectivity in 11 landscapes in relation to landscape configuration, broad-scale recovery potential, vulnerabilities in habitat structure, and management priorities. We generate cumulative resistance kernels to quantify core areas of high predicted movement and areas of broader connectivity, ranking them by strength, extent, protected areas connected, and composite score. Sites along the Thai–Myanmar border had the highest overall rankings, with kernels of high strength and moderate extent, while Northern Myanmar sites were ranked highest by extent. Importantly, broad-scale connectivity potential in the region was represented by only four contiguous core habitat patches within three landscapes of broad-scale connectivity—the Dawna-Tenasserim landscape (DTL), Upper Chindwin landscape (UCL), and Dong Phayayen-Khao Yai forest complex (DPKY)—with the unique spatial configuration of each indicating distinct priorities for metapopulation management and recovery. Results reinforce the critical importance of DTL and potential for population spread from this site, but also highlight vulnerable points where connectivity and long-term persistence may be undermined. UCL's expansive habitat is unrivaled in its potential for facilitating population expansion, though the status of this population remains uncertain. In contrast, DPKY's isolated habitat configuration represents a profound constraint to population spread, underscoring the importance of mitigating barriers to movement. Our study provides timely landscape- and region-wide insight for the development of tiger conservation and recovery strategies as well as a quantitative basis for evaluations of landscape connectivity in this rapidly changing region.
Exploring creaminess perception in ice cream products using a combined static and dynamic sensory approach
Background, Context, or Rationale: Creaminess is a critical determinant of the consumer acceptance of ice cream, yet its multidimensional sensory drivers—particularly across static and temporal dimensions—remain poorly characterised, thus hindering the development of healthier, low-fat alternatives. Aim(s): To identify key textural and temporal attributes governing creaminess perception in ice cream using complementary static (quantitative descriptive analysis, QDA) and dynamic (temporal check-all-that-apply, TCATA) sensory methodologies. Methods: A mixed-method framework was implemented: (1) A word association task with 186 consumers captured spontaneous creaminess descriptors, consolidated into 12 attributes via focus groups; (2) QDA quantified static correlations between creaminess and sensory properties; and (3) TCATA tracked dynamic attribute interactions over 60 s. Major Findings: Static drivers (QDA): Creaminess correlated negatively with melting time, coldness, hardness and iciness (P < 0.05), and positively with thickness and mouth coating (P < 0.05). Temporal dynamics (TCATA): Creaminess perception evolved in two phases: (1) 0–25 s: Driven by viscosity and mouth coating intensity (P < 0.05); (2) 60–120 s: Sustained by thickness and smoothness, delaying perceptual decline. Scientific or Industrial Implications: This dual-axis model advances creaminess characterisation by linking instantaneous texture (thickness and mouth coating) to time-dependent sensory transitions, offering a novel framework for studying complex sensory attributes. Findings enable targeted reformulation of low-fat ice creams by modulating thickness and smoothness in order to mimic fat-derived creaminess.
Preferences for fat, sugar, and oral-sensory food qualities in monkeys and humans.
In humans and other primates, food intake depends on sophisticated, individualized preferences for nutrients and oral-sensory food qualities that guide decision-making and eating behavior. The neural and behavioral mechanisms for such primate-typical food preferences remain poorly understood, despite their importance for human health and their targeting by pharmacological obesity treatments. Here, we review a series of experiments that investigated how the biologically critical properties of foods-their nutrients (sugar, fat, protein) and oral-sensory qualities (viscosity, oral sliding friction)-influence food preferences in monkeys and humans. In an economic nutrient-choice paradigm, macaques flexibly trade nutrients and oral-sensory food qualities against varying food amounts, consistent with the assignment of subjective values. Nutrient-value functions that link objective nutrient content to subjective values accurately model these preferences, predict choices across contexts, and explain individual differences. The monkeys' aggregated choice patterns resulting from their nutrient preferences lead to daily nutrient balances that deviate from dietary reference points, resembling suboptimal human eating patterns when exposed to high-calorie foods. To investigate the sensory basis underlying nutrient values, we developed novel engineering tools that quantify food textures on oral surfaces, using fresh pig tongues. Oral-texture (i.e., mouthfeel) parameters, including viscosity and sliding friction, were shown to mediate monkeys' preferences for high-fat foods. When translated to human subjects, this approach revealed a neural mechanism for preferring high-fat foods from oral texture in the orbitofrontal cortex (OFC)-a key reward system of the brain. Importantly, human OFC responses to oral sliding friction in individual subjects-measured in the MRI scanner-predicted subsequent fat intake in a naturalistic, life-like eating test. These findings suggest that a primate nutrient-reward paradigm offers a promising approach for investigating the behavioral and neural mechanisms for human-typical food reward and food choice, to advance understanding of human eating behavior, overeating, and obesity.
Early-Onset Cone Photoreceptor Degeneration Is Associated With High Myopia in RPGR-Related Retinal Dystrophy.
Purpose: High myopia is a feature of several inherited retinal diseases, including X-linked retinitis pigmentosa (XLRP) which is characterized by childhood onset, centripetal photoreceptor degeneration, and rapid progression to blindness by the fourth decade. Mutations in the retinitis pigmentosa GTPase regulator (RPGR) gene cause over 90% of XLRP cases. It presents with a varied clinical phenotype, categorized into the predominant rod-cone, cone-rod, and cone dystrophy. This case-series study examines the clinical characteristics of patients with RPGR-related retinal dystrophy to identify associations with refractive error. Methods: Data collected between October 2023 and April 2024 from retinal imaging, clinical ophthalmic examination, and genetic analysis were retrospectively analyzed. Results: Twenty-four male patients were identified, with a mean age of 30 years (range 7-57). The median (IQR) best-corrected visual acuity was 60 (55-66) letters in the cone-rod/cone phenotype and 65 (49-73) letters in the rod-cone phenotype. High axial myopia showed preponderance in cone-dominated degenerations. Estimated mean refractive error was -7.92DS (95% CI: [-11.39, -4.44]) in the cone-rod phenotype and -3.52DS (95% CI: [-5.87, -1.17]) in the rod-cone phenotype, adjusting for age and genetic mutation. This difference between phenotype was significant (p=0.041). In a subanalysis, no significant association was found between refractive error and nucleotide position. Evaluation of disease progression found that all patients with a fast-progressing, rod-cone phenotype had high myopia. Conversely, one patient who presented with a slow-progressing, cone-rod phenotype did not have high myopia. Conclusions: Refractive trends in this cohort suggest that cone photoreceptor degeneration occurring during early childhood is associated with high myopia. Image degradation primarily due to cone photoreceptor dysfunction may act as a stimulus to drive myopia development in early childhood. These observations advocate for the earlier treatment of myopia in cone-dominated RPGR-related retinal dystrophy to preserve retinal function and minimize the risks of retinal gene therapy surgery for patients enrolling in clinical trials. Trial Registration: ClinicalTrials.gov identifier: NCT03116113.
Click biology highlights the opportunities from reliable biological reactions.
Click chemistry is a powerful concept that refers to a set of covalent bond-forming reactions with highly favorable properties. In this Perspective, I outline the analogous concept of click biology as a set of reactions derived from the regular building blocks of living cells, rapidly forming covalent bonds to specific partners under cell-friendly conditions. Click biology using protein components employs canonical amino acids and may react close to the diffusion limit, with selectivity in living cells amid thousands of components generated from the same building blocks. I discuss how the criteria for click chemistry can be applied or modified to fit the extra constraints of click biology and achieve favorable characteristics for biological research. Existing reactions that may be described as click biology include split intein reconstitution, spontaneous isopeptide bond formation by SpyTag and SpyCatcher and suicide enzyme reaction with small-molecule ligands (HaloTag and SNAP-tag). I also describe how click biology has created new possibilities in fields including molecular imaging, mechanobiology, vaccines and engineering cellular intelligence.
Permissive central tolerance plus defective peripheral checkpoints license pathogenic memory B cells in CASPR2-antibody encephalitis.
Autoantibody-mediated diseases targeting one autoantigen provide a unique opportunity to comprehensively understand the development of disease-causing B cells and autoantibodies. Convention suggests that such autoreactivities are generated during germinal center reactions. Here, we explore earlier immune checkpoints, focusing on patients with contactin-associated protein-like 2 (CASPR2)-autoantibody encephalitis. In both disease and health, high (~0.5%) frequencies of unmutated CASPR2-reactive naïve B cells were identified. By contrast, CASPR2-reactive memory B cells were exclusive to patients, and their B cell receptors demonstrated affinity-enhancing somatic mutations with pathogenic effects in neuronal cultures and mice. The unmutated, precursor memory B cell receptors showed a distinctive balance between strong CASPR2 reactivity and very limited binding across the remaining human proteome. Our results identify permissive central tolerance, defective peripheral tolerance, and autoantigen-specific tolerance thresholds in humans as sequential steps that license CASPR2-directed pathology. By leveraging the basic immunobiology, we rationally direct tolerance-restoring approaches, with an experimental paradigm applicable across autoimmunity.
Distinctive seizure signature in the first video case-control study of a naturally-occurring feline autoimmune encephalitis model.
BACKGROUND AND OBJECTIVE: Autoimmune encephalitis (AE) is a form of brain inflammation where pathogenic autoantibodies bind surface proteins. In humans, AE is at least as common as infective encephalitis, and seizures are a prominent manifestation. The most common adult human AE is associated with antibodies to leucine-rich glioma-inactivated 1 (LGI1-Ab-E). AE in non-human mammals is also recognised, notably the polar bear 'Knut', diagnosed with N-methyl D-aspartate receptor antibody encephalitis. LGI1-Ab-E is an emerging cause of spontaneously-arising AE in domestic cats. Our objective was to phenotype the seizure profile of feline LGI1-Ab-E and probe parallels to its human counterpart. METHODS: We characterised seizures in naturally-occurring feline LGI1-Ab-E. Three veterinary and two human neurologists independently blind-rated 35 LGI1-antibody positive and negative feline seizure videos from 24 cats (16 LGI1-Ab-E positive, 8 negative). Data analysed included seizure frequency, semiologies and their co-occurrence, localisation, inter-rater agreement, and predictive factors. RESULTS: The mean number of daily seizures at peak was significantly higher in LGI1-antibody positive compared to LGI1-antibody-negative cats (12.6 vs. 1.9/day, pcorr = 0.011). Semiologies statistically significantly enriched in LGI1-Ab-E observations included orofacial automatisms (88/120, 73 % vs. 26/55, 47 %, pcorr = 0.024), salivation (87/120, 73 % vs. 23/55, 42 %, pcorr = 0.004); and mydriasis (79/120, 66 % vs 19/55, 35 %, pcorr = 0.004), and almost exclusively seen in LGI1-Ab-E were circling (39/120, 33 % vs. 1/55, 2 %, pcorr=<0.001) and aggression (14/120, 12 % vs. 0/55, 0 %, non significant after correction). A temporal lobe onset was proposed in 67 % (80/120) of seropositive ratings, compared to 28 % (15/55) LGI1-Ab-E negative (p
Neuronal pSTAT1 hallmarks synaptic pathology in autoimmune encephalitis against intracellular antigens.
Autoimmune encephalitis (AE) is an inflammatory syndrome of the central nervous system (CNS) triggered by aberrant immune responses against neuronal intracellular (IC-AE) or surface (NS-AE) autoantigens. The resulting neuronal alterations and clinical trajectories differ, with IC-AE often leading to fatal outcomes. Unfortunately, the scarce availability of tissue from AE cases has hampered systematic analyses that would allow an understanding of the pathogenesis underlying neuronal alterations in T cell-mediated AE syndromes. Here, we assembled a cohort comprising both NS-AE (n = 8) and IC-AE (n = 12) from multiple institutions to delineate key histopathological features that distinguish neuronal pathology between IC-AE and NS-AE. In contrast to NS-AE, IC-AE lesions present a prominent neuronal pSTAT1 signature, accompanied by a high proportion of brain-resident memory CD8 + T cells and neurodegenerative GPNMB + phagocytes which show synaptic engulfment with little C3-complement deposition. Our findings highlight distinct histopathological features of IC-AE compared to NS-AE, providing actionable biomarkers for diagnostics and treatment strategies.
P21-Activated Kinase 2 as a Novel Target for Ventricular Tachyarrhythmias Associated with Cardiac Adrenergic Stress and Hypertrophy.
Ventricular arrhythmias associated with cardiac adrenergic stress and hypertrophy pose a significant clinical challenge. We explored ventricular anti-arrhythmic effects of P21-activated kinase 2 (Pak2), comparing in vivo and ex vivo cardiomyocyte-specific Pak2 knockout (Pak2cko) or overexpression (Pak2ctg) murine models, under conditions of acute adrenergic stress, and hypertrophy following chronic transverse aortic constriction (TAC). Pak2 was downregulated 5 weeks following the latter TAC challenge. Cellular physiological, optical action potential and Ca2+ transient, measurements, demonstrated increased incidences of triggered ventricular arrhythmias, and prolonged action potential durations (APD) and altered Ca2+ transients with increases in their beat-to beat variations, in Pak2cko hearts. Electron microscopic, proteomic, and molecular biological methods revealed a mitochondrial localization of stress-related proteins on proteomic and phosphoproteomic analyses, particularly in TAC stressed Pak2cko mice. They further yielded accompanying evidence for mitochondrial oxidative stress, increased reactive oxygen species (ROS) biosynthesis, reduced mitochondrial complexes I-V, diminished ATP synthesis and elevated NADPH oxidase 4 (NOX4) levels. Pak2 overexpression and the novel Pak2 activator JB2019A ameliorated these effects, enhanced cardiac function and decreased the frequencies of triggered ventricular arrhythmias. Pak2 activation thus protects against ventricular arrhythmia associated with cardiac stress and hypertrophy, through unique mechanisms offering potential novel therapeutic anti-arrhythmic targets.
p21-Activated Kinases Present a New Drug Target for Hypertrophic Cardiomyopathy
Hypertrophic cardiomyopathy (HCM), primarily involving mutations in sarcomeric proteins, is the most common form of inherited heart disease and a leading cause of sudden death in young adults and athletes. HCM patients present with cardiac hypertrophy, fibrosis, and diastolic dysfunction often in a progressive manner. Despite significant progress made in understanding the molecular genetic basis of HCM, there remains a lack of effective and specific treatment for preventing disease progression in HCM. This article first provides an overview of recent progress in understanding the pathogenic basis of disease progression in HCM, in particular dysfunctional calcium handling, mitochondrial impairment, and endoplasmic reticulum stress. This article then analyses the evidence for critical roles of the multifunctional enzymes P21-activated kinase-1 and 2 (Pak1/2) in the heart and our opinion on their therapeutic value as a promising druggable target in pathological hypertrophy and associated ventricular arrhythmias.