bluuebunny/crossref_metadata_2025 huggingface dataset:
Exploring the roles of memory replay in targeted memory reactivation and birdsong development: Insights from computational models of complementary learning systems
Authors: Yihe Lu , Földes Tamás , Lewis Penelope A
Published: October 2024

Replay facilitates memory consolidation in both biological and artificial systems. Using the complementary learning systems (CLS) framework, we study replay in both humans and birds through computational modelling. We investigate impacts of replay triggered by targeted memory reactivation during sleep and experiments examining how sleep affects the development of birdsong in young songbirds. We show that qualitatively realistic sleep effects can be captured by highly abstracted, idealised CLS models. Our modelling sheds theoretical insights on the mechanisms underlying both strengthening and weakening effects of targeted memory reactivation, and supports the empirical hypothesis that replay drives overnight performance deterioration and correlates positively with the final performance in birdsong development.

Author summary

Taking a computational approach, we investigated the roles of memory replay in two complementary learning systems (CLS) models capturing realistic sleep effects observed in two real-life experiments on targeted memory reactivation (TMR) and birdsong development respectively. Our two CLS models are abstract and identical in architecture, and they are distinct in terms of where replay is generated. While the TMR model produces replay samples using its hippocampus, the birdsong model does so using the sensorimotor cortex. We found that certain TMR effects could characterise different TMR models, which might account for individual differences in human subjects. The results of the birdsong model support the idea that the dramatic overnight oscillations in performance accuracy which are observed during birdsong development are mainly driven by memory replay, and that long-term performance gain can be achieved despite short-term performance deterioration during the early nights of development. As we studied the two experiments using the unified CLS framework, we discuss how replay contributes to sleep-dependent performance changes from the perspective of systems consolidation.
The functional impact of LGI1 autoantibodies on human CA3 pyramidal neurons
Authors: Monni Laura , Kornau Hans-Christian , Podestà Alice , Stumpf Alexander , Kalbhenn Thilo , Simon Matthias , Sauvigny Thomas , Onken Julia , Prüss Harald , Alle Henrik , Geiger Jörg R.P. , Holtkamp Martin , Schmitz Dietmar , Fidzinski Pawel
Published: October 2024

Autoantibodies against leucine-rich glioma inactivated 1 protein (LGI1 mAb) lead to limbic encephalitis characterized by seizures and memory deficits. While animal models provide insights into mechanisms of LGI1 mAb action, species-specific confirmation is lacking. In this study, we investigated the effects of patient-derived LGI1 mAb on human CA3 neurons using culturedex vivoslices. Analysis of intrinsic properties and morphology indicated functional integrity of these neurons under incubation conditions. Human CA3 neurons received spontaneous excitatory currents with large amplitudes and frequencies, suggestive of “giant” AMPA currents. In slices exposed to LGI1 mAb, human CA3 neurons displayed increased neuronal spike frequency, mirroring effects observed with the Kv1.1 channel blocker DTX-K. This increase likely resulted from decreased Kv1.1 channel activity at the axonal initial segment, as indicated by alterations in action potential properties. A detailed analysis revealed differences between LGI1 mAb and DTX-K effects on action potential properties, suggesting distinct mechanisms of action and emphasizing the need for further exploration of downstream pathways. Our findings underscore the importance of species-specific confirmatory studies of disease mechanisms and highlight the potential of human hippocampal slice cultures as a translational model for investigation of disease mechanisms beyond epilepsy, including the effects of pharmacological compounds and autoantibodies.

Significance

This study advances our understanding of how autoantibodies against the LGI1 protein, known to cause limbic encephalitis, impact human neurons. By using cultured slices of human hippocampus derived from epilepsy’s surgical resections, we were able to observe the direct effects of these autoantibodies on neurons, specifically CA3 pyramidal cells. Our findings reveal that the autoantibodies increase neuronal activity, similar to what is seen with potassium channel blockers and in animal models. This work emphasizes the importance of studying living tissue from the human brain to confirm disease mechanisms, and demonstrates the potential of using human brain slices as a model for exploring not only epilepsy but also other neurological diseases and drug effects.
Orthogonal spectral and temporal envelope representation in auditory cortex
Authors: Takahashi Kuniyuki , Guo Tianrui , Yamagishi Tatsuya , Ohshima Shinsuke , Tsukano Hiroaki , Horii Arata
Published: October 2024

Speech sounds are acoustically composed of two main components: spectral and temporal. The spectral component or carrier frequency is important for pitch detection and is perceived through activity at specific locations on the tonotopic map in the auditory cortex. The temporal envelope—the dynamic changes in sound wave amplitude over time—plays an essential role in speech perception by mediating phoneme recognition. However, how the steepness of the envelope, which shapes the temporal structure, is represented in the auditory cortex remains poorly understood. This study investigates how the steepness of the envelope of sound waves is represented as a functional organization in the mouse auditory cortex, in relation to spectral tonotopic organization. Using macroscale calcium imaging in GCaMP6f-expressing mice, we mapped the auditory cortex’s responses to tones with systematically varying rise-ramp steepness and frequencies. Our findings reveal that, in two primary-like regions of the auditory cortex, the steepness of the rise ramp is orderly mapped orthogonally to the tonotopic gradient, forming a two-dimensional representation on the cortical surface. Conversely, a significant representation of rise-ramp steepness was not detected in higher-order-like auditory regions. These findings suggest that a dichotomous functional organization independently processes temporal envelopes and spectral features within mammalian auditory cortical areas, with functional structures mirroring the two acoustic structures.
Inducing a synergistic anti-obesity effect by increasing the bioavailability of the flavonoid rutin with aL. plantarumspecies
Authors: Kang Youn-Goo , Jang Seongjae , Seo Jongcheol , Kim Ah-Ram
Published: October 2024

Flavonoids, plant-derived compounds, are broadly categorized into glycoside (sugar-bonded) and aglycone (sugar-removed) forms and are predominantly found as glycosides in nature. Rutin, a glycoside, is a widely recognized flavonoid with significant potential as an anti-obesity agent. However, its low bioavailability in the body presents challenges in obesity treatment. We aimed to enhance the bioavailability and anti-obesity effect of rutin through microbial involvement.Lactiplantibacillus plantarumHAC03, one of the candidates, demonstrated the ability to hydrolyze rutin into isoquercetin and quercetinin vitro. In a diet-induced obesity mouse model, the combination of rutin and theL. plantarumstrain resulted in significant weight loss, reduced adipocyte size and lowered obesity-related biomarkers in the blood, decreased fat-synthesis related gene expression, and increased fatty acid β-oxidation related gene expression compared to other test groups. This includes groups treated with rutin or quercetin alone or in combination with a different species from the sameLactobacillusgenus, known for its anti-obesity effect but lacking the ability to hydrolyze rutin. This synergistic combination also alleviated insulin resistance and reduced fat in the liver. Gut microbiota analysis revealed localization ofL. plantarumin the ileum and beneficial changes in disrupted microbiota in the intestine. These findings provide insights into underlying mechanisms causing the synergistic effect and suggest a novel combination that is as safe as microbial monotherapies withL. plantarumorL. rhamnosusbut more effective in anti-obesity treatment.
The mechanism of spatial pattern transition in motile bacterial collectives
Authors: Saulnier Jean-Baptiste , Romanos Michèle , Schrohe Jonathan , Cuzin Clémence , Calvez Vincent , Mignot Tâm
Published: October 2024

Understanding how individual behaviours contribute to collective actions is key in biological systems. InMyxococcus xanthus, a bacterial predator, swarming shifts to rippling patterns due to changes in the local environment near prey colonies. Through high-resolution microscopy and theoretical analysis, we demonstrate that two key properties drive this shift: local cellular alignment guided by an extracellular matrix and the ability of cells to reverse to resolve congestion. A tunable refractory period in the reversal system enables collective adaptation, allowing cells to synchronise in rippling and resolve congestion in swarming. These transitions occur without changes in genetic regulation but create stable spatial domains that promote local differentiation, a mechanism of spatial sorting that may be widespread in biology.
Functional interaction between transcription factor Sfp1 and the NuA4 complex in response to nutrient availability
Authors: Xu Ke , Joly Beauparlant Charles , Bianco Stéphanie , Côté Valérie , Hermann Lara , Droit Arnaud , Downey Michael , Nourani Amine , Côté Jacques
Published: October 2024

Ribosome biogenesis is a crucial process requiring enormous transcriptional output. In budding yeast, the expression of 138 ribosomal protein (RP) genes and over 200 ribosome biogenesis (RiBi) genes is regulated by and intricate network of factors, including the nutrient-sensitive transcription activator Sfp1 and the NuA4 coactivator/acetyltransferase complex. Nutrient starvation or inhibition of TORC1 by rapamycin leads to repression of RP and RiBi genes, in part through blocking Sfp1 nuclear localization and NuA4-dependent chromatin acetylation. Here, we demonstrate that Sfp1 physically interacts with NuA4 in a TORC1-independent manner. Our results indicate that Sfp1, along with NuA4, regulate transcription of RiBi and RP genes via distinct mechanisms depending on promoter architectures. Sfp1 promotes NuA4-dependent histone acetylation at the promoter of RiBi and RP genes without affecting NuA4 recruitment. In contrast, NuA4 does impact Sfp1 binding but specifically at two classes of RP genes. Importantly, we found that NuA4 acetylates Sfp1 at lysines 655 and lysine 657, regulating its function. Cells expressing Sfp1 with acetyl-mimicking mutations exhibit increased expression of RiBi genes while RP genes remain stable. However, the same mutants lead to the loss of Sfp1 binding/activity at RiBi genes when cells are under non-optimal growth conditions. Mimicking constitutive acetylation of Sfp1 also limits the transcriptional burst of RP genes upon addition of glucose. Altogether, these results draw an intricate functional relationship between Sfp1 and NuA4 to control ribosome biogenesis, fine-tuning transcription output in different growth conditions.
Nanoscale 3D DNA tracing reveals the mechanism of self-organization of mitotic chromosomes
Authors: Beckwith Kai Sandvold , Brunner Andreas , Morero Natalia Rosalia , Jungmann Ralf , Ellenberg Jan
Published: October 2024

How genomic DNA is folded during cell division to form the characteristic rod-shaped mitotic chromosomes essential for faithful genome inheritance is a long-standing open question in biology. Here, we use nanoscale DNA-tracing in single dividing cells to directly visualize how the 3D fold of genomic DNA changes during mitosis, at scales from single loops to entire chromosomes. Our structural analysis reveals a characteristic genome scaling minimum at 6-8 Mbp in mitosis. Combined with data-driven modeling and molecular perturbations, we can show that very large and strongly overlapping loops formed by Condensins are the fundamental structuring principle of mitotic chromosomes. These loops compact chromosomes locally and globally to the limit set by chromatin self-repulsion. The characteristic length, density and increasingly overlapping structure of mitotic loops we observe in 3D, fully explain how the rod-shaped mitotic chromosome structure emerges by self-organization during cell division.
Making Neurobots and Chimerical Ctenophores
Authors: Moroz Leonid L , Norekian Tigran P.
Published: October 2024

Making living machines using biological materials (cells, tissues, and organs) is one of the challenges in developmental biology and modern biomedicine. Constraints in regeneration potential and immune self-defense mechanisms limit the progress in the field. Here, we present unanticipated features related to self-recognition and ancestral neuro-immune architectures of new emerging reference species - ctenophores or comb jellies. These are descendants of the earliest survival metazoan lineage with unique tissues, organs and independent origins of major animal traits such as neurons, muscles, mesoderm, and through-gut. Thus, ctenophores convergently evolved complex organization, compared to bilaterians. Nevertheless, their neural and immune systems are likely functionally coupled, enabling designs and experimental construction of hybrid neural systems and even entire animals. This report illustrates impressive opportunities to build both chimeric animals and neurobots using ctenophores as models for bioengineering. The obtained neurobots and chimeric animals from three ctenophore species (Bolinopsis, Mnemiopsis, andPleurobrachia) were able to be autonomous and survive for days. In sum, the unification of biodiversity, cell biology, and neuroscience opens unprecedented opportunities for experimental synthetic biology.
Temperature affects conspecific and heterospecific mating rates inDrosophila
Authors: Rader Jonathan A. , Matute Daniel R.
Published: October 2024

Behavioral mating choices and mating success are important factors in the development of reproductive isolation during speciation. Environmental conditions, especially temperature, can affect these key traits. Environmental conditions can vary across, and frequently delimit species’ geographic ranges. Pairing suboptimal conditions with relative rarity of conspecifics at range margins may set the stage for hybridization. Despite the importance of mating behaviors as a reproductive barrier, a general understanding of the interaction between behavioral choices and the environment is lacking, in part because systematic studies are rare. With this report, we begin to bridge that gap by providing evidence that temperature has a significant - but not consistent influence on mating choices and success, and thus on reproductive isolation inDrosophila. We studied mating propensity and success at four different temperatures among 14Drosophilaspecies in non-choice conspecific mating trials and in heterospecific trials among twoDrosophilaspecies triads that are known to regularly hybridize in the wild. We show that mating frequency varies significantly across a 10°C range (from 18ºC to 28ºC), both in 1:1 mating trials and in high-densityen-massetrials, but that the effect of temperature is highly species-specific. We also show that mating frequency is consistently low and that temperature has a moderate effect in some heterospecific crosses. As conspecific mating propensity decreases outside of the optimal thermal range, while heterospecific matings remain constant, the proportion of heterospecific matings at suboptimal temperatures is relatively high. This result indicates that temperature can modulate behavioral choices that impose reproductive barriers and influence the rate of hybridization. More broadly, our results demonstrate that to truly understand how mating choice and reproductive isolation occur in nature, they need to be studied in an environmental context.
Inclusivity in fNIRS Studies: Quantifying the Impact of Hair and Skin Characteristics on Signal Quality with Practical Recommendations for Improvement
Authors: Yücel Meryem A , Anderson Jessica E , Rogers De'Ja , Hajirahimi Parisa , Farzam Parya , Gao Yuanyuan , Kaplan Rini I , Braun Emily J , Muqadam Nishaat , Duwadi Sudan , Carlton Laura , Beeler David , Butler Lindsay , Carpenter Erin , Girnis Jaimie , Wilson John , Tripathi Vaibhav , Zhang Yiwen , Sorger Bettina , von Lühmann Alexander , Somers David , Cronin-Golomb Alice , Kiran Swathi , Ellis Terry D , Boas David A
Published: October 2024

Functional Near-Infrared Spectroscopy (fNIRS) holds transformative potential for research and clinical applications in neuroscience due to its non-invasive nature and adaptability to real-world settings. However, despite its promise, fNIRS signal quality is sensitive to individual differences in biophysical factors such as hair and skin characteristics, which can significantly impact the absorption and scattering of near-infrared light. If not properly addressed, these factors risk biasing fNIRS research by disproportionately affecting signal quality across diverse populations. Our results quantify the impact of various hair properties, skin pigmentation as well as head size, sex and age on signal quality, providing quantitative guidance for future hardware advances and methodological standards to help overcome these critical barriers to inclusivity in fNIRS studies. We provide actionable guidelines for fNIRS researchers, including a suggested metadata table and recommendations for cap and optode configurations, hair management techniques, and strategies to optimize data collection across varied participants. This research paves the way for the development of more inclusive fNIRS technologies, fostering broader applicability and improved interpretability of neuroimaging data in diverse populations.
The claustrum is critical for maintaining working memory information
Authors: Bhattacharjee Anindya S. , Huber Chieko , Unsal Burak , Renfer Jean-Rodolphe , Rodriguez Ivan , Carleton Alan
Published: October 2024

Working memory (WM) enables the mammalian brain to temporarily store and manipulate information, supporting cognitive tasks and communication processes1,2. Rather than depending on a single specialized area, WM is thought to operate through a distributed network spanning cortical and subcortical regions3–5. A dedicated WM storage area would likely require broad reciprocal connections with various cortical regions to accommodate the diverse range of information WM retains. The claustrum (CLA), with its extensive bidirectional connections to the neocortex6–9, presents a compelling candidate for such a role. Here, we examined the involvement of the CLA in WM processes by recording CLA neuronal activity in mice engaged in olfactory and tactospatial delayed non-match-to-sample WM tasks. We identified cue- selective and delay-specific neurons in the CLA that maintained activity for tens of seconds after the stimulus presentation ended. Additionally, population activity in the CLA allowed for decoding of cue identity post-stimulus, although this signal gradually declined over time, aligning with animal behavior. Remarkably, both chemo- and optogenetic inhibition of CLA neurons severely impaired WM performance across multiple types of stored information, highlighting the CLA’s critical role during both cue encoding, delay periods, and target comparison phases. These findings challenge the view that no single brain area is essential for WM storage and support a role for the CLA as an essential WM storage hub.
Microsaccades strongly modulate but do not cause the N2pc EEG marker of spatial attention
Authors: Liu Baiwei , Kong Siyang , van Ede Freek
Published: October 2024

The N2pc is a popular human-neuroscience marker of covert and internal spatial attention that occurs 200-300 ms after being prompted to shift attention – a time window also characterised by the spatial biasing of microsaccades. Here we show how co-occurring microsaccades profoundly modulate N2pc amplitude during the top-down deployment of spatial attention in both perception and working memory. At the same time, we show that a significant – even if severely weakened – N2pc can still be established in the absence of co-occurring microsaccades. Thus, while microsaccade presence and direction strongly modulate N2pc amplitude, microsaccades are not strictly a prerequisite for the N2pc to be observed.
Shifts in Naturalistic Behaviors Induced by Early Social Isolation Stress are Associated with Adult Binge-like Eating in Female Rats
Authors: Simon Timothy B. , Sierra Julio , Williams Arianna , Wright Giara , Rhee Allison , Horn Julius , Lou John , Sharafeddin Fransua , Ontiveros-Angel Perla , Figueroa Johnny D.
Published: October 2024

Binge eating (BE) is a highly pervasive maladaptive coping strategy in response to severe early life stress such as emotional and social neglect. BE is described as repeated episodes of uncontrolled eating and is tightly linked with comorbid mental health concerns. Despite social stressors occurring at a young age, the onset of BE typically does not occur until adulthood providing an interval for potential therapeutic intervention. Currently, our knowledge of longitudinal noninvasive digital biomarkers predictive of BE needs further development. Monitoring longitudinal impacts of adolescent social isolation stress on naturalistic behaviors in rats will enable the identification of noninvasive digital markers of disease progression to predict adult eating strategies. Recognizing adolescent naturalistic behaviors shaped by social stress informs our understanding of the underlying neurocircuits most effected. This study aimed to monitor and identify longitudinal behavioral shifts to enhance predictive capabilities in a rat model of social isolation stress-induced BE. We placed Paired (n=12) and Socially Isolated (SI, n=12) female rats in observational home cages weekly for seven weeks to evaluate the effect of SI on 10 naturalistic behaviors. All 10 naturalistic behaviors were simultaneously detected and tracked using Noldus Ethovision XT automated recognition software. Composite phenotypic z-scores were calculated by standardizing all 10 behaviors. When transitioning into adulthood, all rats underwent conventional emotionality testing and were exposed to a Western-like high fat diet (WD, 43% kcal from fat) to evaluate BE. Longitudinal assessments revealed SI-induced shifts in adolescent phenotypic z-scores and that sniffing, unsupported rearing, jumping, and twitching were the most susceptible to SI. SI increased emotionality compared to the Paired controls. Finally, we identified adolescent twitching as a digital biomarker of adult WD consumption. This study employed novel approaches to identify early life predictive biomarkers of adult eating strategies and laid a foundation for future investigations.
Catecholamines reduce choice history biases
Authors: de Gee Jan Willem , Kloosterman Niels A , Braun Anke , Donner Tobias H
Published: October 2024

Theoretical accounts postulate that the catecholaminergic neuromodulator noradrenaline shapes cognitive behavior by reducing the impact of prior expectations on learning, inference, and decision-making. A ubiquitous effect of dynamic priors on perceptual decisions under uncertainty is choice history bias: the tendency to systematically repeat, or alternate, previous choices, even when stimulus categories are presented in a random sequence. Here, we directly test for a causal impact of catecholamines on these priors. We pharmacologically elevated catecholamine levels through the application of the noradrenaline reuptake inhibitor atomoxetine. We quantified the resulting changes in observers' history biases in a visual perceptual decision task. Choice history biases in this task were highly idiosyncratic, tending toward choice repetition or alternation in different individuals. Atomoxetine decreased these biases (toward either repetition or alternation) compared to placebo. Behavioral modeling indicates that this bias reduction was due to a reduced bias in the accumulation of sensory evidence, rather than of the starting point of the accumulation process. Atomoxetine had no significant effect on other behavioral measures tested, including response time and choice accuracy. We conclude that catecholamines reduce the impact of a specific form of prior on perceptual decisions.
Epigenetic constraint of cellular genomes evolutionarily links genetic variation to function
Authors: Sinniah Enakshi , Mizikovsky Dalia , Shim Woo Jun , Chow Chris Siu Yeung , Souilmi Yassine , Cheng Fei-Fei , Zeng Zhili , Laurie Jordan , Foster Matthew , Shah Sonia , Bodén Mikael , Zeng Jian , Llamas Bastien , Palpant Nathan J.
Published: October 2024

Cellular diversity is a product of evolution acting to drive divergent regulatory programs from a common genome. Here, we use cross-cell-type epigenetic conservation to gain insight into the impact of selective constraints on genome function and phenotypic variation. By comparing chromatin accessibility across hundreds of diverse cell-types, we identify 1.4% of the human genome safeguarded by conserved domains of facultative heterochromatin, which we term regions under “cellular constraint”. We calculate single-base resolution cellular constraint scores and demonstrate robust prediction of functionally important coding and non-coding loci in a cell-type-, trait-, and disease-agnostic manner. Cellular constraint annotation enhances causal variant identification, drug discovery, and clinical diagnostic predictions. Furthermore, cell-constrained sequences share paradoxical evolutionary signals of positive and negative selection, suggesting a dynamic role in driving human adaptation. Overall, this study demonstrates that evolutionary chromatin dynamics can be leveraged to inform the translation of genetic discoveries into effective biological, therapeutic, and clinical outcomes.
Structure of a Putative Terminal Amidation Domain in Natural Product Biosynthesis
Authors: Rankin Michael R. , Khare Dheeraj , Gerwick Lena , Sherman David H. , Gerwick William H. , Smith Janet L.
Published: October 2024

Bacteria are rich sources of pharmaceutically valuable natural products, many crafted by modular polyketide synthases (PKS) and non-ribosomal peptide synthetases (NRPS). PKS and NRPS systems typically contain a thioesterase (TE) to offload a linear or cyclized product from a carrier protein, but alternative chemistry is needed for products with a terminal amide. Several pathways with amidated products also possess an uncharacterized 400-amino acid terminal domain. We present the characterization and structure of this putative terminal amidation domain (TAD). TAD binds NAD with the nicotinamide near an invariant cysteine that is also accessible to an intermediate on a carrier protein, indicating a catalytic role. The TAD structure resembles cyanobacterial acyl-ACP reductase (AAR), which binds NADPH near an analogous catalytic cysteine. Bioinformatic analysis reveals that TADs are broadly distributed across bacterial phyla and often occur at the end of terminal NRPS modules, suggesting many amidated products may yet be discovered.
Levetiracetam prevents Aβ42 production through SV2a-dependent modulation of App processing in Alzheimer’s disease models
Authors: Rao Nalini R. , DeGulis Olivia , Nomura Toshihiro , Lee SeungEun , Hark Timothy J. , Dynes Justin C. , Dexter Emily X. , Dulewicz Maciej , Ge Junyue , Upadhyay Arun , Fornasiero Eugenio F. , Vassar Robert , Hanrieder Jörg , Contractor Anis , Savas Jeffrey N.
Published: October 2024

In Alzheimer’s disease (AD), amyloid-beta (Aβ) peptides are produced by proteolytic cleavage of the amyloid precursor protein (APP), which can occur during synaptic vesicle (SV) cycling at presynapses. Precisely how amyloidogenic APP processing may impair presynaptic proteostasis and how to therapeutically target this process remains poorly understood. UsingAppknock-in mouse models of early Aβ pathology, we found proteins with hampered degradation accumulate at presynaptic sites. At this mild pathological stage, amyloidogenic processing leads to accumulation of Aβ42inside SVs. To explore if targeting SVs modulates Aβ accumulation, we investigated levetiracetam (Lev), a SV-binding small molecule drug that has shown promise in mitigating AD-related pathologies despite its mechanism of action being unclear. We discovered Lev reduces Aβ42levels by decreasing amyloidogenic processing of APP in a SV2a-dependent manner. Lev corrects SV protein levels and cycling, which results in increased surface localization of APP, where it favors processing via the non-amyloidogenic pathway. Using metabolic stable isotopes and mass spectrometry we confirmed that Lev prevents the production of Aβ42in vivo. In transgenic mice with aggressive pathology, electrophysiological and immunofluorescent microscopy analyses revealed that Lev treatment reduces SV cycling and minimizes synapse loss. Finally, we found that human Down syndrome brains with early Aβ pathology, have elevated levels of presynaptic proteins, confirming a comparable presynaptic deficit in human brains. Taken together, we report a mechanism that highlights the therapeutic potential of Lev to modify the early stages of AD and represent a promising strategy to prevent Aβ42pathology before irreversible damage occurs.

One Sentence Summary

We discovered that the SV-binding drug levetiracetam prevents Aβ42production by modulating SV cycling which alters APP localization and thus proteolytic processing, highlighting its therapeutic potential for AD.
Mechanism of NACHO-mediated assembly of pentameric ligand-gated ion channels
Authors: Hooda Yogesh , Sente Andrija , Judy Ryan M. , Smalinskaitė Luka , Chew Sew-Yeu Peak- , Naydenova Katerina , Malinauskas Tomas , Hardwick Steven W. , Chirgadze Dimitri Y. , Aricescu A. Radu , Hegde Ramanujan S.
Published: October 2024

Pentameric ligand-gated ion channels (pLGICs) are cell surface receptors of crucial importance for animal physiology1–4. This diverse protein family mediates the ionotropic signals triggered by major neurotransmitters and includesγ-aminobutyric acid receptors (GABAARs) and acetylcholine receptors (nAChRs). Receptor function is fine-tuned by a myriad of endogenous and pharmacological modulators3. A functional pLGIC is built from five homologous, sometimes identical, subunits, each containing a β-scaffold extracellular domain (ECD), a four-helix transmembrane domain (TMD) and intracellular loops of variable length. Although considerable progress has been made in understanding pLGICs in structural and functional terms, the molecular mechanisms that enable their assembly at the endoplasmic reticulum (ER)5in a vast range of potential subunit configurations6remain unknown. Here, we identified candidate pLGICs assembly factors selectively associated with an unassembled GABAAR subunit. Focusing on one of the candidates, we determined the cryo-EM structure of an assembly intermediate containing two α1 subunits of GABAAR each bound to an ER-resident membrane protein NACHO. The structure showed how NACHO shields the principal (+) transmembrane interface of α1 subunits containing an immature extracellular conformation. Crosslinking and structure-prediction revealed an adjacent surface on NACHO for β2 subunit interactions to guide stepwise oligimerisation. Mutations of either subunit-interacting surface on NACHO also impaired the formation of homopentameric α7 nAChRs, pointing to a generic framework for pLGIC assembly. Our work provides the foundation for understanding the regulatory principles underlying pLGIC structural diversity.
Resolving complex duplication variants in autism spectrum disorder using long-read genome sequencing
Authors: Eisfeldt Jesper , Higginbotham Edward J. , Lenner Felix , Howe Jennifer , Fernandez Bridget A. , Lindstrand Anna , Scherer Stephen W. , Feuk Lars
Published: October 2024

Rare or de novo structural variation, primarily in the form of copy number variants, is detected in 5%–10% of autism spectrum disorder (ASD) families. While complex structural variants involving duplications can generally be detected using microarray or short-read genome sequencing (GS), these methods frequently fail to characterize breakpoints at nucleotide resolution, requiring additional molecular methods for validation and fine-mapping. Here, we use Oxford Nanopore Technologies PromethION long-read GS to characterize complex genomic rearrangements (CGRs) involving large duplications that segregate with ASD in five families. In total, we investigated 13 CGR carriers and were able to resolve all breakpoint junctions at nucleotide resolution. While all breakpoints were identified, the precise genomic architecture of one rearrangement remained unresolved with three different potential structures. The findings in two families include potential fusion genes formed through duplication rearrangements, involvingIL1RAPL1–DMDandSUPT16H–CHD8. In two of the families originating from the same geographical region, an identical rearrangement involvingANK2was identified, which likely represents a founder variant. In addition, we analyze methylation status directly from the long-read data, allowing us to assess the activity of rearranged genes and regulatory regions. Investigation of methylation across the CGRs reveals aberrant methylation status in carriers across a rearrangement affecting theCREBBPlocus. In aggregate, our results demonstrate the utility of nanopore sequencing to pinpoint CGRs associated with ASD in five unrelated families, and highlight the importance of a gene-centric description of disease-associated complex chromosomal rearrangements.
Long-read RNA sequencing reveals allele-specific N6-methyladenosine modifications
Authors: Park Dayea , Cenik Can
Published: October 2024

Long-read sequencing technology enables highly accurate detection of allele-specific RNA expression, providing insights into the effects of genetic variation on splicing and RNA abundance. Furthermore, the ability to directly sequence RNA using the Oxford Nanopore technology promises the detection of RNA modifications in tandem with ascertaining the allelic origin of each molecule. Here, we leverage these advantages to determine allele-biased patterns of N6-methyladenosine (m6A) modifications in native mRNA. We utilized human and mouse cells with known genetic variants to assign allelic origin of each mRNA molecule combined with a supervised machine learning model to detect read-level m6A modification ratios. Our analyses revealed the importance of sequences adjacent to the DRACH-motif in determining m6A deposition, in addition to allelic differences that directly alter the motif. Moreover, we discovered allele-specific m6A modification (ASM) events with no genetic variants in close proximity to the differentially modified nucleotide, demonstrating the unique advantage of using long reads and surpassing the capabilities of antibody-based short-read approaches. This technological advancement promises to advance our understanding of the role of genetics in determining mRNA modifications.
Geometric deep learning framework for de novo genome assembly
Authors: Vrček Lovro , Bresson Xavier , Laurent Thomas , Schmitz Martin , Kawaguchi Kenji , Šikić Mile
Published: October 2024

The critical stage of every de novo genome assembler is identifying paths in assembly graphs that correspond to the reconstructed genomic sequences. The existing algorithmic methods struggle with this, primarily due to repetitive regions causing complex graph tangles, leading to fragmented assemblies. Here, we introduce GNNome, a framework for path identification based on geometric deep learning that enables training models on assembly graphs without relying on existing assembly strategies. By leveraging only the symmetries inherent to the problem, GNNome reconstructs assemblies from PacBio HiFi reads with contiguity and quality comparable to those of the state-of-the-art tools across several species. With every new genome assembled telomere-to-telomere, the amount of reliable training data at our disposal increases. Combining the straightforward generation of abundant simulated data for diverse genomic structures with the AI approach makes the proposed framework a plausible cornerstone for future work on reconstructing complex genomes with different ploidy and aneuploidy degrees. To facilitate such developments, we make the framework and the best-performing model publicly available, provided as a tool that can directly be used to assemble new haploid genomes.
Quarkonium polarization in medium from open quantum systems and chromomagnetic correlators
Authors: Yang Di-Lun , Yao Xiaojun
Published: October 2024

We study the spin-dependent in-medium dynamics of quarkonia by using the potential nonrelativistic QCD (pNRQCD) and the open quantum system framework. We consider the pNRQCD Lagrangian valid up to the order rM0=r and r0M=1M in the double power counting. By considering the Markovian condition and applying the Wigner transformation upon the diagonal spin components of the quarkonium density matrix with the semiclassical expansion, we systematically derive the Boltzmann transport equation for quarkonia with polarization dependence in the quantum optical limit. Unlike the spin-independent collision terms governed by certain chromoelectric field correlators, new gauge invariant correlators of chromomagnetic fields determine the recombination and dissociation terms with polarization dependence at the order we are working. We also derive a Lindblad equation describing the in-medium transitions between spin-singlet and spin-triplet heavy quark-antiquark pairs in the quantum Brownian motion limit. The Lindblad equation is governed by new transport coefficients defined in terms of the chromomagnetic field correlators. Our formalism is generic and valid for both weakly coupled and strongly coupled quark gluon plasmas. It can be further applied to study spin alignment of vector quarkonia in heavy ion collisions.

Published by the American Physical Society
2024
Lepton-flavor-violating ALP signals with TeV-scale muon beams
Authors: Batell Brian , Davoudiasl Hooman , Marcarelli Roman , Neil Ethan T. , Trojanowski Sebastian
Published: October 2024

We explore the feasibility of using TeV-energy muons to probe lepton-flavor-violating (LFV) processes mediated by an axionlike particle (ALP) a with mass O(10  GeV). We focus on μτ LFV interactions and assume that the ALP is coupled to a dark state χ, which can be either less or more massive than a. Such a setup is demonstrated to be consistent with χ being a candidate for dark matter, in the experimentally relevant regime of parameters. We consider the currently operating NA64-

μ

experiment and proposed FASERν2 detector as both the target and the detector for the process μA→τAa, where A is the target nucleus. We also show that a possible future active muon fixed-target experiment operating at a 3 TeV muon collider or in its preparatory phase can provide an impressive reach for the LFV process considered, with future FASERν2 data providing a pilot study towards that goal. The implications of the muon anomalous magnetic moment (g−2)μ measurements for the underlying model, in case of a positive signal, are also examined, and a sample UV completion is outlined.

Published by the American Physical Society
2024
Dark Population Transfer Mechanism for Sterile Neutrino Dark Matter
Authors: Fuller George M. , Gráf Lukáš , Patwardhan Amol V. , Spisak Jacob
Published: October 2024

We present a mechanism for producing a cosmologically significant relic density of one or more sterile neutrinos. This scheme invokes two steps: First, a population of “heavy” sterile neutrinos is created by scattering-induced decoherence of active neutrinos. Second, this population is transferred, via sterile neutrino self-interaction-mediated scatterings and decays, to one or more lighter mass (∼10  keV to ∼1  GeV) sterile neutrinos that are far more weakly (or not at all) mixed with active species and could constitute dark matter. Dark matter produced this way can evade current electromagnetic and structure-based bounds, but may nevertheless be probed by future observations.

Published by the American Physical Society
2024
pH Modulates Friction Memory Effects in Protein Folding
Authors: Dalton Benjamin A. , Netz Roland R.
Published: October 2024

Protein folding is an intrinsically multitimescale problem. While it is accepted that non-Markovian effects are present on short timescales, it is unclear whether memory-dependent friction influences long-timescale protein folding reaction kinetics. We combine friction memory-kernel extraction techniques with recently published extensive all-atom simulations of the α3D protein under neutral and reduced pH conditions, and we show that the pH reduction modifies the friction acting on the folding protein by dramatically decreasing the friction memory decay time. This switches α3D folding reaction kinetics from the pronounced non-Markovian regime, where memory significantly accelerates folding, to the Markovian regime, where memory does not influence the folding time. We explore salt-bridge interactions, which are eliminated under pH reduction, as a key microscopic origin of non-Markovian friction in α3D.

Published by the American Physical Society
2024
Comprehensive Screening of Plasma-Facing Materials for Nuclear Fusion
Authors: Fedrigucci Andrea , Marzari Nicola , Ricci Paolo
Published: October 2024

Plasma-facing materials (PFMs) represent one of the most significant challenges for the design of future nuclear fusion reactors. Inside the reactor, the divertor will experience the harshest material environment: intense bombardment of neutrons and plasma particles coupled with extremely large and intermittent heat fluxes. The material designated to cover this role in ITER is tungsten. While no other materials have shown the potential to match the properties of tungsten, many drawbacks associated with its application remain, including cracking and erosion induced by a low recrystallization temperature combined with a high ductile-brittle transition temperature and neutron-initiated embrittlement; surface morphology changes (helium bubbles and fuzz layer) due to plasma-tungsten interaction with subsequent risk of spontaneous material melting and delamination; and low oxidation resistance in the case of air contamination. Exploring alternatives to tungsten requires the design of a multivariable optimization problem. This work aims to produce a structured and comprehensive material screening of PFM candidates based on known inorganic materials. The method applied in this study to identify the most promising PFM candidates combines peer-reviewed data present in the PAULING FILE database and first-principles density-function theory calculations focusing on two key PFM defects—namely, the sputtering of surface atoms and the incorporation of interstitial hydrogen, respectively characterized by the surface binding energy and the interstitial formation energy. The crystal structures and their related properties, extracted from the PAULING FILE, are ranked according to the heat-balance equation of a PFM subjected to the heat loads in the divertor region of an ITER-like tokamak. The materials satisfying the requirements are critically compared with the state-of-the-art in plasma-facing materials research and in studies of refractory materials exposed to high temperatures, plasma, and neutron bombardment. This comparison assesses their thermo-mechanical properties under such conditions, identifying a subset of promising materials for first-principles electronic structure calculations. Most previously known and extensively studied PFMs, such as tungsten, molybdenum, and carbon-based materials, are captured by this screening process, confirming its reliability. Additionally, less familiar refractory materials suggest performance that calls for further investigations.

Published by the American Physical Society
2024
Formulation of perfect-crystal diffraction from Takagi–Taupin equations: numerical implementation in the crystalpy library
Authors: Guigay Jean-Pierre , Sanchez del Rio Manuel
Published: October 2024

The Takagi–Taupin equations are solved in their simplest form (zero deformation) to obtain the Bragg-diffracted and transmitted complex amplitudes. The case of plane-parallel crystal plates is discussed using a matrix model. The equations are implemented in an open-source Python library crystalpy adapted for numerical applications such as crystal reflectivity calculations and ray tracing.
Integrating sustainable development goals into architectural design education: a case study in second-year design studio
Authors: Akgün Yenal , Doğrusoy İlknur Türkseven , Özsöyler Damla
Published: October 2024

Purpose

The main objective of this paper is to investigate how Sustainable Development Goals (SDGs) can be integrated into architectural design education through a second-year architectural design studio experience, exploring ways to create awareness among students regarding SDGs.

Design/methodology/approach

To arrive at this aim, a case study has been conducted. In this study, the entire curriculum of the second-year design studio has been specifically tailored to correspond with the SDGs and their three dimensions. This alignment covers all stages of the studio, from concept development to material selection, ensuring a direct association with different SDGs. At the end of the semester, all qualitative and quantitative data obtained from the final project submission of the students and the results of a comprehensive questionnaire that has been applied to students aiming at assessing their awareness of the SDGs were evaluated simultaneously.

Findings

The design studio process during the semester, the data obtained from the final submissions of the students, and the student survey have proved that the integration of SDGs and related targets widens the vision of students and creates awareness not only of environmental issues but also of social and economic sustainability.

Originality/value

Although there are many studies in literature searching for opportunities to integrate SDGs into the architecture curriculum, there are only a few studies directly using SDGs as the main concept generator of the design studio course. This paper contributes to this missing point in the literature.