bluuebunny/crossref_metadata_2025 huggingface dataset:
Targeted memory reactivation is not more effective during slow wave sleep than sleep stage 2
Authors: Carbone Julia , Bibian Carlos , Born Jan , Forcato Cecilia , Diekelmann Susanne
Published: October 2023

Sleep facilitates memory consolidation, which is assumed to rely on the reactivation of newly encoded memories orchestrated by the temporal interplay of slow oscillations (SO), fast spindles and ripples. SO as well as the number of spindles coupled to SO are more frequent during slow wave sleep (SWS) compared to lighter sleep stage 2 (S2). But, it is unclear whether memory reactivation is more effective during SWS than during S2. To test this question, we applied Targeted Memory Reactivation (TMR) by presenting learning-associated sound cues during SWS vs. S2 in a counterbalanced within-subject design. Contrary to our hypothesis, memory performance was not significantly better when cues were presented during SWS. Event-related potential (ERP) amplitudes were significantly higher for cues presented during SWS than S2, and the density of SO and SO-spindle complexes was generally higher during SWS than during S2. Whereas SO density increased during and after the TMR period, SO-spindle complexes decreased. None of the parameters were associated with memory performance. These findings suggest that the efficacy of TMR does not depend on whether it is administered during SWS or S2, despite differential processing of memory cues in these sleep stages.
Spontaneous network transitions predict somatosensory perception
Authors: Sharma Abhinav , Lange Joachim , Vidaurre Diego , Florin Esther
Published: October 2023

Sensory perception is essential for transforming incoming information in the brain into targeted behavior. Our brains are everlastingly active, and variations in perception are ubiquitously associated with human behavioral performance. Previous studies indicate that changes in spontaneous neural activity within local sensory areas correlate with the perception of ambiguous stimuli. However, the contribution of whole brain spontaneous networks to perception is not well understood. Using an ambiguous tactile temporal discrimination task, we demonstrate that the interaction between wholebrain networks in the seconds of the spontaneous pre-stimulus period also contributes to perception during the task. Transitions to a frontal and a multi-frequency network across the brain are essential for the correct percept. Conversely, incorrect percepts are mainly preceded by transitions to an alphaparietal network. Brain transitions occur faster during the period before stimulus presentation for correct stimuli detection, suggesting the need for enhanced network flexibility during this phase.

Significance statement

Our brain is constantly engaged in processing sensory input and translating it into sensory perceptions. When confronted with ambiguous sensory information, individuals do not always have the same perceptual experience. We demonstrate that brain network transitions to frontal areas are essential for the correct percept. Conversely, incorrect percepts are mainly preceded by transitions to an alpha-parietal network. Correct stimuli detections are characterized by faster transitions, suggesting the need for enhanced network flexibility. These results extend our knowledge of perception by pointing to the relevance of whole-brain spontaneous networks and their dynamic properties.
Pharmacological and behavioral effects of tryptamines present in psilocybin-containing mushrooms
Authors: Rakoczy Ryan J. , Runge Grace N. , Sen Abhishek K. , Sandoval Oscar , Nguyen Quynh , Roberts Brianna R. , Sciortino Jon H. , Gibbons William J. , Friedberg Lucas M. , Andrew Jones J. , McMurray Matthew S.
Published: October 2023

Demand for more efficacious antidepressants, particularly those with a rapid onset of action, has resulted in a reevaluation of psychedelic drugs for their therapeutic potential. Several tryptamines found in psilocybin-containing ‘magic’ mushrooms share chemical similarities with psilocybin, and early work suggests they may also share receptor targets. However, few studies have explored their pharmacological and behavioral effects. To accomplish this, we compared baeocystin, norbaeocystin, and aeruginascin with psilocybin to determine if they are metabolized by the same enzymes, penetrate the blood brain barrier, serve as ligands for similar centrally located receptors, and modulate behavior in rodents similarly. We first assessed the stability and optimal storage and handling conditions for each compound.In vitroenzyme kinetics assays then found that all compounds shared nearly identical rates of dephosphorylation via alkaline phosphatase and metabolism by monoamine oxidase. Further, we found that only the dephosphorylated products of baeocystin and norbaeocystin could cross a blood brain barrier mimetic to a similar degree as the dephosphorylated form of psilocybin, psilocin. Behaviorally, only psilocybin was found to induce head twitch responses in rats, a marker of 5HT2A agonism and indicator of the compound’s hallucinogenic potential. However, like psilocybin, norbaeocystin was also found to improve outcomes in the forced swim test. All compounds were found to cause minimal changes to metrics of renal and hepatic health, suggesting innocuous safety profiles. Collectively, this work suggests that other naturally-occurring tryptamines, especially norbaeocystin, may share the same therapeutic potential as psilocybin, but without causing hallucinations.

HIGHLIGHTS

Baeocystin, norbaeocystin, and aeruginascin may have similar therapeutic value to psilocybin, but are understudied

Compound stability varied widely, with dephosphorylated forms showing lowest stability

Rates of metabolism by alkaline phosphatase and monoamine oxidase were similar across compounds

Blood brain barrier penetration was limited to dephosphorylated forms of psilocybin, baeocystin, and norbaeocystin

Rat behavioral testing suggested norbaeocystin may have therapeutic utility similar to psilocybin, without causing hallucinations
Pan-cortical 2-photon mesoscopic imaging and neurobehavioral alignment in awake, behaving mice
Authors: Vickers Evan D. , McCormick David A.
Published: October 2023

The flow of neural activity across the neocortex during active sensory discrimination is constrained by task-specific cognitive demands, movements, and internal states. During behavior, the brain appears to sample from a broad repertoire of activation motifs. Understanding how these patterns of local and global activity are selected in relation to both spontaneous and task-dependent behavior requires in-depth study of densely sampled activity at single neuron resolution across large regions of cortex. In a significant advance toward this goal, we developed procedures to record mesoscale 2-photon Ca2+imaging data from two novelin vivopreparations that, between them, allow simultaneous access to nearly all of the mouse dorsal and lateral neocortex. As a proof of principle, we aligned neural activity with both behavioral primitives and high-level motifs to reveal the existence of large populations of neurons that coordinated their activity across cortical areas with spontaneous changes in movement and/or arousal. The methods we detail here facilitate the identification and exploration of widespread, spatially heterogeneous neural ensembles whose activity is related to diverse aspects of behavior.
From mice to humans: Cross-species transcriptomics analysis to uncover distinct mechanisms of Diabetic Retinopathy (DR)
Authors: Adda Siddharth , Legendre Christophe , Rangasamy Sampath
Published: October 2023

Diabetic Retinopathy (DR) is the leading risk for vision loss in working adults worldwide, affecting more than 100 million people. While risk factors such as diabetes duration, hyperglycemia, and dyslipidemia are well-acknowledged, the unifying molecular mechanisms underlying the pathogenesis of DR remain incompletely understood across different species. To bridge this gap, we conducted a comprehensive RNA-sequencing (RNA-seq) meta-analysis on retinal tissue samples from mice, rats, and humans with diabetes. Our integrative bioinformatics analysis elucidated both conserved and species-specific transcriptional landscapes associated with DR. Notably, pro-inflammatory pathways were ubiquitously activated in the retinal tissues across all examined species. However, unique human-specific immune-metabolic signatures emerged, which were not observed in rodent models. In summary, our investigation unveils both universal and species-specific molecular underpinnings of DR, enhancing our understanding of its complex pathobiology. These findings validate the utility of animal models in DR research and underscore the importance of human-focused studies to uncover mechanisms uniquely relevant to human pathology.
Expression of Lanthipeptides in Human Cells
Authors: Eslami Sara M. , Rahman Imran R. , van der Donk Wilfred A.
Published: October 2023

Cyclic peptides represent a burgeoning area of interest in therapeutic and biotechnological research. In opposition to their linear counterparts, cyclic peptides, such as certain ribosomally synthesized and post-translationally modified peptides (RiPPs), are more conformationally constrained and less susceptible to proteolytic degradation. The lanthipeptide RiPP cytolysin L forms a covalently enforced helical structure that may be used to disrupt helical interactions at protein-protein interfaces. Herein, an expression system is reported to produce lanthipeptides and structurally diverse cytolysin L derivatives in mammalian cells. Successful targeting of lanthipeptides to the nucleus is demonstrated. In vivo expression and targeting of such peptides in mammalian cells may allow for screening of lanthipeptide inhibitors of native protein-protein interactions.

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In vivoaffinity maturation of murine B cells reprogrammed to express human antibodies
Authors: Yin Yiming , Guo Yan , Jiang Yuxuan , Quinlan Brian , Peng Haiyong , Crynen Gogce , He Wenhui , Zhang Lizhou , Ou Tianling , Bailey Charles C. , Farzan Michael
Published: October 2023

CRISPR-edited murine B cells engineered to express human antibody variable chains proliferate, class switch, and secrete these antibodies in vaccinated mice. However, current strategies disrupt the heavy-chain locus, resulting in inefficient somatic hypermutation without functional affinity maturation. Here we show that recombined murine heavy- and kappa-variable genes can be directly and simultaneously overwritten, using Cas12a-mediated cuts at their 3’-most J segments and 5’ homology arms complementary to distal V segments. Cells edited in this way to express the HIV-1 broadly neutralizing antibodies 10-1074 or VRC26.25-y robustly hypermutated and generated potent neutralizing plasma in vaccinated recipient mice. 10-1074 variants isolated from these mice bound and neutralized HIV-1 envelope glycoprotein more efficiently than wild-type 10-1074 while maintaining or improving its already low polyreactivity and longin vivohalf-life. We further validated this approach by generating substantially broader and more potent variants of the anti-SARS-CoV-2 antibodies ZCB11 and S309. Thus, B cells edited at their native loci affinity mature, facilitating development of broad, potent, and bioavailable antibodies and expanding the potential applications of engineered B cells.
Noise robustness and metabolic load determine the principles of central dogma regulation
Authors: Lo Teresa W. , Choi Han James , Huang Dean , Wiggins Paul A.
Published: October 2023

The processes of gene expression are inherently stochastic, even for essential genes required for growth. How does the cell maximize fitness in light of noise? To answer this question, we build a mathematical model to explore the trade-off between metabolic load and growth robustness. The model predicts novel principles of central dogma regulation: Optimal protein expression levels for many genes are in vast overabundance. Essential genes are transcribed above a lower limit of one message per cell cycle. Gene expression is achieved by load balancing between transcription and translation. We present evidence that each of these novel regulatory principles is observed. These results reveal that robustness and metabolic load determine the global regulatory principles that govern gene expression processes, and these principles have broad implications for cellular function.

One-sentence summary

Fitness maximization predicts protein overabundance, a transcriptional floor, and the balancing of transcription and translation.
Role of Seasonal Importation and Random Genetic Drift on Selection for Drug-Resistant Genotypes ofPlasmodium falciparumin High Transmission Settings
Authors: Zupko Robert J. , Servadio Joseph L. , Nguyen Tran Dang , Tran Thu Nguyen-Anh , Tran Kien Trung , Somé Anyirékun Fabrice , Boni Maciej F.
Published: October 2023

HistoricallyPlasmodium falciparumhas followed a pattern of drug resistance first appearing in low transmission settings before spreading to high transmission settings. Several features of low-transmission regions are hypothesized as explanations: higher chance of symptoms and treatment seeking, better treatment access, less within-host competition among clones, and lower rates of recombination. Here, we test whether importation of drug-resistant parasites is more likely to lead to successful emergence and establishment in low-transmission or high-transmission periods of the same epidemiological setting, using a spatial, individual-based stochastic model of malaria and drug-resistance evolution calibrated for Burkina Faso. Upon controlling for the timing of importation of drug-resistant genotypes and examination of key model variables, we found that drug-resistant genotypes imported during the low transmission season were, (1) more susceptible to stochastic extinction due to the action of random genetic drift, and (2) more likely to lead to establishment of drug resistance when parasites are able to survive early stochastic loss due to drift. This implies that rare importation events are more likely to lead to establishment if they occur during a high-transmission season, but that constant importation (e.g., neighboring countries with high levels of resistance) may produce a greater risk during low-transmission periods.
An Artificial Intelligence Method for Phenotyping of OCT Scans Using Unsupervised and Self-supervised Deep Learning
Authors: Kazeminasab Saber , Sekimitsu Sayuri , Fazli Mojtaba , Eslami Mohammad , Shi Min , Tian Yu , Luo Yan , Wang Mengyu , Elze Tobias , Zebardast Nazlee
Published: October 2023

Artificial intelligence (AI) has been increasingly used to analyze optical coherence tomography (OCT) images to better understand physiology and genetic architecture of ophthalmic diseases. However, to date, research has been limited by the inability to transfer OCT phenotypes from one dataset to another. In this work, we propose a new AI method for phenotyping and clustering of OCT-derived retinal layer thicknesses using unsupervised and self-supervised methods in a large clinical dataset using glaucoma as a model disease and subsequently transfer our phenotypes to a large biobank. The model includes a deep learning model, manifold learning, and a Gaussian mixture model. We also propose a correlation analysis for the performance evaluation of our model based on Pearson correlation coefficients. Our model was able to identify clinically meaningful OCT phenotypes and successfully transfer phenotypes from one dataset to another. Overall, our results will contribute to stronger research methodologies for future research in OCT imaging biomarkers, augment testing of OCT phenotypes in multiple datasets, and ultimately improve our understanding of pathophysiology and genetic architecture of ocular diseases.
Molecular mechanism of α-synuclein aggregation on lipid membranes revealed
Authors: Dear Alexander J. , Teng Xiangyu , Ball Sarah R. , Lewin Joshua , Horne Robert I. , Clow Daniel , Harper Natasha , Yahya Kim , Michaels Thomas C.T. , Linse Sara , Knowles Tuomas P. J. , Yang Xiaoting , Brewerton Suzanne C. , Thomson John , Habchi Johnny , Meisl Georg
Published: October 2023

The central hallmark of Parkinson’s disease pathology is the aggregation of theα-synuclein protein, which, in its healthy form, is associated with lipid membranes. Purified monomericα-synuclein is relatively stable in vitro, but its aggregation can be triggered by the presence of lipid vesicles. Despite this central importance of lipids in the context ofα-synuclein aggregation, their mechanistic role in this process has not been established to date. Here, we use chemical kinetics to develop a detailed mechanistic model that is able to globally describe the aggregation behaviour ofα-synuclein in the presence of DMPS lipid vesicles, across a range of lipid and protein concentrations. Through the application of our kinetic model to experimental data, we find that the reaction is a co-aggregation process involving both protein and lipids and that lipids promote aggregation predominantly by enabling the elongation process. Moreover, we find that the initial formation of aggregates, via primary nucleation, takes place not on the surface of lipid vesicles but at the interfaces present in vitro. Our model will enable mechanistic insights, also in other lipid-protein co-aggregation systems, which will be crucial in the rational design of drugs that inhibit aggregate formation and act at the key points in theα-synuclein aggregation cascade.
Dissociable causal roles of dorsolateral prefrontal cortex and primary motor cortex as a function of motor skill expertise
Authors: Nguyen Quynh N. , Michon Katherine J. , Lee Taraz G.
Published: October 2023

Established models of motor skill learning posit that early stages of learning are dominated by an attentionally demanding, effortful mode of control supported by associative corticostriatal circuits involving the dorsolateral prefrontal cortex (DLPFC). As expertise develops, automatic and “effortless” performance coincides with a transition to a reliance on sensorimotor circuits that include primary motor cortex (M1). However, the dynamics of how control evolves during the transition from novice to expert are currently unclear. This lack of clarity is due, in part, to the fact that most motor learning studies comprise a limited number of training sessions and rely on correlative techniques such as neuroimaging. Here, we train human participants on a discrete motor sequencing task over the course of six weeks, followed by an assessment of the causal roles of DLPFC and M1 at varying levels of expertise. We use repetitive transcranial magnetic stimulation to transiently disrupt activity in these regions immediately prior to performance in separate sessions. Our results confirm the dissociable importance of DLPFC and M1 as expertise develops. DLPFC stimulation leads to larger behavioral deficits for novice skills than expert skills, while M1 stimulation leads to relatively larger deficits as expertise develops. However, our results also reveal that prefrontal disruption causes performance deficits at all levels of expertise. These findings challenge existing models and indicate an evolving rather than a strictly diminishing role for DLPFC throughout learning.

Significance Statement

Motor skills involve the sequential chaining of individual actions. For example, playing the piano involves learning to rapidly transition to from one finger press to another. Human neuroimaging studies have shown that primary motor cortex (M1) and dorsolateral prefrontal cortex (DLPFC) support novice motor sequencing skills, but activity in both regions declines over training. This has been interpreted as increased efficiency in M1 and yet a reduction in the involvement of DLPFC as expertise develops. We causally test this assumption by using non-invasive brain stimulation to transiently disrupt cortical activity following extended skill training. Although we confirm dissociable contributions of DLPFC and M1 as expertise develops, we show that both regions are necessary for performance regardless of skill level.
Quantitative imaging of three-dimensional fiber orientation in the human brain via two illumination angles using polarization-sensitive optical coherence tomography
Authors: Liu Chao J. , Ammon William , Jones Robert J. , Nolan Jackson C. , Gong Dayang , Maffei Chiara , Edlow Brian L. , Augustinack Jean C. , Magnain Caroline , Yendiki Anastasia , Villiger Martin , Fischl Bruce , Wang Hui
Published: October 2023

The accurate measurement of three-dimensional (3D) fiber orientation in the brain is crucial for reconstructing fiber pathways and studying their involvement in neurological diseases. Optical imaging methods such as polarization-sensitive optical coherence tomography (PS-OCT) provide important tools to directly quantify fiber orientation at micrometer resolution. However, brain imaging based on the optic axis by PS-OCT so far has been limited to two-dimensional in-plane orientation, preventing the comprehensive study of connectivity in 3D. In this work, we present a novel method to obtain the 3D fiber orientation in full angular space with only two illumination angles. We measure the optic axis orientation and the apparent birefringence by PS-OCT from a normal and a 15 deg tilted illumination, and then apply a computational method yielding the 3D optic axis orientation and true birefringence. We verify that our method accurately recovers a large range of through-plane orientations from -85 deg to 85 deg with a high angular precision. We further present 3D fiber orientation maps of entire coronal sections of human cerebrum and brainstem with 10 μm in-plane resolution, revealing unprecedented details of fiber configurations. We envision that further development of our method will open a promising avenue towards large-scale 3D fiber axis mapping in the human brain and other complex fibrous tissues at microscopic level.
Gene-specific reactivation of X-linked genes upon Xist loss is linked to the chromatin states in extraembryonic endoderm and epiblast stem cells
Authors: Arava M , Majumdar S , Sowjanya LS , Naik HC , Baro R , Gayen S
Published: October 2023

In eutherian mammals, X-chromosome dosage between sexes is balanced through the inactivation of one of the two X-chromosomes in female cells. In mouse, X-inactivation initiates at ∼4-8 cell stages of embryogenesis, where paternal-X undergoes imprinted X-inactivation. Subsequently, it switches to random X-inactivation in post-iplantation epiblast. The initiation of XCI is orchestrated by Xist. However, the role of Xist in the maintenance of X-chromosome inactivation remains underexplored. Here, we have explored the role of Xist in the maintenance of X-inactivation in extraembryonic endoderm stem cells (XEN) and epiblast stem cells (EpiSC), which undergo imprinted and random form of X-inactivation respectively. We show that removal of Xist leads to the partial reactivation of inactive-X chromosome. Intriguingly, many reactivated genes were found to be common between XEN and EpiSC, indicating these genes require Xist to maintain their silent state irrespective of the lineages or forms of X-inactivation. Notably, despite Xist ablation and the subsequent removal of DNA methylation, several X-linked genes remained resistant to reactivation, indicating the involvement of other factors in maintaining the silencing of these genes. On the other hand, we show that genes on the inactive-X with low levels of H3K9me3 and high levels of H3K27me3 are more susceptible to reactivation upon the loss of Xist. Interestingly, active-X homolog of the reactivated genes was found to be enriched with H3K4me3 and H3K27ac. Taken together, our study sheds light on the role of chromatin states in the reactivation of X-linked genes following the loss of Xist in XEN and EpiSC.
Critical reproductive behaviors in Scaled Quail and Northern Bobwhite are affected by thermal variability and mean temperature
Authors: Kirkpatrick William , Sauer Erin , Carroll Rachel , Cohen Jeremy , Davis Craig , Fuhlendorf Samuel , DuRant Sarah
Published: October 2023

Animals can respond differently to shifting thermal variability versus thermal averages, both of which are changing due to climate warming. How these thermal variables affect parental care behaviors can reveal the ability of parents to modify their behaviors to meet the competing demands of their offspring’s thermal needs and self-maintenance, which becomes critical in suboptimal thermal conditions. Further, the time frame used to examine the interplay between temperature and behavioral shifts (e.g., seasonal patterns in care vs. drivers of individual care decisions) can provide different information about the plasticity of parental care behavior. We investigated the relationship between thermal means, thermal variability, and incubation behaviors across multiple timescales in Scaled Quail and Northern Bobwhite. Both species decreased off-bout length during periods of high thermal variability, a novel finding among studies of avian parental behavior. Further relationships between thermal endpoints (mean vs. variation) and behavior differed depending on the temporal scale. For instance, total daily time spent off the nest was not influenced by daily average temperature, yet individual off-bout duration increased with increasing average temperature in the two hours prior to the off-bout. These results provide evidence that thermal-behavioral relationships differ across scales and likely represent a bird’s ability to modify their incubation strategy to rapidly respond to the immediate thermal environment (altering individual off-bout length based on temperature) to meet self-maintenance needs while resulting in a similar outcome for their nest (total daily off-bout time). However, longer off-bout durations during high temperature events can come with reproductive costs, sometimes resulting in acute offspring mortality when eggs or chicks experience lethal temperatures.
High-resolution CTCF footprinting reveals impact of chromatin state on cohesin extrusion dynamics
Authors: Sept Corriene E. , Tak Y. Esther , Cerda-Smith Christian G. , Hutchinson Haley M. , Goel Viraat , Blanchette Marco , Bhakta Mital S. , Hansen Anders S. , Joung J. Keith , Johnstone Sarah , Eyler Christine E. , Aryee Martin J.
Published: October 2023

DNA looping is vital for establishing many enhancer-promoter interactions. While CTCF is known to anchor many cohesin-mediated loops, the looped chromatin fiber appears to predominantly exist in a poorly characterized actively extruding state. To better characterize extruding chromatin loop structures, we used CTCF MNase HiChIP data to determine both CTCF binding at high resolution and 3D contact information. Here we presentFactorFinder, a tool that identifies CTCF binding sites at near base-pair resolution. We leverage this substantial advance in resolution to determine that the fully extruded (CTCF-CTCF) state is rare genome-wide with locus-specific variation from ~1-10%. We further investigate the impact of chromatin state on loop extrusion dynamics, and find that active enhancers and RNA Pol II impede cohesin extrusion, facilitating an enrichment of enhancer-promoter contacts in the partially extruded loop state. We propose a model of topological regulation whereby the transient, partially extruded states play active roles in transcription.
Genomic epidemiology and antifungal-resistant characterization ofCandida auris, Colombia, 2016-2021
Authors: Misas Elizabeth , Escandon Patricia L. , Gade Lalitha , Caceres Diego H. , Hurst Steve , Le Ngoc , Min Brian , Lyman Meghan , Duarte Carolina , Chow Nancy A.
Published: October 2023

Since 2016 in Colombia, ongoing transmission ofCandida aurishas been reported in multiple cities. Here, we provide an updated description ofC. aurisgenomic epidemiology and the dynamics of antifungal resistance in Colombia. We sequenced 99 isolates fromC. auriscases with collection dates ranging from June 2016 to January 2021; the resulting sequences coupled with 103 previously generated sequences fromC. auriscases were described in a phylogenetic analysis.

AllC. auriscases were of clade IV. Of the 182 isolates with antifungal susceptibility data, 67 (37%) were resistant to fluconazole, and 39 (21%) were resistant to amphotericin B. Isolates predominately clustered by country except for 16 isolates from Bogotá, Colombia, which grouped with isolates from Venezuela. The largest cluster (N=166 isolates) contained two subgroups. The first subgroup contained 26 isolates, mainly from César; of these 85% (N=22) were resistant to fluconazole. The second subgroup consisted of 47 isolates from the north coast; of these, 81% (N=38) were resistant to amphotericin B.

Mutations in theERG11andTAC1Bgenes were identified in fluconazole-resistant isolates, and two amino acid substitutions in PSK76257-(FLO8) and PSK74852 genes were associated with higher minimum inhibitory concentration values for amphotericin B. This work may help identify mechanisms conferring azole and amphotericin B resistance inC. auris.

Overall,C. auriscases from different geographic locations in Colombia exhibited high genetic relatedness, suggesting continued transmission between cities since 2016. These findings also suggest a lack of or minimal introductions of different clades ofC. aurisinto Colombia.

IMPORTANCE

Candida aurisis an emerging fungus that presents a serious global health threat and has caused multiple outbreaks in Colombia. This work discusses the likelihood of introductions and local transmission ofC. aurisand provides an updated description of the molecular mechanisms associated with antifungal resistance in Colombia. Efforts like this tracking genomic variation provide information about the evolvingC. aurisburden that could help guide public health strategies to controlC. aurisspread.
Structural characterization of SLYM - a 4thmeningeal membrane
Authors: Plá Virginia , Bitsika Styliani , Giannetto Michael , Ladron-de-Guevara Antonio , Gahn-Martinez Daniel , Mori Yuki , Nedergaard Maiken , Møllgård Kjeld
Published: October 2023

Traditionally, the meninges are described as 3 distinct layers, dura, arachnoid and pia. Yet, the classification of the connective meningeal membranes surrounding the brain is based on postmortem macroscopic examination. Ultrastructural and single cell transcriptome analyses have documented that the 3 meningeal layers can be subdivided into several distinct layers based on cellular characteristics. We here re-examined the existence of a 4thmeningeal membrane,SubarachnoidLymphatic-likeMembrane or SLYM in Prox1-eGFP reporter mice. Imaging of freshly resected whole brains showed that SLYM covers the entire brain and brain stem and forms a roof shielding the subarachnoid cerebrospinal fluid (CSF)-filled cisterns and the pia-adjacent vasculature. Thus, SLYM is strategically positioned to facilitate periarterial influx of freshly produced CSF and thereby support unidirectional glymphatic CSF transport. Histological analysis showed that, in spinal cord and parts of dorsal cortex, SLYM fused with the arachnoid barrier layer, while in the basal brain stem typically formed a 1-3 cell layered membrane subdividing the subarachnoid space into two compartments. However, great care should be taken when interpreting the organization of the delicate leptomeningeal membranes in tissue sections. We show that hyperosmotic fixatives dehydrate the tissue with the risk of shrinkage and dislocation of these fragile membranes in postmortem preparations.
Zbtb11 interacts with Otx2 and patterns the anterior neuroectoderm inXenopus
Authors: Satou-Kobayashi Yumeko , Takahashi Shuji , Haramoto Yoshikazu , Asashima Makoto , Taira Masanori
Published: October 2023

Thezinc finger and BTB domain-containing 11gene (zbtb11) is expressed in theXenopusanterior neuroectoderm, but the molecular nature of the Zbtb11 protein during embryonic development remains to be elucidated. Here, we show the role of Zbtb11 in anterior patterning of the neuroectoderm and the cooperative action with the transcription factor Otx2. Both overexpression and knockdown ofzbtb11caused similar phenotypes: expanded expression of the posterior genegbx2in the neural plate, and later microcephaly with reduced eyes, suggesting that a proper level ofzbtb11expression is necessary for normal patterning of the neuroectoderm, including eye formation. Co-immunoprecipitation assays showed that Zbtb11 formed a complex with itself and with a phosphomimetic and repressive form of Otx2, suggesting that Zbtb11 forms a dimer or oligomer and interacts with Otx2 in a phosphorylation-dependent manner. Reporter analysis further showed that Zbtb11 enhanced the activity of the phosphomimetic Otx2 to repress a silencer element of the posterior genemeis3. These data suggest that Zbtb11 coordinates with phosphorylated Otx2 to specify the anterior neuroectoderm by repressing posterior genes.
Representational drift in barrel cortex is receptive field dependent
Authors: Alisha Ahmed , Bettina Voelcker , Simon Peron
Published: October 2023

Cortical populations often exhibit changes in activity even when behavior is stable. How behavioral stability is maintained in the face of such ‘representational drift’ remains unclear. One possibility is that some neurons are stable despite broader instability. We examine whisker touch responses in superficial layers of primary vibrissal somatosensory cortex (vS1) over several weeks in mice stably performing an object detection task with two whiskers. While the number of touch neurons remained constant, individual neurons changed with time. Touch-responsive neurons with broad receptive fields were more stable than narrowly tuned neurons. Transitions between functional types were non-random: before becoming broadly tuned neurons, unresponsive neurons first pass through a period of narrower tuning. Broadly tuned neurons with higher pairwise correlations to other touch neurons were more stable than neurons with lower correlations. Thus, a small population of broadly tuned and synchronously active touch neurons exhibit elevated stability and may be particularly important for downstream readout.
Conversion of mouse-derived hybridomas to Tasmanian devil recombinant IgG antibodies
Authors: Slyp Bailey , Darby Jocelyn M. , Flies Andrew S.
Published: October 2023

The hybridoma method for production of monoclonal antibodies has been a cornerstone of biomedical research for several decades. Here we convert the monoclonal antibody sequence from mouse-derived hybridomas into a “devilised” recombinant antibody with devil IgG heavy chain and IgK light chain. The chimeric recombinant antibody can be used in functional assays, immunotherapy, and to improve understanding of antibodies and Fc receptors in Tasmanian devils. The process can be readily modified for other species.
Bioactive coatings on 3D printed scaffolds for bone regeneration: Translation fromin vitrotoin vivomodels and the impact of material properties and growth factor concentration
Authors: Marshall Karen. M. , Wojciechowski Jonathan P. , Jayawarna Vineetha , Hasan Abshar , Echalier Cécile , Øvrebø Øystein , Yang Tao , Kanczler Janos M. , Mata Alvaro , Salmeron-Sanchez Manuel , Stevens Molly M. , Oreffo Richard O. C.
Published: October 2023

Bone tissue engineering is a rapidly advancing field that seeks to develop new functional bone tissue, harnessing materials for application in bone defects which may fail to heal without intervention, as seen in critical-sized bone defects. The material properties must be developed, tailored and optimised as the environment progresses, through increasing animal size and complexity, of the target bone defect site. This study has examined the potential of a poly(caprolactone) trimethacrylate (PCL-TMA) 3D-printable scaffold with select bioactive coatings to function as a scaffold to augment bone formation. Three bioactive coatings were examined, i) elastin-like protein (ELP), ii) poly (ethyl acrylate) (PEA), fibronectin (FN) and bone morphogenetic protein-2 (BMP-2) applied sequentially (PEA/FN/BMP-2) and iii) both ELP and PEA/FN/BMP-2 coatings applied concurrently. The PCL-TMA scaffold construct was observed to be a robust scaffold material and the bioactive coatings applied were found to be biocompatible, with a significant osteogenic response from human skeletal cell populations observedin vitro. The PCL-TMA scaffold and bioactive coatings supported angiogenesis and displayed excellent biocompatibility following evaluation on the chorioallantoic membrane (CAM) assay. Biocompatibility was confirmed, however, no significant bone formation was detected, following examination of heterotopic bone formation in the murine subcutaneous implantation model, whereas extensive mineralisation was observed in the positive control material of collagen sponge with BMP-2. The absence of bone formation on the PCL-TMA scaffolds,in vivo, was potentially a consequence of the method of action of the applied coatings, the surface area of the scaffold construct for BMP-2 binding and the necessity of an appropriatein vivoenvironment to facilitate skeletal cell ingress, warranting future examination in an orthotopic bone defect model of bone tissue repair. The current studies demonstrate the development of a range of innovative scaffold constructs within vitroefficacy and clearly illustrate the importance of an appropriatein vivoenvironment to validatein vitrofunctionality prior to scale up and preclinical application.
Multi-attribute decision-making in macaques relies on direct attribute comparisons
Authors: Perkins Aster Q. , Gillis Zachary S. , Rich Erin L.
Published: October 2023

In value-based decisions, there are frequently multiple attributes, such as cost, quality, or quantity, that contribute to the overall goodness of an option. Since one option may not be better in all attributes at once, the decision process should include a means of weighing relevant attributes. Most decision-making models solve this problem by computing an integrated value, or utility, for each option from a weighted combination of attributes. However, behavioral anomalies in decision-making, such as context effects, indicate that other attribute-specific computations might be taking place. Here, we tested whether rhesus macaques show evidence of attribute-specific processing in a value-based decision-making task. Monkeys made a series of decisions involving choice options comprising a sweetness and probability attribute. Each attribute was represented by a separate bar with one of two mappings between bar size and the magnitude of the attribute (i.e., bigger=better or bigger=worse). We found that translating across different mappings produced selective impairments in decision-making. When like attributes differed, monkeys were prevented from easily making direct attribute comparisons, and choices were less accurate and preferences were more variable. This was not the case when mappings of unalike attributes within the same option were different. Likewise, gaze patterns favored transitions between like attributes over transitions between unalike attributes of the same option, so that like attributes were sampled sequentially to support within-attribute comparisons. Together, these data demonstrate that value-based decisions rely, at least in part, on directly comparing like attributes of multi-attribute options.

Significance Statement

Value-based decision-making is a cognitive function impacted by a number of clinical conditions, including substance use disorder and mood disorders. Understanding the neural mechanisms, including online processing steps involved in decision formation, will provide critical insights into decision-making deficits characteristic of human psychiatric disorders. Using rhesus monkeys as a model species capable of complex decision-making, this study shows that decisions involve a process of comparing like features, or attributes, of multi-attribute options. This is contrary to popular models of decision-making in which attributes are first combined into an overall value, or utility, to make a choice. Therefore, these results serve as an important foundation for establishing a more complete understanding of the neural mechanisms involved in forming complex decisions.
Concurrent behavioral modelling and multimodal neuroimaging reveals how feedback affects the performance of decision making in internet gaming disorder
Authors: Zeng Xinglin , Sun Ying Hao , Gao Fei , Hua Lin , Tan Weijie , Yuan Zhen
Published: October 2023

Internet gaming disorder (IGD) raises questions on how feedback from the previous gaming round affects the risk-taking behavior in the subsequent round. Forty-two participants underwent a sequential risk-taking task, which was measured be behavioral modeling. Concurrent electroencephalogram and functional near-infrared spectroscopy (EEG-fNIRS) recordings were performed to demonstrate when, where and how the previous-round feedback affects the decision making to the next round. We discovered that the IGD illustrated heightened risk-taking propensity as compared to the HCs, indicating by the computational modeling (p= 0.028). EEG results also showed significant time window differences in univariate and multivariate pattern analysis between the IGD and HCs after the loss of the game. Further, reduced brain activation in the prefrontal cortex during the task was detected in IGD as compared to that of the control group. Risky decision-making in IGD might be due to the complex interplay between emotional response and other cognitive factors.
Design of intrinsically disordered protein variants with diverse structural properties
Authors: Pesce Francesco , Bremer Anne , Tesei Giulio , Hopkins Jesse B. , Grace Christy R. , Mittag Tanja , Lindorff-Larsen Kresten
Published: October 2023

Intrinsically disordered proteins (IDPs) perform a wide range of functions in biology, suggesting that the ability to design IDPs could help expand the repertoire of proteins with novel functions. Designing IDPs with specific structural or functional properties has, however, been diffcult, in part because determining accurate conformational ensembles of IDPs generally requires a combination of computational modelling and experiments. Motivated by recent advancements in effcient physics-based models for simulations of IDPs, we have developed a general algorithm for designing IDPs with specific structural properties. We demonstrate the power of the algorithm by generating variants of naturally occurring IDPs with different levels of compaction and that vary more than 100 fold in their propensity to undergo phase separation, even while keeping a fixed amino acid composition. We experimentally tested designs of variants of the low-complexity domain of hnRNPA1 and find high accuracy in our computational predictions, both in terms of single-chain compaction and propensity to undergo phase separation. We analyze the sequence features that determine changes in compaction and propensity to phase separate and find an overall good agreement with previous findings for naturally occurring sequences. Our general, physics-based method enables the design of disordered sequences with specified conformational properties. Our algorithm thus expands the toolbox for protein design to include also the most flexible proteins and will enable the design of proteins whose functions exploit the many properties afforded by protein disorder.
The evolution of gestation length in eutherian mammals
Authors: Danis Thodoris , Rokas Antonis
Published: October 2023

Gestation length, or the duration of pregnancy, is a critical component of mammalian reproductive biology1. Eutherian mammals exhibit striking variation in their gestation lengths2–5, which has traditionally been linked to and allometrically scales with variation in other life history traits, including body mass and lifespan5–8. How the phenotypic landscape of gestation length variation, including its associations with body mass and lifespan variation, changed over mammalian evolution remains unknown. Phylogeny-informed analyses of 845 representative extant eutherian mammals showed that gestation length variation substantially differed in both whether and how strongly it was associated with body mass and lifespan across mammalian clades. For example, gestation length variation in Chiroptera and Cetacea was not associated with lifespan or body mass but was strongly associated only with body mass in Carnivora. We also identified 52 adaptive shifts in gestation length variation across the mammal phylogeny and 14 adaptive shifts when considering all three life history traits; the placements of six adaptive shifts are common in the two analyses. Notably, two of these shifts occurred at the roots of Cetacea and Pinnipedia, respectively, coinciding with the transition of these clades to the marine environment. The varying dynamics of the phenotypic landscape of gestation length, coupled with the varying patterns of associations between gestation length and two other major life history traits, raise the hypothesis that evolutionary constraints on gestation length have varied substantially across mammalian phylogeny. This variation in constraints implies that the genetic architecture of gestation length differs between mammal clades.
Exploring the Roles of RNAs in Chromatin Architecture Using Deep Learning
Authors: Kuang Shuzhen , Pollard Katherine S.
Published: October 2023

Recent studies have highlighted the impact of both transcription and transcripts on 3D genome organization, particularly its dynamics. Here, we propose a deep learning framework, called AkitaR, that leverages both genome sequences and genome-wide RNA-DNA interactions to investigate the roles of chromatin-associated RNAs (caRNAs) on genome folding in HFFc6 cells. In order to disentangle thecis- andtrans-regulatory roles of caRNAs, we compared models with nascent transcripts,trans-located caRNAs, open chromatin data, or DNA sequence alone. Both nascent transcripts andtrans-located caRNAs improved the models’ predictions, especially at cell-type-specific genomic regions. Analyses of feature importance scores revealed the contribution of caRNAs at TAD boundaries, chromatin loops and nuclear sub-structures such as nuclear speckles and nucleoli to the models’ predictions. Furthermore, we identified non-coding RNAs (ncRNAs) known to regulate chromatin structures, such as MALAT1 and NEAT1, as well as several novel RNAs, RNY5, RPPH1, POLG-DT and THBS1-IT, that might modulate chromatin architecture throughtrans-interactions in HFFc6. Our modeling also suggests that transcripts from Alus and other repetitive elements may facilitate chromatin interactions throughtransR-loop formation. Our findings provide new insights and generate testable hypotheses about the roles of caRNAs in shaping chromatin organization.
Fertility is compromised after oocyte-specific deletion of Katanin A-subunit,Katna1, but notKatnal1
Authors: Yuen Wai Shan , Zhang Qing-Hua , Dunstan Monique , Aidhikari Deepak , O’Connor Anne E , Dunleavy Jessica EM , O’Bryan Moira K , Carroll John
Published: October 2023

Katanins are microtubule severing enzymes that play roles in shaping diverse microtubule-based structures during all cell cycle stages. To address the role of katanin A-subunits in mammalian oocytes, we have used theZp3-CreLoxapproach to specifically delete katanin A1 (Katna1) and katanin A-like 1 (Katnal1) from the start of oocyte growth in mice. Here, we show thatKatnal1is not required for normal female fertility, but that deletion ofKatna1causes a 50% decrease in fertility. Further investigation inKatna1-/-oocytes revealed no effect on MI spindle morphology but a significant effect on the morphology of MII spindles. This was accompanied by a decreased rate of fertilisation. ResultantKatna1+/-heterozygous embryos that reached the 2-cell stage developed at normal rates to the blastocyst stage. Diploid homozygous parthenotes derived fromKatna1-/-oocytes revealed a reduced rate of blastocyst formation, decreased cell number and increased nuclear size. The ability of the paternal allele to rescue preimplantation development suggests the origin of the decrease in the fertility of conditionalKatna1-/-mice lies in abnormalities arising in the egg to embryo transition prior to embryonic genome activation.