bluuebunny/crossref_metadata_2025 huggingface dataset:
Werner syndrome RECQ helicase participates in and directs maintenance of the protein complexes of constitutive heterochromatin in proliferating human cells
Authors: Lazarchuk Pavlo , Nguyen Matthew Manh , Curca Crina M. , Pavlova Maria N. , Oshima Junko , Sidorova Julia M.
Published: January 2024

The WRN RECQ helicase is responsible for the Werner syndrome of premature aging and cancer predisposition. Substantial progress has been made in delineating WRN functions in multiple aspects of DNA metabolism, including DNA replication, repair, transcription, and telomere maintenance. Nevertheless, a complete mechanistic understanding of how loss of WRN accelerates aging in humans has not been achieved yet. Here we show that WRN is involved in the maintenance of constitutive heterochromatin, CH, in proliferating, immortalized human fibroblasts. WRN is found within a complex with histone deacetylase 2, HDAC2, and WRN/HDAC2 association is mediated by heterochromatin protein alpha, HP1α. WRN deficiency derepresses SATII pericentromeric satellite repeats and reduces a subset of protein-protein interactions that participate in the organization of CH in the nucleus. In particular, WRN deficiency reduces the complexes involving Lamin B1 and Lamin B receptor, LBR. Both mRNA level and subcellular distribution of LBR are affected by WRN deficiency, and the latter phenotype does not require WRN catalytic activities. At the mRNA level, WRN supports complete maturation of the LBR mRNA. All signs of heterochromatin disruption seen in WRN-deficient proliferating fibroblasts are also observed in WRN-proficient fibroblasts undergoing replicative or oncogene-induced senescence, and WRN complexes with HP1α and HDAC2 are also markedly downregulated in these senescing cells. The data suggest that WRN loss affects heterochromatin independently of the senescence program but can mimic aspects of it and thus sensitize cells to triggers of senescence.
FtsZ-mediated spatial-temporal control over septal cell wall synthesis
Authors: Hu Longhua , Perez Amilcar , Nesterova Tanya , Lyu Zhixin , Yahashiri Atsuhi , Weisss David S. , Xiao Jie , Liu Jian
Published: January 2024

FtsZ, the tubulin-like GTPase, is the central organizer of the bacterial divisome, a macromolecular complex that synthesizes new septal cell wall and degrades old septal cell wall (made of septal peptidoglycan, sPG) to allow cell wall constriction and cytokinesis. InE. coli, it is well accepted that 1) FtsZ recruits all essential divisome proteins to the septum, including the core sPG synthase complex, FtsWI/QLB and its activator, FtsN; 2) FtsWI/QLB must complex with FtsN to produce sPG under the wild-type background; and 3) the Brownian ratcheting by treadmilling FtsZ polymers drives the directional movements of sPG synthase proteins along the septum circumference; and 4) FtsZ is essential for the early stage, but dispensable for the late stage of cell wall constriction. However, it remains unclear how FtsZ spatial-temporally organizes the divisome for robust bacterial cytokinesis throughout cell wall constriction process. Combining theoretical modeling with experiments inE. coli, we show that at the early stage during cell division, the Brownian ratcheting by FtsZ treadmilling acts both as a template to corral FtsWI/QLB and FtsN into close contacts for FtsWI/QLB-FtsN complex formation and as a conveyor to maximally homologize the septal distribution of sPG synthesis activities to avoid uneven cell wall constriction. When the septum constricts progressively, the FtsN septal density increases via binding to denuded sPG; consequently, the denuded PG-bound FtsN serves as the template to activate FtsWI/QLB for continued sPG synthesis, rendering FtsZ dispensable. Our work establishes an overarching framework that FtsZ spatial-temporally controls over septal cell wall constriction.

Significance

Bacteria utilize FtsZ, the tubulin-like GTPase, to organize cell wall enzymes during cell division. FtsZ forms treadmilling polymers along the septum circumference and drives the directional movement of cell wall enzymes for robust cell wall constriction. How this role is achieved is unclear. We show that FtsZ treadmilling acts both as a template to corral cell wall enzymes into close contacts for priming and as a conveyor to homologize the septal distribution of cell wall synthesis activities for even septum constriction. These roles evolve at different stages of cell division and are modulated differentially by different bacteria; they likely define an overarching principle for robust cell division across the microbial world.
Stimulating the medial prefrontal cortex disrupts inhibitory control over memory by modulating frontal and parietal brain regions
Authors: Khan Ahsan , Eden Ti Chun Hang , Yuan Kai , Garcia Maite Crespo , Anderson Michael C. , Tong Raymond Kai-Yu
Published: January 2024

The act of recalling memories can paradoxically lead to the forgetting of other associated memories, a phenomenon known as retrieval-induced forgetting (RIF). This effect is thought to be mediated by inhibitory control mechanisms in the prefrontal cortex of the brain. Here we investigated whether stimulation of the medial prefrontal cortex (mPFC) with transcranial direct current stimulation modulates inhibitory control during memory retrieval in a RIF paradigm. In a randomized study, fifty participants received either real or sham stimulation, before performing retrieval practice on target memories. After retrieval practice, a final test was administered to measure the impact of stimulation on RIF. We found that stimulation selectively increased the retrieval accuracy of non-target memories and thus decreased RIF, suggesting a disruption of inhibitory control. Meanwhile, no change arose for the retrieval accuracy of target memories. The reduction in RIF was caused by a more pronounced beta desynchronization within the left dorsolateral prefrontal cortex (left-DLPFC), in an early time window (<500 msec) after the onset of the cue during retrieval practice. This, in turn, led to a stronger beta desynchronization within the parietal cortex in a later time window, an established marker for successful memory retrieval. Together, our results establish the causal involvement of the mPFC in actively suppressing competing memories and we demonstrate that while forgetting arises as a consequence of retrieving specific memories, these two processes are functionally independent. Finally, we demonstrate that beta desynchronization in the fronto-parietal brain regions indicates the disruption of inhibitory control.
Macrophages protect against sensory axon degeneration in diabetic neuropathy
Authors: Hakim Sara , Jain Aakanksha , Petrova Veselina , Indajang Jonathan , Kawaguchi Riki , Wang Qing , Duran Elif Sude , Nelson Drew , Adamson Stuart S. , Greene Caitlin , Woolf Clifford J.
Published: January 2024

Diabetic peripheral neuropathy (DPN) is a common complication of diabetes, causing sensory loss and debilitating neuropathic pain1,2. Although the onset and progression of DPN have been linked with dyslipidemia and hyperglycemia3, the contribution of inflammation in the pathogenesis of DPN has not been investigated. Here, we use a High Fat High Fructose Diet (HFHFD) to model DPN and the diabetic metabolic syndrome in mice. Diabetic mice develop persistent heat hypoalgesia after three months, but a reduction in epidermal skin innervation only manifests at 6 months. Using single-cell sequencing, we find that CCR2+ macrophages infiltrate the sciatic nerves of diabetic mice well before axonal degeneration is detectable. We show that these infiltrating macrophages share gene expression similarities with nerve crush-induced macrophages4and express neurodegeneration-associated microglia marker genes5although there is no axon loss or demyelination. Inhibiting this macrophage recruitment in diabetic mice by genetically or pharmacologically blocking CCR2 signaling results in a more severe heat hypoalgesia and accelerated skin denervation. These findings reveal a novel neuroprotective recruitment of macrophages into peripheral nerves of diabetic mice that delays the onset of terminal axonal degeneration, thereby reducing sensory loss. Potentiating and sustaining this early neuroprotective immune response in patients represents, therefore, a potential means to reduce or prevent DPN.
A deep-learning strategy to identify cell types across species from high-density extracellular recordings
Authors: Beau Maxime , Herzfeld David J. , Naveros Francisco , Hemelt Marie E. , D’Agostino Federico , Oostland Marlies , Sánchez-López Alvaro , Chung Young Yoon , Maibach Michael , Kyranakis Stephen , Stabb Hannah N. , Martínez Lopera M. Gabriela , Lajko Agoston , Zedler Marie , Ohmae Shogo , Hall Nathan J. , Clark Beverley A. , Cohen Dana , Lisberger Stephen G. , Kostadinov Dimitar , Hull Court , Häusser Michael , Medina Javier F.
Published: January 2024

High-density probes allow electrophysiological recordings from many neurons simultaneously across entire brain circuits but don’t reveal cell type. Here, we develop a strategy to identify cell types from extracellular recordings in awake animals, revealing the computational roles of neurons with distinct functional, molecular, and anatomical properties. We combine optogenetic activation and pharmacology using the cerebellum as a testbed to generate a curated ground-truth library of electrophysiological properties for Purkinje cells, molecular layer interneurons, Golgi cells, and mossy fibers. We train a semi-supervised deep-learning classifier that predicts cell types with greater than 95% accuracy based on waveform, discharge statistics, and layer of the recorded neuron. The classifier’s predictions agree with expert classification on recordings using different probes, in different laboratories, from functionally distinct cerebellar regions, and across animal species. Our classifier extends the power of modern dynamical systems analyses by revealing the unique contributions of simultaneously-recorded cell types during behavior.
Can we trace the social affiliation of rooks (Corvus frugilegus) through their vocal signature?
Authors: Martin Killian , Cornero Francesa M. , Danby Emily , Daunay Virgile , Nervet Louise , Clayton Nicola S. , Obin Nicolas , Dufour Valérie
Published: January 2024

Inter-individual recognition is crucial for stable social relationships and it is frequently mediated through vocal signatures. In socially complex species, recognition may additionally require additional levels corresponding to other layers of social organisation such as the pair, family, social group or colony. Additional vocal signatures may encode these different levels of social organisations for recognition. We investigated this hypothesis in the calls of the rook (Corvus frugilegus), a highly social corvid. Rooks form large breeding colonies where multiple pairs nest in clusters. We recorded the calls of five colonies located in France and in Great Britain, including both wild and captive colonies. To exclude variations due to different call types, we focused on the loud nest call produced exclusively by nesting females during the breeding season. We compared the acoustic distance of calls from each individual and between individuals at various levels of nest proximity, i.e. from the same nest cluster, from different nest clusters, from colonies within the same country, and from colonies in different countries. The only vocal signatures we found were at the individual level, but not at the nest cluster or colony level. This suggests a lack of vocal convergence in this species, at least for the nest call, which may be important for pair recognition in large colonies. Further studies should now evaluate if types of calls other than the nest call better carry vocal signatures as markers of different layers of sociality in this species, or if vocal divergence is a more general vocal phenomenon. In that case, applying new methods of monitoring vocal signatures in wild individuals should help understand the cognitive, social and environmental mechanisms underlying this vocal singularisation.

1.

Significance statement

Inter-individual recognition is crucial for social relationships in animals, and is often mediated by individual-specific acoustic characteristics in vocalisations, called a vocal signature. High levels of social organisations, such as a social group of familiar conspecifics or a breeding colony, may likewise be signalled by vocal signatures shared by multiple individuals. We used machine-learning techniques to investigate vocal signatures at multiple social levels in the nest call of brooding female rooks, a corvid species that breeds colonially but lives year-round in social groups. We find evidence of a strong individual vocal signature, but no common vocal signature even in females that nest close together, or in the same colony. A strong individual vocal signature may be a potent tool to monitor populations in this species with minimal disturbance and minimal material, especially as corvids are frequently targeted by human-fauna conflicts in continental Europe.
The HSFA1a is stabilized by the co-chaperone HSP70-HSP90 organizing protein HOP in Arabidopsis
Authors: Toribio René , Navarro Aurora , Castellano M. Mar
Published: January 2024

Living organisms have the capacity to sense and respond to environmental stimuli, including warm conditions. Upon the increase of temperature, eukaryotic cells promote the onset of a universal transcriptional response called the heat stress response (HSR). HSR is triggered by the activation of the heat shock factor 1 (HSF1), whose activity is highly regulated in all eukaryotes. A common process of HSFA1 regulation involves its binding to HSP70 and HSP90 chaperones. However, the effect of this binding differs among eukaryotes and is not fully elucidated in plants. Moreover, the role of chaperone auxiliary proteins, such as HOP, in HSF1 regulation remains unknown. Here, we show that HOP is involved in the folding and stabilization of the HSFA1a and is required for the onset of the HSR during thermomorphogenesis in Arabidopsis. Our results demonstrate that the members of the AtHOP family bind in vivo to the HSFA1a and that the expression of multiple genes involved in the HSR, including numerous HSFA1a-responsive genes, is altered in thehop1 hop2 hop3mutant under warm temperature. HOP is not involved in the subcellular localization of the AtHSFA1a. Instead, HSFA1a is accumulated at lower levels in thehop1 hop2 hop3mutant while control levels are recovered in the presence of the proteasome inhibitor MG132 or the synthetic chaperone TUDCA. This uncovers the HSFA1a as a new client of HOP in plants and reveals the participation of HOP in HSFA1a stability, expanding the notorious function of the co-chaperone HOP in thermomorphogenesis.
ThePrimula edelbergii S-locus is an example of a jumping supergene
Authors: Potente Giacomo , Yousefi Narjes , Keller Barbara , Mora-Carrera Emiliano , Szövényi Péter , Conti Elena
Published: January 2024

Research on supergenes, non-recombining genomic regions housing tightly linked genes that control complex phenotypes, has gained prominence in genomics, with supergenes having been described in most eukaryotic lineages. Heterostyly, a floral heteromorphism promoting outcrossing in several angiosperm families, is controlled by theS-locus supergene. Historically, theS-locus has been studied primarily in closely relatedPrimulaspecies and, more recently, in other groups that independently evolved heterostyly. However, it remains unknown whether genetic architecture and composition of theS-locus are maintained among species that share a common origin of heterostyly and subsequently diverged across larger time scales. To address this research gap, we present a chromosome-scale genome assembly ofPrimula edelbergii, a species that shares the same origin of heterostyly withPrimula veris(whoseS-locus has been characterized) but diverged from it ca. 18 million years ago. Comparative genomic analyses betweenP. edelbergiiandP. verisallowed us to show, for the first time, that theS-locus can ‘jump’ (i.e. translocate) between chromosomes. Additionally, we found that fourS-locus genes were maintained across time but were reshuffled within the supergene, seemingly without affecting their expression. Furthermore, we confirmed thatS-locus hemizygosity counteracts genetic degeneration, otherwise expected in supergenes. Finally, we investigatedP. edelbergiievolutionary history within Ericales in terms of whole genome duplications and transposable element accumulation. In summary, our work provides a valuable resource for comparative analyses aimed at investigating the genetics of heterostyly and the pivotal role of supergenes in shaping the evolution of complex phenotypes.
Uniquome: Construction and Decoding of a Novel Proteomic Atlas that Contains New Peptide Entities
Authors: Kontopodis Evangelos , Pierros Vasileios , Vorgias Constantinos E. , Papassideri Issidora S. , Stravopodis Dimitrios J. , Tsangaris George Th.
Published: January 2024

Cellular and molecular uniqueness has recently gained eminent importance, due to the large amount of data produced by “-omics” technologies. Herein, we have constructed and decoded the “Uniquome”, by introduction of the new peptide entities: (a) “Core Unique Peptide” (CrUP), defined as the peptide whose sequence is accommodated, specifically and exclusively, only in one protein in a given proteome, and also bears the minimum length of amino acid sequence; (b) “Composite Unique Peptide” (CmUP), defined as the peptide composed by the linear unification of CrUPs, when two or more successive in order CrUPs overlap one another; (c) “Family Unique Peptide” (FUP), defined as the CrUPs that are common between all members of a given family, but unique only for the protein members of the particular family, and (d) “Universal Unique Peptides” (UUPs), which are the common CrUPs in a given protein across organisms, carrying the important ability to securely identify a protein independently of an organism. By these entities as tool-box, we have analyzed the human and model organisms, respective, proteomes. We demonstrate that these novel peptide entities play a crucial role for protein identification, protein-function prediction, cell physiology, tissue pathology, therapeutic oncology and translational medicine. Finally, we suggest that across species the conserved sequences are not DNA nucleotides but CrUPs entities.

One-Sentence Summary

We constructed and decoded the “Uniquome”, by introducing the new peptide entities Core Unique Peptide, Composite Unique Peptide, Family Unique Peptide and Universal Unique Peptide
Single-cell Rapid Capture Hybridization sequencing (scRaCH-seq) to reliably detect isoform usage and coding mutations in targeted genes at a single-cell level
Authors: Peng Hongke , Jabbari Jafar S. , Tian Luyi , Chua Chong Chyn , Anstee Natasha S. , Amin Noorul , Wei Andrew H. , Davidson Nadia M. , Roberts Andrew W. , Huang David C. S. , Ritchie Matthew E. , Thijssen Rachel
Published: January 2024

Single-cell long-read sequencing has transformed our understanding of isoform usage and the mutation heterogeneity between cells. Despite unbiased in-depth analysis, the low sequencing throughput often results in insufficient read coverage thereby limiting our ability to perform mutation calling for specific genes. Here, we developed asingle-cellRapid CaptureHybridizationsequencing (scRaCH-seq) method that demonstrated high specificity and efficiency in capturing targeted transcripts using long-read sequencing, allowing an in-depth analysis of mutation status and transcript usage for genes of interest. The method includes creating a probe panel for transcript capture, using barcoded primers for pooling and efficient sequencing via Oxford Nanopore Technologies platforms. scRaCH-seq is applicable to stored and indexed single-cell cDNA which allows analysis to be combined with existing short-read RNA-seq datasets. In our investigation of BTK and SF3B1 genes in samples from patients with chronic lymphocytic leukaemia (CLL), we detected SF3B1 isoforms and mutations with high sensitivity. Integration with short-read scRNA-seq data revealed significant gene expression differences in SF3B1-mutated CLL cells, though it did not impact the sensitivity of the anti-cancer drug venetoclax. scRaCH-seq’s capability to study long-read transcripts of multiple genes makes it a powerful tool for single-cell genomics.
The structure of the Orm2-containing serine palmitoyltransferase complex reveals distinct inhibitory potentials of yeast Orm proteins
Authors: Körner Carolin , Schäfer Jan-Hannes , Esch Bianca M. , Parey Kristian , Walter Stefan , Teis David , Januliene Dovile , Schmidt Oliver , Moeller Arne , Fröhlich Florian
Published: January 2024

The levels of sphingolipids are crucial determinants of neurodegenerative disorders. Therefore, sphingolipid levels have to be tightly regulated. The Orm protein family and ceramides act as inhibitors in the rate-limiting step of sphingolipid biosynthesis – the condensation of L-serine and palmitoyl-CoA. The two yeast isoforms Orm1 and Orm2 form a complex with the serine palmitoyltransferase (SPT). While the sequences of the Orm proteins are highly similar, however, Orm1 and Orm2 are differentially regulated in yeast cells. The mechanistic details of the differential regulation remain elusive. To elucidate the regulatory mechanism, we determined the cryo-electron microscopy structure of the SPT complex containing Orm2. Throughin vitroactivity assays and a newly developed plasmid coverage assay combined with targeted lipidomics, we demonstrate that the SPT complex with Orm2 exhibits lower activity in comparison to the complex containing Orm1. This collectively suggests a higher inhibitory potential of Orm2, despite the remarkably similar structures of the Orm1- and Orm2 containing complexes. The high conservation of the SPT from yeast to man implies that the three human ORMDL isoforms could also have different regulatory capacities, which might be essential to understanding their role in sphingolipid-mediated neurodegenerative disorders.

Highlights

Cryo-EM structures of serine palmitoyltransferase with Orm2 fromS. cerevisiae

Ceramide-mediated inhibition on SPT activity is conserved amongst SPTs

The two yeast Orm isoforms have different regulatory capacity
The limits of predicting maladaptation to future environments with genomic data
Authors: Lind Brandon M. , Lotterhos Katie E.
Published: January 2024

Anthropogenically driven changes in land use and climate patterns pose unprecedented challenges to species persistence. To understand the extent of these impacts, genomic offset methods have been used to forecast maladaptation of natural populations to future environmental change. However, while their use has become increasingly common, little is known regarding their predictive performance across a wide array of realistic and challenging scenarios. Here, we evaluate four offset methods (Gradient Forests, the Risk-Of-Non-Adaptedness, redundancy analysis, and LFMM2) using an extensive set of simulated datasets that vary demography, adaptive architecture, and the number and spatial patterns of adaptive environments. For each dataset, we train models using eitherall, adaptive, orneutralmarker sets and evaluate performance usingin silicocommon gardens by correlating known fitness with projected offset. Using over 4,850,000 of such evaluations, we find that 1) method performance is largely due to the degree of local adaptation across the metapopulation (LAΔSA), 2)adaptivemarker sets provide minimal performance advantages, 3) within-landscape performance is variable across gardens and declines when offset models are trained using additional non-adaptive environments, and 4) despite (1), performance declines more rapidly in novel climates for metapopulations with higherLAΔSAthan lowerLAΔSA. We discuss the implications of these results for management, assisted gene flow, and assisted migration.
Examining motor evidence for the pause-then-cancel model of action-stopping: Insights from motor system physiology
Authors: Tatz Joshua R. , Carlson Madeline O. , Lovig Carson , Wessel Jan R.
Published: January 2024

Stopping initiated actions is fundamental to adaptive behavior. Longstanding, single-process accounts of action-stopping have been challenged by recent, two-process, ‘pause-then-cancel’ models. These models propose that action-stopping involves two inhibitory processes: 1) a fast Pause process, which broadly suppresses the motor system as the result of detecting any salient event, and 2) a slower Cancel process, which involves motor suppression specific to the cancelled action. A purported signature of the Pause process is global suppression, or the reduced corticospinal excitability (CSE) of task-unrelated effectors early on in action-stopping. However, unlike the Pause process, few (if any) motor system signatures of a Cancel process have been identified. Here, we used single- and paired-pulse TMS methods to comprehensively measure the local physiological excitation and inhibition of both responding and task-unrelated motor effector systems during action-stopping. Specifically, we measured CSE, short-interval intracortical inhibition (SICI), and the duration of the cortical silent period (CSP). Consistent with key predictions from the pause-then-cancel model, CSE measurements at the responding effector indicated that additional suppression was necessary to counteract Go-related increases in CSE during-action-stopping, particularly at later timepoints. Increases in SICI on Stop-signal trials did not differ across responding and non-responding effectors, or across timepoints. This suggests SICI as a potential source of global suppression. Increases in CSP duration on Stop- signal trials were more prominent at later timepoints. SICI and CSP duration therefore appeared most consistent with the Pause and Cancel processes, respectively. Our study provides further evidence from motor system physiology that multiple inhibitory processes influence action-stopping.
Cortical multi-area model with joint excitatory-inhibitory clusters accounts for spiking statistics, inter-area propagation, and variability dynamics
Authors: Pronold Jari , Morales-Gregorio Aitor , Rostami Vahid , van Albada Sacha J.
Published: January 2024

The primate brain uses billions of interacting neurons to produce macroscopic dynamics and behavior, but current methods only allow neuroscientists to investigate a subset of the neural activity. Computational modeling offers an alternative testbed for scientific hypotheses, by allowing full control of the system. Here, we test the hypothesis that local cortical circuits are organized into joint clusters of excitatory and inhibitory neurons by investigating the influence of this organizational principle on cortical resting-state spiking activity, inter-area propagation, and variability dynamics. The model represents all vision-related areas in one hemisphere of the macaque cortex with biologically realistic neuron densities and connectivities, expanding on a previous unclustered model of this system. Each area is represented by a square millimeter microcircuit including the full density of neurons and synapses, avoiding downscaling artifacts and testing cortical dynamics at the natural scale. We find that joint excitatory-inhibitory clustering normalizes spiking activity statistics in terms of firing rate distributions and inter-spike interval variability. A comparison with data from cortical areas V1, V4, FEF, 7a, and DP shows that the clustering enables the resting-state activity of especially higher cortical areas to be better captured. In addition, we find that the clustering supports signal propagation across all areas in both feedforward and feedback directions with reasonable latencies. Finally, we also show that localized stimulation of the clustered model quenches the variability of neural activity, in agreement with experimental observations. We conclude that joint clustering of excitatory and inhibitory neurons is a likely organizational principle of local cortical circuits, supporting resting-state spiking activity statistics, inter-area propagation, and variability dynamics.
Acute sleep deprivation reduces fear memories in male and female mice
Authors: Foilb Allison R. , Taylor-Yeremeeva Elisa M. , Schmidt Brett D. , Ressler Kerry J. , Carlezon William A.
Published: January 2024

Sleep problems are a prominent feature of mental health conditions including post-traumatic stress disorder (PTSD). Despite its potential importance, the role of sleep in the development of and/or recovery from trauma-related illnesses is not understood. Interestingly, there are reports that sleep deprivation immediately after a traumatic experience can reduce fear memories, an effect that could be utilized therapeutically in humans. While the mechanisms of this effect are not completely understood, one possible explanation for these findings is that immediate sleep deprivation interferes with consolidation of fear memories, rendering them weaker and more sensitive to intervention. Here, we allowed fear-conditioned mice to sleep immediately after fear conditioning during a time frame (18 hr) that includes and extends beyond periods typically associated with memory consolidation before subjecting them to 6 hr of sleep deprivation. Mice deprived of sleep with this delayed regimen showed dramatic reductions in fear during tests conducted immediately after sleep deprivation, as well as 24 hr later. This sleep deprivation regimen also increased levels of mRNA encoding brain-derived neurotrophic factor (BDNF), a molecule implicated in neuroplasticity, in the basolateral amygdala (BLA), a brain area implicated in fear and its extinction. These findings raise the possibility that the effects of our delayed sleep deprivation regimen are not due to disruption of memory consolidation, but instead are caused by BDNF-mediated neuroadaptations within the BLA that actively suppress expression of fear. Treatments that safely reduce expression of fear memories would have considerable therapeutic potential in the treatment of conditions triggered by trauma.
Bold zebrafish (danio rerio) learn faster in an associative learning task
Authors: Corcoran Jamie , Storks Levi , Wong Ryan Y.
Published: January 2024

Animals differ in their ability to learn. One potential factor contributing to learning differences is personality types. We investigated the relationship between learning and the bold-shy continuum by comparing performance of bold and shy zebrafish in conditioned place preference (CPP) and 2 choice tasks. Bold fish learned significantly faster than the shy fish but there were no differences in their final performance. When tested in the 2 choice task, we found no clear evidence of learning, however bold fish made more initial choices than shy fish. Overall,our study suggests that bold fish tend to be faster learners when compared to shy fish. The lack of differences in the final change in behavior suggests that the learning difference is due to neophobic tendencies and resulting initial interactions with the learning stimulus.
DE Novo emerged gene SEarch in Eukaryotes with DENSE
Authors: Roginski Paul , Grandchamp Anna , Quignot Chloé , Lopes Anne
Published: January 2024

The discovery of de novo emerged genes, originating from previously noncoding DNA regions, challenges traditional views of species evolution. Indeed, the hypothesis of neutrally evolving sequences giving rise to functional proteins is highly unlikely. This conundrum has sparked numerous studies to quantify and characterize these genes, aiming to understand their functional roles and contributions to genome evolution. Yet, no fully automated pipeline for their identification is available. Therefore, we introduce DENSE (DE Novo emerged gene Search), an automated Nextflow pipeline based on two distinct steps: detection of Taxonomically Restricted Genes (TRGs) through phylostratigraphy, and filtering of TRGs for de novo emerged genes via genome comparisons and synteny search. DENSE is available as a user-friendly command-line tool, while the second step is accessible through a web server upon providing a list of TRGs. Highly flexible, DENSE provides various strategy and parameter combinations, enabling users to adapt to specific configurations or define their own strategy through a rational framework, facilitating protocol communication, and study interoperability. We apply DENSE to seven model organisms, exploring the impact of its strategies and parameters on de novo gene predictions. This thorough analysis across species with different evolutionary rates reveals useful metrics for users to define input datasets, identify favorable/unfavorable conditions for de novo gene detection, and control potential biases in genome annotations. Additionally, predictions made for the seven model organisms are compiled into a requestable database, that we hope will serve as a reference for de novo emerged gene lists generated with specific criteria combinations.

Significance Statement

The identification and classification of de novo genes, which originate from noncoding regions of DNA, remain an ongoing challenge in genomics research. While various approaches have been employed for their identification, the lack of a standardized protocol has resulted in varying lists of de novo genes across studies. This study introduces a novel tool: DENSE, that formalizes the common practices used in the field into a comprehensive and automated pipeline. DENSE streamlines the identification of taxonomically restricted genes, homology searches, and synteny analysis. This standardized methodology aims to enhance the accuracy and reliability of de novo gene identification, fostering a deeper understanding of the evolutionary mechanisms that drive gene birth and shape the genetic diversity of organisms.
A spinal cord injury time and severity consensus transcriptomic reference suite in rat reveals translationally-relevant biomarker genes
Authors: Grillo-Risco Rubén , Hidalgo Marta R. , Rojas Beatriz Martínez , Moreno-Manzano Victoria , García-García Francisco
Published: January 2024

Spinal cord injury (SCI) is a devastating condition that leads to motor, sensory, and autonomic dysfunction. Current therapeutic options remain limited, emphasizing the need for a comprehensive understanding of the underlying SCI-associated molecular mechanisms. This study characterized distinct SCI phases and severities at the gene and functional levels, focusing on biomarker gene identification. Our approach involved a systematic review, individual transcriptomic analysis, gene meta-analysis, and functional characterization. We compiled a total of fourteen studies with 273 samples, leading to the identification of severity-specific biomarker genes for injury prognosis (e.g., Srpx2, Hoxb8, Acap1, Snai1, and Aadat) and phase-specific genes for the precise classification of the injury profile (e.g., Il6, Fosl1, Cfp, C1qc, Cp). We investigated the potential transferability of severity-associated biomarkers and identified a twelve-gene signature that predicted injury prognosis from human blood samples. We also report the development of MetaSCI-app - an interactive web application designed for researchers - that allows the exploration and visualization of all generated results (https://metasci-cbl.shinyapps.io/metaSCI). Overall, we present a transcriptomic reference and provide a comprehensive framework for assessing SCI considering severity and time perspectives.

Teaser

A transcriptomic meta-analysis of spinal cord injury provides a consensus reference and biomarker genes for injury phase/severity.
A comparison between low-cost library preparation kits for low coverage sequencing
Authors: Stewart Caitlin M. , Gibson Matthew JS , Parsa Jahan-Yar , Li Jeremiah H.
Published: January 2024

In the fields of human health and agricultural research, low coverage whole-genome sequencing followed by imputation to a large haplotype reference panel has emerged as a cost-effective alternative to genotyping arrays for assaying large numbers of samples. However, a systematic comparison of library preparation methods tailored for low coverage sequencing remains absent in the existing literature. In this study, we evaluated one full sized kit from IDT and miniaturized and evaluated three Illumina-compatible library preparation kits—the KAPA HyperPlus kit (Roche), the DNA Prep kit (Illumina), and an IDT kit—using 96 human DNA samples. Metrics evaluated included imputation concordance with high-depth genotypes, coverage, duplication rates, time for library preparation, and additional optimization requirements. Despite slightly elevated duplication rates in IDT kits, we find that all four kits perform well in terms of imputation accuracy, with IDT kits being only marginally less performant than Illumina and Roche kits. Laboratory handling of the kits was similar: thus, the choice of a kit will largely depend on (1) existing or planned infrastructure, such as liquid handling capabilities, (2) whether a specific characteristic is desired, such as the use of full-length adapters, shorter processing times, or (3) use case, for instance, long vs short read sequencing. Our findings offer a comprehensive resource for both commercial and research workflows of low-cost library preparation methods suitable for high-throughput low coverage whole genome sequencing.
The evolutionary origins of the lysosome-related organelle sorting machinery reveal fundamental homology in post-endosome trafficking pathways
Authors: More Kiran J. , Dacks Joel B. , Manna Paul T.
Published: January 2024

The major organelles and pathways of the endomembrane system were in place by the time of the last eukaryotic common ancestor (LECA) (∼1.5 billion years ago) and their acquisition were defining milestones during the process of eukaryogenesis itself. Comparative cell biology and evolutionary analyses show multiple instances of homology in the protein machinery controlling distinct inter-organelle trafficking routes. Resolving these homologous relationships allows us to explore processes underlying the emergence of new cellular compartments, infer ancestral states pre-dating LECA, and can even provide insight into the process of eukaryogenesis itself. Here we undertake a molecular evolutionary analysis, including providing a transcriptome of the jakobid flagellateReclinomonas americana,exploring the origins of the machinery responsible for the biogenesis of lysosome-related organelles, the so-called Biogenesis of Lysosome-related Organelle Complexes (BLOCs 1,2, and 3). This pathway has been studied only in animals and is not considered a feature of the basic eukaryotic cell plan. We show that this machinery, and by inference the corresponding sorting pathway, was likely in place prior to the divergence of eukaryotes and is found in a much more diverse array of eukaryotes than is currently assumed. As such, this sorting pathway is likely an underappreciated facet of broader eukaryotic cellular function. Moreover, we resolve multiple points of ancient homology between all three BLOCs and other post-endosomal retrograde trafficking machinery (BORC, CCZ1/MON1, and a newly identified relationship with HOPS/CORVET) offering a mechanistic and evolutionary unification of these trafficking pathways. Overall, this study provides a comprehensive account of the rise of the LRO biogenesis machinery from prokaryotic origins to current eukaryotic diversity, Asgard archaea to animals, integrating it into the larger mechanistic framework describing endomembrane evolution.
Functional magnetic resonance imaging of the lumbosacral cord during a lower extremity motor task
Authors: Kündig Christian W. , Finsterbusch Jürgen , Freund Patrick , David Gergely
Published: January 2024

Blood-oxygen-level dependent (BOLD) functional magnetic resonance imaging (fMRI) can be used to map neuronal function in the cervical cord, yet conclusive evidence supporting its applicability in the lumbosacral cord is still lacking. This study aimed to (i) demonstrate the feasibility of BOLD fMRI in mapping neuronal activation in the lumbosacral cord during a unilateral lower extremity motor task and (ii) investigate the impact of echo time (TE) on the BOLD effect size. Twelve healthy volunteers underwent BOLD fMRI using four reduced-field-of-view single-shot gradient-echo echo planar imaging sequences, all with the same geometry but different TE values ranging from 20 to 42 ms. Each sequence was employed to acquire a single 6-minute rest run and two 10-minute task runs, which included alternating 15-second blocks of rest and unilateral ankle dorsi- and plantar flexion. We detected lateralized task-related neuronal activation at neurological levels S4 to L1, centered at the ipsilateral (right) ventral spinal cord but also extending into the ipsilateral dorsal spinal cord. This pattern of activation is consistent with our current understanding of spinal cord organization, wherein lower motor neurons are located in the ventral gray matter horn, while sensory neurons of the proprioceptive pathway, activated during the movement, are located in the dorsal horns. At the subject level, BOLD activation showed considerable variability but was lateralized in all participants. The highest BOLD effect size within the ipsilateral ventral spinal cord was observed at TE=42 ms. Sequences with a shorter TE (20 and 28 ms) also detected activation in the medioventral part of the spinal cord, likely representing a large vein effect. In summary, our results demonstrate the feasibility of detecting neuronal activation in the lumbosacral cord induced by voluntary lower limb movements. BOLD fMRI in the lumbosacral cord has significant implications for assessing motor function and its alterations in disease or after spinal cord injury.
Recording γ-secretase activity in living mouse brains
Authors: Hou Steven S. , Ikegawa Yuya , Kwon Yeseo , Wieckiewicz Natalia , Houser Mei C.Q. , Lundin Brianna , Bacskai Brian J. , Berezovska Oksana , Maesako Masato
Published: January 2024

γ-Secretase plays a pivotal role in the central nervous system. Our recent development of genetically encoded Förster resonance energy transfer (FRET)-based biosensors has enabled the spatiotemporal recording of γ-secretase activity on a cell-by-cell basis in live neuronsin culture. Nevertheless, how γ-secretase activity is regulatedin vivoremains unclear. Here we employ the near-infrared (NIR) C99 720-670 biosensor and NIR confocal microscopy to quantitatively record γ-secretase activity in individual neurons in living mouse brains. Intriguingly, we uncovered that γ-secretase activity may influence the activity of γ-secretase in neighboring neurons, suggesting a potential “cell non-autonomous” regulation of γ-secretase in mouse brains. Given that γ-secretase plays critical roles in important biological events and various diseases, our new assayin vivowould become a new platform that enables dissecting the essential roles of γ-secretase in normal health and diseases.
Employers, recruitment and activation programmes experimental evidence from the Czech labour market
Authors: Vyhlídal Jiří
Published: January 2024

Purpose

The purpose of this paper is to test the impact of selected characteristics of jobseekers on employers’ decisions regarding potential hires (direct and probabilistic signals). The main focus of the study is to test the impact of jobseekers’ participation in selected active labour market programmes on employers’ hiring decisions for three positions: unskilled worker, skilled worker and administrative employee. Other characteristics tested include age, gender, presence of children in the household, state of health, experience of short- and long-term unemployment and indebtedness.

Design/methodology/approach

This study analyses data from a representative survey of employers with five or more employees in the Czech Republic. The survey was conducted in December 2020 using stratified random sampling, combining online questionnaires and personal interviews. The study includes 1,040 employers and uses the factorial survey experiment (FSE) design.

Findings

The results of the FSE suggest that the perceived positive impact of completing one of the activation programmes depends on the position for which the candidate is being recruited. While for the unskilled job category, the completion of any of the tested schemes (training, subsidised jobs or public works) had a positive effect; for the skilled job category, only the training and subsidised jobs schemes had a positive effect; and for the administrative job category, public works programme even had a negative effect.

Research limitations/implications

A somewhat limiting factor in the context of this study seems to be the definitions of the positions tested (unskilled and skilled workers and administrative staff). The decision-making of the respondents was somewhat restricted by such broadly defined categories. Typically, studies with FSE designs have a focus on a specific sector of the economy, which allows for a better definition of the positions or jobs under test. The relationship between position and the impact of individual characteristics is clearly a matter for further research.

Practical implications

The results of the study confirm that completion of the activation programme, as well as other candidate characteristics, constitute differentiating signals for employers that influence their hiring decisions. At the same time, there is evidence that the training programme and the subsidised jobs programme are effective in terms of increasing participants’ chances of employment.

Originality/value

The demand side should be included in the evaluation of activation policies. The design of the FSE provides an appropriate way to test the impact of activation measures on the decision-making of employers.
Adoption of building information modelling for post-construction in Nigeria: examination of barriers and strategies development
Authors: Bello Abdulkabir Opeyemi , Ayegba Calistus
Published: January 2024

Purpose

Despite successfully adopting building information modelling (BIM) for design and construction, its adoption in post-construction is critically lagging. This study aims to investigate the adoption of BIM for post-construction in Nigeria. Specifically, it aims to investigate the barriers hindering BIM adoption, propose strategies to facilitate its integration into the post-construction phase and examine the relationship between the barriers and strategies towards adopting BIM for post-construction.

Design/methodology/approach

This study employs a quantitative approach to gather numerical data on BIM perceived barriers among International Facility Management Association (IFMA) members. The study also develops strategies from an extensive literature review and combines them with insights from preliminary investigation. The data were analysed using descriptive and inferential statistics.

Findings

The top perceived barriers among the professionals are lack of BIM awareness, software availability issues and difficulties using new technologies. Institute training/workshops on BIM software for the professionals in the organisation, including BIM software courses in various related professional exams, and encouraging adoption of BIM from the grassroots, such as higher institutions, emerge as the top strategies. The findings further show a significant relationship between the barriers and strategies, emphasising the recognition that understanding barriers prompts the active development and implementation of strategies.

Originality/value

This study holds originality in its examination of the relationship between the barriers and strategies associated with BIM adoption in Nigerian Architecture, Construction, Engineering and Operation.