bluuebunny/crossref_metadata_2025 huggingface dataset:
Intestinal Dysbiosis Alters Acute Seizure Burden and Antiseizure Medicine Activity in the Theiler’s Virus Model of Encephalitis
Authors: Erickson Inga , Davidson Stephanie , Choi Hanna , Rho Seongheon , Guignet Michelle , Peagler Kristen , Thummel Kenneth , Ericsson Aaron , Barker-Haliski Melissa
Published: November 2024

Objective

Brain infection with Theiler’s virus (TMEV) in C57BL/6J mice produces an etiologically relevant model of acquired seizures. Dietary changes can modify acute seizure presentation following TMEV brain infection and influence intestinal microbiome diversity and composition. Intestinal dysbiosis may thus similarly affect seizure burden and antiseizure medicine (ASM) activity in this model, independent of pharmacokinetic effects. We thus sought to define the influence of antibiotic (ABX)-induced gut dysbiosis on acute seizure presentation, anticonvulsant activity of carbamazepine (CBZ), and CBZ pharmacokinetics with TMEV infection.

Methods

Male C57BL/6J mice (4-5 weeks) received oral (p.o.) ABX or saline (SAL) once daily beginning on arrival through Day 7 post-TMEV infection (p.i.). Mice were infected with TMEV or PBS on Day 0. Mice received intraperitoneal (i.p.; 20 mg/kg) CBZ or vehicle (VEH) twice daily Days 3-7 p.i. and were assessed for handling-induced seizures 30 min after treatment. Plasma was collected on Day 7 p.i. at 15 and 60 min post-CBZ administration for bioanalysis.

Results

TMEV infection induced acute seizures, but ABX-induced gut dysbiosis altered seizure presentation. There were 75% SAL-VEH, 35% SAL-CBZ, 35% ABX-VEH, and 72% ABX- CBZ mice with seizures during the 7-day monitoring period. There was a significant pretreatment x ASM interaction (p=0.0001), with differences in seizure burden in SAL- versus ABX-pretreated mice (p=0.004). CBZ significantly increased latency to seizure presentation; an effect absent in ABX-CBZ mice. Plasma CBZ concentrations did not differ between SAL and ABX pretreatment groups, suggesting that ABX did not influence CBZ pharmacokinetics.

Significance

ABX-induced gut dysbiosis markedly altered acute disease trajectory with TMEV- induced encephalitis, reflecting a novel contribution of the gut microbiome to seizure presentation. ABX-induced gut dysbiosis also significantly changed acute seizure control by CBZ, but did not influence plasma CBZ concentrations. The gut-brain axis is thus an under- recognized contributor to TMEV infection-induced seizures, ASM activity, and disease burden.

Key Points:

Theiler’s virus infection in mice models encephalitis that exhibits differential disease trajectory with gut microbiome modulation.

Experimentally evoked gut dysbiosis, i.e. a disrupted gut microbiome, dramatically shifts the anticonvulsant activity of carbamazepine.

There is no concomitant shift in circulating carbamazepine concentrations in TMEV- infected mice with and without a dysbiotic microbiome.

The gut microbiome is an under-recognized driver of seizure risk and antiseizure medicine activity in the Theiler’s virus mouse model.
Lower-limb express visuomotor responses are spared in Parkinson’s Disease during step initiation from a stable position
Authors: Billen Lucas S. , Nonnekes Jorik , Corneil Brian D. , Weerdesteyn Vivian
Published: November 2024

While motor impairments have been extensively studied in Parkinson’s Disease, rapid visuomotor transformations for flexible interaction with the environment have received surprisingly little attention. In recent years, such rapid visuomotor transformations have been studied in the form of express visuomotor responses (EVRs), which are goal-directed bursts of muscle activity that are thought to originate from superior colliculus, reaching the periphery via the tecto-reticulospinal pathway.

Here, we examined EVRs in the lower limbs during goal-directed step initiation in 20 people with Parkison’s Disease (PwPD) and 20 age-matched healthy control participants (HC). As lower-limb EVRs in the young have been shown to interact with postural control - which is often affected in PwPD – we manipulated the postural demands by varying initial stance width and target location. In the low postural demand condition, EVRs were robustly present in both the PwPD (17/20) and HC (16/20) group. However, when postural demands were high, EVRs were largely absent in both groups and, instead, strong anticipatory postural adjustments (APAs) were required prior to foot off. EVR magnitudes were, on average, stronger in PwPD compared to HC, but they decreased with increasing disease severity, suggesting that the EVR network may become compromised or down-regulated in later stages of the disease. While APA magnitudes were smaller in PwPD compared to HC, subsequent stepping performance (step reaction time, duration, size, velocity) was remarkably similar between the two groups. We suggest that the EVR network may be upregulated in the early stages of Parkinson’s disease in order to compensate for some of the emerging motor deficits experienced in daily life.
Nonequilibrium brain dynamics elicited as the origin of perturbative complexity
Authors: Stikvoort Wiep , Pérez-Ordoyo Eider , Mindlin Iván , Escrichs Anira , Sitt Jacobo D. , Kringelbach Morten L. , Deco Gustavo , Perl Yonatan Sanz
Published: November 2024

Assessing the level of consciousness someone is in, is not a trivial question and physicians have to rely on behavioural evaluations instead of quantifiable metrics. Many studies have empirically investigated measures related to the complexity elicited after the brain is stimulated to quantify and assess the level of consciousness across different states. Here we hypothesized that the level of non-equilibrium dynamics of the unperturbed brain already contains the information needed to know how the system will react to an external stimulus. We created personalized whole-brain models fitted to resting state fMRI data recorded in participants in different states of reduced consciousness (such as deep sleep and disorders of consciousness) to infer the effective connections underlying their brain dynamics. We then measured the out-of-equilibrium nature of the unperturbed brain by evaluating the level of asymmetry of the inferred connectivity, the time irreversibility in each model and compared this with the elicited complexity generated afterin silicoperturbations. Crucially, we found that states of reduced consciousness had a lower level of asymmetry in their effective connectivities compared to control subjects, as well as a lower level of irreversibility in their simulated dynamics, and a lower complexity. We demonstrated that the asymmetry in the underlying connections drives the nonequilibrium state of the system and in turn the differences in complexity as a response to the external stimuli.
Early changes in the properties of CA3 engram cells explored with a novel viral tool
Authors: Cupollilo Dario , Grosjean Noëlle , Marneffe Catherine , Viotti Julio , Reynaud Célia , Deforges Séverine , Carta Mario , Mulle Christophe
Published: November 2024

Forming new memories after a one-time experience requires initial encoding then consolidation over time. During learning, multimodal information converges onto the hippocampus, activating sparse neuronal assemblies which are thought to form a memory representation through concerted activity and synaptic interconnectivity. In this work, we use a novel tool for fast-labeling of engram neurons (FLEN). FLEN is based on c-Fos activity-dependent transient expression of a destabilized fluorescent marker ZsGreen1 rapidly after one-trial learning. With FLEN, we explore the electrophysiological properties of c-Fos activated CA3 pyramidal neurons a few hours following one-trial learning of an episodic-like memory. In parallel, we employ the Robust Activity Marker (RAM) system, which provides activity-dependent labelling 24 hours following a novel experience. Comparing FLEN+ and RAM+ neurons allows to characterize how the properties of neuronal assemblies evolve during an initial phase of consolidation. Whereas no difference was observed in the excitability of FLEN+ vs. FLEN-neurons, RAM+ neurons were more excitable than RAM-neurons. This suggests that CA3 pyramidal neurons recruited in an engram progressively acquire increased excitability as compared to neurons which were not activated by the one-trial contextual memory task. In contrast, FLEN+ CA3 neurons show an increased number of excitatory inputs. Overall, with the FLEN strategy, we can show that both the intrinsic excitability and the synaptic properties of CA3 pyramidal neurons undergo progressive plastic changes over the first day following a one-trial memory task.
In vivo modulation of network activity drives the nanoscale reorganisation of axo-axonic synapses at the axon initial segment
Authors: Compans B. , Mastrolia V. , Lenherr C. , Burrone J.
Published: November 2024

Chemical synapses control their strength through the nanoscale clustering of postsynaptic receptors into sub-synaptic domains (SSDs). Despite their importance in synapse function, the properties and plasticity of these domains are not well understoodin vivo, particularly in inhibitory synapses. We used direct Stochastic Optical Resolution Microscopy (dSTORM) to show that Gephyrin, the main inhibitory receptor scaffold protein, is organised into SSDsin vivo, with distinct arrangements depending on their sub-cellular location and presynaptic partner. Furthermore, chronic chemogenetic increases in cortical activity caused a reduction in Gephyrin SSD volume specifically in axo-axonic, but not axo-dendritic, synapses. Functionally, this resulted in a weakening of axo-axonic contacts. We show that the nanoscale arrangement of synapses in the brain is plastic and used to fine-tune synaptic gainin vivo.
Holistic genetic barcoding reveals a lineage tree of tissue macrophage development
Authors: Frank Larissa , Postrach Daniel , Langhinrichs Maurice , Höfer Thomas , Rodewald Hans-Reimer
Published: November 2024

Tissue macrophages are crucial for organ development and homeostasis, yet the developmental routes leading to tissue macrophages remain controversial. By combining unbiasedPolyloxbarcoding with computational inference, we comprehensively mapped tissue macrophage ontogeny in mice from gastrulation to adult organs. Our data reveal a lineage tree of all tissue macrophages. This tree originates from a pan-hematopoietic progenitor at embryonic day (E)6.5 and branches, via oligolineage progenitors (E7.5-E9.5), into organ-specific macrophage lineages by E10.5. Barcode analysis in embryonic tissues and adult organ fragments suggests that local macrophage colonies, formed by organ-specific progenitors, persist into adulthood. Indeed, spatial fate mapping withPolytopebarcoding detects local Kupffer cell colonies of the size predicted by the lineage tree model. Our findings uncover the origin of tissue-resident macrophages from a lineage tree, and show how holistic barcoding can comprehensively map complex cellular lineage specification.

One-Sentence Summary

Holistic, time- and space-resolved barcoding in the embryo reveals a unified lineage tree for all tissue macrophages, generating local macrophage colonies persisting in adult organs.
Increased fear generalization results in reduced generalization of extinction
Authors: Lopez-Moraga Alba , Gültekin Zeynep , Luyten Laura , Beckers Tom
Published: November 2024

Generalization of conditioned fear is adaptive for survival. However, overgeneralization of fear from threat cues to loosely similar yet safe stimuli is a hallmark of anxiety-related disorders. Such overgeneralization may moreover impact other fear learning processes. In particular, broad fear generalization might limit the effectiveness of extinction training, which may further maintain anxiety.

Hypothesizing that increased generalization of conditioned fear might weaken the later generalization of fear extinction, we here compared rats conditioned with moderate-versus high-intensity foot shocks, the latter group expected to show stronger generalization of acquired fear than the former. Within each shock intensity group, we then conducted extinction training using the original conditioned stimulus (CS) for half of the animals and a generalization stimulus (GS) for the others. We found significantly less generalization of extinction to the CS if rats had initially been conditioned using the high-intensity foot shock than if they had been conditioned using the moderate-intensity foot shock, in line with our hypothesis.

In conclusion, increased generalization of acquisition from a CS to a GS appears to go hand in hand with weaker generalization of extinction from that GS back to the CS. This may be important to consider in extinction-based exposure therapy because patients often present with broadly generalized fears, and exposure is usually not performed with the exact cues or situations for which fear was initially acquired.
Identification of clinical carbapenemases, 478 novel β-lactamases and putative seven new bacterial phyla from wastewater contaminated high arctic fjord sediments
Authors: Victor Manish P. , Øvreås Lise , Marathe Nachiket P.
Published: November 2024

Arctic microbiota is enigmatic and highly underexplored. With the aim of understanding the resistome and microbiota of high-Arctic fjord sediments and the effect of wastewater discharge on sediment microbiota, we analysed sediments using metagenomics. We show presence of 888 clinically relevant antibiotic resistance genes including genes coding resistance against last-resort antibiotics such as carbapenems, colistin, vancomycin, linezolid and tigecycline in sediment microbiota. Using computational models, 478 novel β-lactamases belonging to 217 novel β-lactamases families were revealed in sediment microbiota from Adventfjorden in Svalbard. We identified hosts for 69 novel gene families and showed that these genes are widespread in the Arctic environment. Further, in 644 metagenome-assembled genomes (MAGs) from sediment metagenomes >97% belong to novel taxa, representing seven putative novel phyla. These MAGs encoded important functions like nutrient cycling and methane metabolism etc. Our study demonstrated mixing of human associated bacteria and Arctic sediment microbiota. It provides the first comprehensive dataset of the distribution and diversity of novel microbes and β-lactamases in the high Arctic sediments.
Dissecting the differential role of C-terminal truncations in the regulation of aSyn pathology formation and the biogenesis of Lewy bodies
Authors: Mahul-Mellier Anne-Laure , Altay Melek Firat , Maharjan Niran , Ait-Bouziad Nadine , Chiki Anass , Jagannath Somanath , Limorenko Galina , Novello Salvatore , Ricci Jonathan , Vingill Siv , Wade-Martins Richard , Holton Janice , Strand Catherine , Haikal Caroline , Li Jia-Yi , Hamelin Romain , Croisier Marie , Knott Graham , Mairet-Coello Georges , Weerens Laura , Michel Anne , Downey Patrick , Citron Martin , Lashuel Hilal A.
Published: November 2024

Alpha-synuclein (aSyn) post-translational modifications (PTMs), particularly phosphorylation at serine 129 and C-terminal truncations, are highly enriched in Lewy bodies (LBs), Lewy neurites, and other types of aSyn pathological aggregates in the brain of patients with Parkinson’s disease (PD) and other synucleinopathies. However, our knowledge about the precise role of PTMs in regulating the different stages of pathology formation, neurodegeneration, and aSyn pathology spreading remains incomplete. In this work, we applied a systematic approach to address this knowledge gap with an emphasis on mapping and elucidating the role of post-fibrillization C-terminal aSyn truncations in regulating the uptake, processing, seeding activity, and formation of LB-like inclusions and maturations in a well-established neuronal seeding model that recapitulates all the stages leading to LB formation and neurodegeneration. Our work shows that C-terminal cleavage of aSyn fibrils at multiple sites is a conserved process that occurs rapidly after and during the formation of intracellular LB-like aSyn inclusions in all neuronal seeding models. Interestingly, blocking the cleavage of internalized fibrils does not influence their seeding activity, whereas inhibiting the enzymes that regulate the cleavage of newly formed fibrils (e.g., calpains 1 and 2) significantly alters the formation of LB-like inclusions. We also show that C-terminal truncations, in combination with other PTMs, play a crucial role in regulating the interactome and remodeling of newly formed aSyn fibrils, including their shortening, lateral association, and packing during LB formation and maturation. Altogether, our results demonstrate that post-fibrillization C-terminal truncations have a differential role at different stages of aSyn aggregation and pathology formation. These insights, combined with the abundance of truncated aSyn species in LBs, have significant implications in understanding aSyn pathological diversity and developing therapeutic strategies targeting the C-terminus of aSyn or its proteolytic processing.
Embedded Extremum Seeking: A Bio-synthetic Optimiser
Authors: Smart Benjamin , Marucci Lucia , Renson Ludovic
Published: November 2024

In cybergentics, internal control uses synthetic genetic circuits to bypass the sensing and actuation limits of external control. Currently, embedded controllers are limited to basic controllers, like PID. Here, we introduce the Embedded Extremum Seeking Controller, the first example of a bio-synthetic optimiser. Extremum Seeking combines an integral and oscillator circuit to adjust system parameters and achieve a desired optimal steady state. This system uses an integral circuit and oscillator that already exist in synthetic biology. The Extremum Seeker is demonstratedin silicoon a Labour Division system, where the controller tunes a kinematic parameter, optimising the ratio of the culture subpopulations to maximise production. This controller paves the way for embedded controllers that precisely direct cellular behaviour without needing external actuation and sensing.
Inferring global exponents in subsampled neural systems
Authors: Conte Davide , de Candia Antonio
Published: November 2024

In systems displaying an activity charaterized by avalanches, critical exponents may give informations on the mechanisms underlying the observed behaviour or on the topology of the connections. However, when only a small fraction of the units composing the system are observed and sampled, the measured exponents may differ significantly from the true ones. We show that some of the exponents, namely the ones governing the power spectrum and the detrended fluctuation analysis of the system activity, are more robust and are unaffected in some intervals of frequencies by the subsampling. They may be used therefore to extract in a simple and unbiased way some of the exponents of the unobserved full system.
Gamma Synchrony Mediates Figure-Ground Perception
Authors: Karimian Maryam , Roberts Mark J. , De Weerd Peter , Senden Mario
Published: November 2024

Gamma synchrony is ubiquitous in visual cortex, but whether it contributes to perceptual grouping remains contentious based on observations that gamma frequency is not consistent across stimulus features and that gamma synchrony depends on distances between image elements. These stimulus dependencies have been argued to render synchrony among neural assemblies encoding components of the same object difficult. Alternatively, these dependencies may shape synchrony in meaningful ways. Using the theory of weakly coupled oscillators (TWCO), we demonstrate that stimulus dependence is crucial for gamma’s role in perception. Synchronization among coupled oscillators depends on frequency dissimilarity and coupling strength, which in early visual cortex relate to local feature dissimilarity and physical distance, respectively. We manipulated these factors in a texture segregation experiment wherein human observers identified the orientation of a figure defined by reduced contrast heterogeneity compared to the background. Human performance followed TWCO predictions both qualitatively and quantitatively, as formalized in a computational model. Moreover, we found that when enriched with a Hebbian learning rule, our model also predicted human learning effects. Increases in gamma synchrony due to perceptual learning predicted improvements in behavioral performance across sessions. This suggests that the stimulus-dependence of gamma synchrony is adaptable to the statistics of visual experiences, providing a viable neural grouping mechanism that can improve with visual experience. Together our results highlight the functional role of gamma synchrony in visual scene segmentation and provide a mechanistic explanation for its stimulus-dependent variability.
Kernel-based LFP estimation in detailed large-scale spiking network model of mouse visual cortex
Authors: Meneghetti Nicolò , Rimehaug Atle E. , Einevoll Gaute T. , Mazzoni Alberto , Ness Torbjørn V.
Published: November 2024

Simulations of large-scale neural activity are powerful tools for investigating neural networks. Calculating measurable brain signals like local field potentials (LFPs) bridges the gap between model predictions and experimental observations. However, accurately simulating LFPs from large-scale models has traditionally required highly detailed multicompartmental neuron models, posing significant computational challenges. Here, we demonstrate that a kernel-based method can efficiently and accurately estimate LFPs in a state-of-the-art multicompartmental model of the mouse primary visual cortex (V1). Beyond its computational efficiency, the kernel method aids analysis by disentangling contributions of individual neuronal populations to the LFP. Using this approach, we found that LFPs in the V1 model were dominated by external synaptic inputs, with local synaptic activity playing a minimal role. Our findings establish the kernel method as a powerful tool for LFP estimation in large-scale network models and for uncovering the synaptic mechanisms underlying brain signals.
An optical brain-machine interface reveals a causal role of posterior parietal cortex in goal-directed navigation
Authors: Sorrell Ethan , Wilson Daniel E. , Rule Michael E. , Yang Helen , Forni Fulvio , Harvey Christopher D. , O’Leary Timothy
Published: November 2024

Cortical circuits contain diverse sensory, motor, and cognitive signals, and form densely recurrent networks. This creates challenges for identifying causal relationships between neural populations and behavior. We developed a calcium imaging-based brain-machine interface (BMI) to study the role of posterior parietal cortex (PPC) in controlling navigation in virtual reality. By training a decoder to estimate navigational heading and velocity from PPC activity during virtual navigation, we discovered that mice could immediately navigate toward goal locations when control was switched to BMI. No learning or adaptation was observed during BMI, indicating that naturally occurring PPC activity patterns are sufficient to drive navigational trajectories in real time. During successful BMI trials, decoded trajectories decoupled from the mouse’s physical movements, suggesting that PPC activity relates to intended trajectories. Our work demonstrates a role for PPC in navigation and offers a BMI approach for investigating causal links between neural activity and behavior.
NaDyNet: A Toolbox for Dynamic Network Analysis of Naturalistic Stimuli
Authors: Yang Junjie , Hu Zhe , Li Junjing , Guo Xiaolin , Gao Xiaowei , Liu Jiaxuan , Wang Yaling , Qu Zhiheng , Li Wanchun , Li Zhongqi , Li Wanjing , Huang Yien , Chen Jiali , Wen Hao , Yuan Binke
Published: November 2024

Experiments with naturalistic stimuli (e.g., listening to stories or watching movies) are emerging paradigms in brain function research. The content of naturalistic stimuli is rich and continuous. The fMRI signals of naturalistic stimuli are complex and include different components. A major challenge is isolate the stimuli-induced signals while simultaneously tracking the brain’s responses to these stimuli in real-time. To this end, we have developed a user-friendly graphical interface toolbox called NaDyNet (Naturalistic Dynamic Network Toolbox), which integrates existing dynamic brain network analysis methods and their enhanced versions. The main features of NaDyNet are: 1) extracting signals of interest from naturalistic fMRI signals; 2) incorporating six commonly used dynamic analysis methods and three static analysis methods; 3) enhanced versions of these dynamic methods by adopting inter-subject analysis to eliminate the effects of non-interest signals; 4) performing K-means clustering analysis to identify temporally reoccurring states along with their temporal and spatial attributes. We then introduced the rationale for incorporating inter-subject analysis to improve existing dynamic brain network analysis methods, and presented numerous examples. We also summarized research progress in comparing methodological efficacy, offered our recommendations for method selection in dynamic network analysis, and discussed the limitations of current approaches and directions for future research. We hope that this open source toolbox will promote the development of naturalistic neuroscience. The toolbox is available athttps://github.com/yuanbinke/Naturalistic-Dynamic-Network-Toolbox.
Acute restraint stress and pain modulation depend on the interaction between the periaqueductal gray and the lateral septum
Authors: Shah Devanshi Piyush , Chaudhury Yatika , Barik Arnab
Published: November 2024

Acute restraint stress is known to cause analgesia in humans and laboratory animals, but the mechanisms are unknown. Recently, we have shown that a multi-nodal circuitry between the dorsal lateral septum (dLS)-lateral hypothalamic area (LHA)-rostral ventromedial medulla (RVM) plays an instructive role in restraint stress-induced analgesia. We found that the LS neurons are activated when mice struggle to escape the restraint, and we wondered about the origin of the escape signals. Hence, we performed retrograde viral labeling from the LS and found that the ventrolateral periaqueductal gray (vlPAG), a known anatomical substrate for escape behaviors, provides inputs to the LS. Through anatomical, behavioral, and in-vivo fiber photometry, we show that the PAG and LS neurons are synaptically connected; activation of either PAG or the post-synaptic LS neurons is sufficient to cause analgesia and sufficiently cause hyperalgesia. Moreover, we found that the LS neurons that receive inputs from PAG send axonal projections to the LHA. Together, we found that the vlPAG neurons encoding nociceptive and escape behaviors provide synaptic inputs to the dLS-LHA-RVM circuitry to mediate acute restraint stress-induced analgesia.

Significance statement

Forced restraint causes stress, and this paradigm has been used in the laboratory to study the physiological effects of stress, including pain modulation. The dorsal lateral septum (LS) has been shown to mediate restraint-mediated stress and analgesia. It is unknown what signals encoded in the LS allow it to instruct stress and pain. A novel neural pathway between the periaqueductal gray (PAG) and LS is activated when mice try to escape the restraint. Repeated activity in the PAG-LS circuitry due to the inescapability of the restraint causes stress and analgesia
Rostral ventromedial medulla (RVM) projects to the lateral hypothalamic area (LHA) to drive aversion and anxiety
Authors: Rani Mousmi , Shah Devanshi Piyush , Barik Arnab
Published: November 2024

Neurons in the LHA are critical drivers of behavioral and physiological responses to acute and chronic stress. However, the roles of the specific pre-synaptic inputs to the LHA in driving stress and resultant physiological effects are yet to be fully understood. Here, taking advantage of mouse viral genetics, rabies tracing, optogenetics, chemogenetics, and fiber photometry, we show that the excitatory projections from the RVM to LHA drive stress-induced anxiety. This is a surprising finding since, traditionally, RVM has been studied in the context of opioidergic pain modulation through its inhibitory projections to the spinal cord. We find that the LHA neurons receiving inputs from the RVM, when activated, do not alter the nociceptive thresholds yet are sufficient to drive anxiety-like behaviors. These LHA neurons are recruited by acute restraint, which is known to cause stress. On the other hand, the LHA-projecting RVM neurons are responsive to both noxious thermal stimuli and acute restraint, promoting stress-induced anxiety, yet with no effect on pain thresholds. Together, we found an ascending neural pathway between RVM and LHA that mediates stress-induced anxiety.

Significance statement

There is a strong correlation between pain and anxiety. However, the underlying neural mechanisms are poorly understood. Here, we reveal a novel neural pathway between the rostral ventromedial medulla (RVM) and lateral hypothalamus (LHA) that can potentially convert painful experiences into stress and anxiety. The traditional role of RVM is opioidergic modulation of pain. However, here we show that in addition to nociception, RVM neurons can play an essential role in the affective-motivational components of pain.
The impact of systemic blockade of dopamine receptors on the acquisition of two-way active avoidance in rats
Authors: Vercammen L. , Lopez-Moraga A. , Beckers T. , Vervliet B. , Luyten L.
Published: November 2024

Active threat avoidance is a core aspect of adaptive and maladaptive behavior, yet its underlying mechanisms are not fully understood. Prior studies concluded that pharmacologically blocking dopaminergic receptors (DRs) disrupted avoidance acquisition, but it remains unclear whether such effects on learning persist during a drug-free follow-up test. To assess the involvement of D1R and D2R in avoidance acquisition, we conducted two experiments. In Experiment 1, thirty-six male Wistar rats underwent a single avoidance training session involving 30 tone-shock pairings. Rats could avoid the shock by moving to the opposite compartment of the shuttle box. Twenty minutes before training, rats received either D1R antagonist SCH 23390 (0.05 mg/kg), D2R antagonist sulpiride (20 mg/kg), or vehicle. While sulpiride did not affect avoidance, 0.05 mg/kg SCH 23390 significantly reduced the number of avoidance responses. In a separate test, 0.05 mg/kg SCH 23390 also reduced locomotor activity. In Experiment 2 (N = 24), a lower dose of SCH 23390 (0.025 mg/kg) was administered, and a drug-free avoidance test under continued reinforcement was added 24 hours later to test for sustained effects of D1R blockade on avoidance in the absence of acute drug effects. Although animals avoided less with SCH 23390 in the system, this effect did not persist 24 hours later, suggesting that effects of D1R blockade during avoidance training might reflect an acute disruption of secondary processes involved in the performance of avoidance behavior rather than an actual impairment of avoidance learning.
From phenotype to receptor: validating physiological clustering ofEscherichia coliphages through comprehensive receptor analysis
Authors: Kaneko Tomoyoshi , Osaka Toshifumi , Inagaki Minoru , Tsuneda Satoshi
Published: November 2024

Understanding the relationship between bacteriophage (phage) classification and target receptors is crucial for phage ecology and applied research. In this study, we compared 13 previously isolatedEscherichia coliphages based on physiological characteristics, whole-genome sequences, and tail fiber protein phylogenetics. We combined genomic analysis and lipopolysaccharide (LPS) structural analysis of phage-resistantE. colistrains to identify target receptors of the phages. The results revealed that phylogenetically distinctE. coliphages target different sites in the LPS R-core region (modified by WaaV, WaaW, WaaT, and WaaY), membrane proteins (NfrB, TolA, YhaH), or flagella. Notably, subtle chemical modifications of LPS (such as Heptose phosphorylation) were shown to be important forE. coliphage recognition. Furthermore, physiological characteristics, tail fiber phylogenetics, and whole genome analysis independently classified the phages into five identical groups. Meanwhile, classification based on target receptors placed them into six groups, which was very similar to the grouping pattern based on the three independent parameters described above. Our results suggest that phage phenotypes and genotypes are closely related to target receptor specificity and the physiological characteristics ofE. coliphages. Here, we elucidated the diversity and specificity ofE. coliphage target receptors, providing new insights into the classification ofE. coliphages and phage-host interactions.
Integrating Ideal Bayesian Searcher and Neural Networks Models for Eye Movement Prediction in a Hybrid Search Task
Authors: Ruarte Gonzalo , Care Damián , Bujia Gaston , Ison Matias J , Kamienkowski Juan E.
Published: November 2024

Visual search, where observers search for a specific item, is a crucial aspect of daily human interaction with the visual environment. Hybrid search extends this by requiring observers to search for any item from a given set of objects. While there are models proficient at simulating human eye movement in visual search tasks within natural scenes, none are able to do so in Hybrid search tasks within similar environments. In this work, we present an enhanced version of the neural network Entropy Limit Minimization (nnELM) model, which is based on a Bayesian framework and decision theory. We also present the Hybrid Search Eye Movements (HSEM) Dataset, comprising several thousands of human eye movements during hybrid search tasks in natural scenes. A key challenge in Hybrid search, absent in visual search, is that participants might search for different objects at different time points. To address this, we developed a strategy based on the posterior probability distribution generated after each fixation. By adjusting the model’s peripheral visibility, we made early search stages more efficient, aligning it closer to human behaviour. Additionally, limiting the model’s memory capacity reduced its success in longer searches, mirroring human performance. To validate these improvements, we compared our model against participants from the HSEM dataset and against existing models in a visual search benchmark. Altogether, the new nnELM model not only successfully explains Hybrid search tasks, but also closely replicates human behaviour in natural scenes. This work advances our understanding of complex processes underlying visual and Hybrid search while maintaining model interpretability.
Mutations in the microexon splicing regulatorsrrm4have minor phenotypic effects on zebrafish neural development
Authors: Gupta Tripti , Margolin Gennady , Burgess Harold A.
Published: November 2024

Achieving a diversity of neuronal cell types and circuits during brain development requires alternative splicing of developmentally regulated mRNA transcripts. Microexons are a type of alternatively spliced exon that are 3–27 nucleotides in length and are predominantly expressed in neuronal tissues. A key regulator of microexon splicing is the RNA-binding protein Serine/arginine repetitive matrix 4 (Srrm4).Srrm4is a highly conserved, vertebrate splicing factor that is part of an ancient family of splicing proteins. To better understand the function ofSrrm4during brain development, we examined neural expression of zebrafishsrrm4from days 1–5 of development using fluorescencein situhybridization. We found thatsrrm4has a dynamically changing expression pattern, with expression in diverse cell types and stages during development. We then used CRISPR-based mutagenesis to generate zebrafishsrrm4mutants. Unlike previously described morphant phenotypes,srrm4mutants did not show overt morphological defects. Moreover, sequencing of wild-type and mutant transcriptomes revealed only minor changes in splicing.srrm4thus appears to have a limited role in zebrafish neural development.
Red means heavy: Action intentions reactivate representations of task-relevant cognitive cues
Authors: Lee Nina , Guo Lin Lawrence , Nestor Adrian , Niemeier Matthias
Published: November 2024

Recent research shows that the intention to act on an object alters its neural representation in ways as afforded by underlying sensorimotor processes. For example, the intention to grasp and pick up an object results in representations of the object’s weight. But these representations become grasp-specific only immediately before object lift if weight information is relayed through object material. This feature triggers earlier representations regardless of intention probably because material-weight contingencies are overlearned. By contrast, recently learned weight cues should be recalled deliberately during grasp planning resulting in early grasp-specific representations. Here, we examined how action intentions affect the representation of newly acquired colour-weight contingencies. We recorded electroencephalography while human participants grasped or reached for objects that varied in shape and density as indicated by their colour. Multivariate analyses revealed a grasp-specific reactivation of colour during planning that was mirrored in beta band. This suggests that task-relevancy influences the representation of colour such that previously encoded colour-weight contingencies may be reactivated as required for grasping, mediated top-down via working memory. Grasp-specific representations of shape and colour were also present in theta band, perhaps reflecting attentional activity. These results provide novel insights into the interplay between cognition and motor planning processes.
Crystal structure of a short-chain dehydrogenase from Burkholderia cenocepacia J2315 in complex with NADP+ and benzoic acid
Authors: Belfon Kafi K. J. , Beyer Olive , Abendroth Jan , Dranow David M. , Lorimer Donald D. , Abramov Ariel , Latimore Yazmine , Hamilton Connor , Dawkins Aniah , Hinojosa Isabella , Martinez Xavier , Mirabel Sofia , Duncan Miriam , Womack Reagan , Hicks Lillian , Turlington Zachary R. , Edwards Thomas E. , Torelli Andrew T. , Hicks Katherine A. , French Jarrod B.
Published: November 2024

Burkholderia cenocepacia is an opportunistic human pathogen that can cause lethal infections in immunocompromised individuals, particularly those with cystic fibrosis. As such, there is a critical need to identify and characterize the structure and function of enzymes that participate in the metabolic pathways of this bacterium. Here, the high-resolution X-ray crystal structure of a short-chain dehydrogenase reductase (SDR) from B. cenocepacia J2315 (BcSDR) in complex with the coenzyme NADP+ and a benzoic acid ligand is presented. This protein has the conserved Rossmann fold of the SDR superfamily and the characteristic TGxxxGxG motif of the classical SDR subfamily. However, unlike classical SDRs, the active site of BcSDR has a leucine residue in place of the highly conserved and catalytically important tyrosine residue. Sequence analysis confirms that this leucine residue is conserved in this SDR across the Burkholderiales order. This suggests that BcSDR is more appropriately classified into the divergent SDR subfamily. In addition, this enzyme would necessarily employ a different enzyme mechanism to that proposed as a general mechanism for most SDRs.
Does financing startups impact the profitability of microfinancing institutions?
Authors: Singh Kuldeep , Sharma Arpita
Published: November 2024

Purpose

Funding startups is usually perceived as a risky investment for money lenders and investors due to the high failure rate of such early-stage firms. Therefore, funding startups may negatively impact the profitability of the lending institutions. The current study aims to test how financing startups (the percentage of financed enterprises that are startups) affects the profitability of microfinancing institutions (MFIs). It also attempts to determine the conditions that allow MFIs to limit the negative effects of such risky investments on their profitability.

Design/methodology/approach

The study considers panel data of 2,694 global MFIs hosted on the Microfinance Information Exchange Market on the World Bank website. Dynamic panel data methodology (generalized methods of moment) is applied to conduct the econometric analysis. In addition to regression analysis, to test the main and interaction effects, interaction graphs are plotted to elaborate on the findings.

Findings

Direct evidence implies that financing startups negatively impacts the profitability of MFIs. Therefore, MFIs should act per two necessary conditions to reduce risks associated with startups financing. First, MFIs should optimize their risk cover and use these funds to finance startups. Second, an increased use of non-earning liquid funds to finance startups is recommended to maintain profitability.

Practical implications

The findings of our study will help MFIs continue lending to startups while protecting their profitability.

Originality/value

The findings contribute to the institutionalization approach of MFIs while providing favorable conditions for financing startups and protecting profitability at the same time.
Analysis methodology for dynamic structural behaviour modelling of highway bridges based on Monte Carlo simulations (MCS) considering vehicle-pavement-bridge interaction
Authors: Cardoso Marilene Lobato , Alencar Guilherme , Santos da Silva José Guilherme
Published: November 2024

Purpose

To develop an analysis methodology to evaluate the dynamic behaviour and fatigue assessment of highway bridges due to vehicle passage on irregular pavement surfaces. The approach considers the non-deterministic nature of the parameters of the vehicle-bridge system using Monte Carlo simulations.

Design/methodology/approach

In the proposed approach, 11 vehicle-bridge system parameters are modelled as random variables with predefined probability distributions. The dynamic analysis considers the vehicle-structure-pavement interaction, in which road surface roughness is defined based on the use of the power spectral density function, as an expression of the road surface random irregularities. Based on the results of the dynamic analysis, a fatigue assessment is performed. To demonstrate the applicability of the methodology, a case study of a 40-m-span steel-concrete composite highway bridge was selected, considering two levels of pavement quality.

Findings

The results reveal that vehicle speed, sprung masses, bridge mass and rear axle and tire stiffness are the parameters that most influence vertical displacement, bending stress and fatigue life. Numerical simulations showed that the pavement deterioration reduced fatigue life by up to 98.6%, increasing the failure probability.

Originality/value

The dynamic behaviour and fatigue of a highway bridge are evaluated by means of vehicle-structure interaction analyses, in which the randomness of 11 parameters of the vehicle-bridge system is simulated. This includes dynamic parameters of the suspension and tires, whose variability is rarely considered due to the difficulty in obtaining sample data.
Dilemmatic commitments following psychological contract breach and its contrasting implications for voluntary turnover and organizational citizenship behaviour
Authors: Conway Neil , Clinton Michael E.
Published: November 2024

Purpose

We introduce the notion of dilemmatic commitments to psychological contract theory and research – where breach lowers affective commitment while raising continuance commitment – and present its contrasting implications for explaining outcomes.

Design/methodology/approach

We draw on longitudinal survey data, along with objective data on actual employee turnover from organizational records.

Findings

We find opposing mediating pathways between psychological contract breach and employee turnover, via dilemmatic commitments where the effect of breach on employee turnover is positive via affective commitment and negative via continuance commitment.

Originality/value

The dual opposing commitment pathways following breach may explain why previous research finds small associations between breach and employee turnover. While dilemmatic commitment suggests that continuance commitment can offset the affective commitment pathway in limiting actual employee turnover, it represents a “mixed blessing” as both pathways reduced employee engagement in organizational citizenship behaviours.
Land coverage prediction using convolutional neural network for enhanced wind loading estimation
Authors: Alinejad Nasrollah , Jung Sungmoon , Cai Jinglun , Liu Xiuwen
Published: November 2024

Purpose

The wind loading on a building is likely to deviate further from the known wind loading due to the complexity of the real-world land coverage. To address this issue, research is needed in two separate areas. First, wind tunnel testing needs to be conducted for more complex terrains. Second, research is needed to classify real-world land coverage with high accuracy, specifically for wind engineering applications. This paper deals with this second area of research. The machine learning-based land cover prediction is a promising technique because it can remove subjectivity in human interpretation of upwind terrain.

Design/methodology/approach

This paper presents a new deep neural network for land coverage prediction that can distinguish low- and mid-rise buildings in the built environment to enhance the estimation of surface roughness necessary in wind engineering. For the dataset, Landsat 8 satellite images were used. A patch-based convolutional neural network was employed and improved. The network predicted the land coverage at the center of the patch. Two different label schemes were used where the proposed network either achieved better accuracy than the conventional model or recognized additional building types while maintaining a similar level of accuracy.

Findings

Compared to the validation accuracy of 78% in a previous study, the proposed method achieved the validation accuracy of 90% thanks to the improvements made in this study as well as the consolidation of labels with similar surface roughness. When additional building categories were added, the validation decreased to 80%, which is comparable to the previous study but is now able to predict different building types.

Originality/value

The improvement of the proposed method will depend on the site characteristics. For the sites tested in this paper, the error reduction in wind speed and pressure was up to about 55%. In addition to more accurate wind speed and pressure, better identification of buildings will benefit wind engineering research, as different building types cause different downwind effects. An example application would be automated recognition of areas that have a certain distance from the target building type to identify downwind areas affected by high winds.