bluuebunny/crossref_metadata_2025 huggingface dataset:
Perception of Motion Salience Shapes the Emergence of Collective Motions
Authors: Xiao Yandong , Lei Xiaokang , Zheng Zhicheng , Xiang Yalun , Liu Yang-Yu , Peng Xingguang
Published: December 2023

As one of the most common and spectacular manifestations of coordinated behavior, collective motion is the spontaneous emergence of the ordered movement in a system consisting of many self-propelled agents, e.g., flocks of birds, schools of fish, herds of animals, and human crowds. Despite extensive studies on collective motions, a systems-level understanding of different motion patterns of collective behaviors is still lacking. This further hinders the adoption of bio-inspired mechanisms for applications of swarm robotics. Here, by leveraging three large bird-flocking datasets, we systematically investigate the emergence of different patterns of collective motions:mobbing, circling, andtransit. We find that flocks with higher maneuverable motions (i.e.,mobbingandcircling) prefer to evolve a more nested structure of leader-follower (LF) relations and a clear hierarchy to mitigate the damage of individual freedom to group cohesion. In contrast, flocks with smooth motion (i.e.,transit) do not display this tactful strategy to organize the group. To explain this empirical finding, we propose a measure based on the perception of motion salience (MS) to quantify the trade-off between individual freedom and group cohesion. Moreover, we perform the correlation analysis between LF and MS, finding that individuals with higher MS tend to lead the group with higher maneuverable motions. Those findings prompt us to develop a swarm model with adaptive MS-based (AMS) interactions and confirm that AMS interactions are responsible for the emergence of nested and hierarchical LF relations in the flocks with highly maneuverable motions. Finally, we implement AMS interactions in swarm robotics that consists of ∼102miniature mobile robots. The swarm experiments of collective following and collective evacuation demonstrate that AMS interactions not only empower the swarm to promptly respond to the transient perturbation but also strengthen the self-organization of collective motions in terms of temporal cognition.
Dynamic Causal Modelling Highlights the Importance of Decreased Self-Inhibition of the Sensorimotor Cortex in Motor Fatigability
Authors: Heimhofer Caroline , Bächinger Marc , Lehner Rea , Frässle Stefan , Balsters Joshua Henk , Wenderoth Nicole
Published: December 2023

Motor fatigability emerges when challenging motor tasks must be maintained over an extended period of time. It is a frequently observed phenomenon in everyday life which affects patients as well as healthy individuals. Motor fatigability can be measured using simple tasks like finger tapping at maximum speed for 30s. This typically results in a rapid decrease of tapping frequency, a phenomenon called motor slowing. In a previous study (Bächinger et al. 2019), we showed that motor slowing goes hand in hand with a gradual increase of activation in the primary sensorimotor cortex (SM1), supplementary motor area (SMA), and dorsal premotor cortex (PMd). Previous electrophysiological measurements further suggested that the increase in SM1 activity might reflect a breakdown of inhibition and, particularly, a breakdown of surround inhibition which might have led to heightened coactivation of antagonistic muscles. It is unclear what drives the activity increase in SM1 caused by motor slowing and whether motor fatigability affects the dynamic interactions between SM1 and upstream motor areas like SMA and PMd. Here, we performed dynamic causal modelling to answer this question. Our main findings revealed that motor slowing was associated with a significant reduction in SM1 self-inhibition which is in line with previous electrophysiological results. Additionally, the model revealed a significant decrease in the driving input to premotor areas suggesting that structures other than cortical motor areas might cause motor fatigability.
Continuous estimation of reaching space in superficial layers of the motor cortex
Authors: Galiñanes Gregorio Luis , Huber Daniel
Published: December 2023

Motor cortex plays a key role in controlling voluntary arm movements towards spatial targets. The cortical representation of spatial information has been extensively studied and was found to range from combinations of muscle synergies to cognitive maps of locations in space. How such abstract representations of target space evolve during a behavior, how they integrate with other behavioral features and what role they play in movement control is less clear. Here we addressed these questions by recording the activity of layer 2/3 (L2/3) neurons in the motor cortex using two-photon calcium imaging in head-restrained mice, while they reached for water droplets presented at different spatial locations around their snout. Our results reveal that a majority (>80%) of L2/3 neurons with task-related activity are target-space selective and their activity is contingent on a single target position in an ego-centric reference frame. This spatial framework is preferentially organized along three cardinal directions (Center, Left and Right). Surprisingly, the coding of target space is not limited to the activity during movement planning or execution, but is also predominant during preceding and subsequent phases of the task, and even persists beyond water consumption. More importantly, target specificity is independent of the movement kinematics and is immediately updated when the target is moved to a new position. Our findings suggest that, rather than descending motor commands, the ensemble of L2/3 neurons in the motor cortex conjointly encode internal (behavioral) and external (spatial) aspects of the task, playing a role in higher-order representations related to estimation processes of the ongoing actions.
Mild blast TBI raises gamma connectivity, EEG power, and reduces GABA interneuron density
Authors: May Hazel G , Tsikonofilos Konstantinos , Donat Cornelius K , Sastre Magdalena , Kozlov Andriy S , Sharp David J , Bruyns-Haylett Michael
Published: December 2023

At least one traumatic brain injury (TBI) will be experienced by approximately 50-60 million of the world’s population in their lifetime and is the biggest cause of death and disability in those under 40. Mild traumatic brain injury (mTBI) can induce subtle changes but have long-lasting effects that may be difficult to detect through conventional neurological assessment, including standard clinical imaging techniques. These changes can lead to an increased risk of future neurodegeneration and emphasises the need to use more sensitive diagnostic tools such as EEG in order to identify injury and opportunities for therapeutic intervention.

In this study, we investigated electrophysiological and histopathological changes in a rat model of mild blast-induced TBI. We used a 32-channel EEG electrode array to detect global and local changes in neural activity and functional connectivity in acute (3 to 4-hours) as well as chronic phases (1 and 3-months) post-injury. GABAergic inhibitory interneurons, crucial for maintaining an excitatory/inhibitory balance, were quantified using immunohistochemistry.

Mild blast-induced TBI had minimal effects on resting power and connectivity at the acute timepoint but resulted in resting-state global power increases at all frequencies as well as a relative power increase in slow-wave frequencies in the chronic phase post-injury. Functional connectivity increases in the gamma frequency along with increases in power in the chronic phase pointed towards an alteration in the excitatory/inhibitory balance. Indeed, electrophysiological changes were associated with reduced density of GABAergic interneurons at 7-days, 1-month, and 3months post-injury, with a decrease in somatostatin-positive cell density in the 5th layer of all cortical regions of interest, and a parvalbumin decrease in the 5thlayer of the primary auditory cortex. In contrast, the total number of neurons, measured by NeuN did not change significantly, thus demonstrating a biased impact on inhibitory interneuron populations.

Our work demonstrates that the techniques and metrics of injury assessment employed in this study are sensitive enough to reflect the subtle changes present in mTBI and therefore hold potential clinical relevance. By using non-invasive EEG assessments and histopathology, we were able to reveal direct correlates and potential sources of the abnormalities caused by mild blast-induced TBI.
Application of an NMR/crystallography fragment screening platform for the assessment and rapid discovery of new HIV-CA binding fragments
Authors: Lang Stuart , Fletcher Daniel A. , Petit Alain-Pierre , Luise Nicola , Fyfe Paul , Zuccotto Fabio , Porter David , Hope Anthony , Bellany Fiona , Kerr Catrina , Mackenzie Claire J. , Wyatt Paul G. , Gray David W.
Published: December 2023

Identification and assessment of novel targets is essential to combat drug resistance in the treatment of HIV/AIDS. HIV Capsid (HIV-CA), the protein playing a major role in both the early and late stages of the viral life cycle, has emerged as an important target. We have applied an NMR fragment screening platform and identified molecules that bind to theN-terminal domain (NTD) of HIV-CA at a site close to the interface with theC-terminal domain (CTD). Using X-ray crystallography, we have been able to obtain crystal structures to identify the binding mode of these compounds. This allowed for rapid progression of the initial, weak binding, fragment starting points to compounds37and38, which have19F-pK values of 5.3 and 5.4 respectively.

Abstract Figure
Factors influencingAgrobacterium-mediated genetic transformation efficiency in wheat
Authors: Karthikeyan Thiyagarajan , Miguel Noguera Luis , Pacheco Mario , Govindan Velu , Vikram Prashant
Published: December 2023

Assessment of the efficiency ofAgrobacterium tumefaciensmediated transformation in four bread wheat varieties was focused and upon optimization of experiments done to obtain tangible results. The four varieties namely Fielder, Navojoa, Baj and Kachu/saul were transformed with optimized protocols, subsequently randomly selected from selection medium amalgamated with phosphinothricin (Glufosinate). Initially the variety Fielder was proceeded with 36 different concentrations of synthetic auxins 2,4-D and Picloram as 36 treatments. The treatment 30 (48 μg of 2,4-D and 64 μg of Picloram) has shown higher efficiency and is comparable in terms of the three traits studied. Additionally, antioxidants and growth regulators were adjusted to obtain better result towards reasonable transformation frequency. Based on the optimization for the variety Fielder, additional varieties were also tested and selected against the selectable marker PPT. Selected genotypes were subjected forgusAorBargene PCR amplification. The result revealed the frequency of transgenesis with the range of 60-70% with the varieties studied, however the whole experiment needs further repetitions for confirmatory result. Transgenic genotypes of the Fielder variety showed moderate to strongGUSexpression in leaves, anthers, seeds, seed coats, roots compare to non-transgenic control plant tissues. PPT leaf painting assay showed the lack of necrosis on painted area of leaves in transgenic genotypes compared to the non-transgenic ones.
Knockout ofHsp70genes significantly affects locomotion speed and gene expression in leg skeletal muscles ofDrosophila melanogaster
Authors: Makhnovskii Pavel A. , Kukushkina Inna V. , Kurochkina Nadia S. , Popov Daniil V.
Published: December 2023

The functions of theHsp70genes were studied using a line ofD. melanogasterwith knockout of six these genes out of thirteen. Namely, effect of knockout ofHsp70genes on negative geotaxis climbing (locomotor) speed and the ability to adapt to climbing training (0.5-1.5 h/day, 7 days/week, 19 days) were examined. Seven- and 23-day-oldHsp70−flies demonstrated a comparable reduction (2-fold) in locomotor speed and widespread changes in leg skeletal muscle transcriptome (RNA-seq), compared tow1118flies. To identify the functions of genes related to decreased locomotor speed the overlapped differentially expressed genes at both time points were analyzed: the up-regulated genes encoded extracellular proteins, regulators of drug metabolism and antioxidant response, while down-regulated genes encoded regulators of carbohydrate metabolism and transmembrane proteins. Additionally, inHsp70−flies, activation of transcription factors related to disruption of the fibril structure and heat shock response (Hsf) were predicted, using the position weight matrix approach. In the control flies, adaptation to chronic exercise training was associated mainly with gene response to a single exercise bout, while the predicted transcription factors were related to stress/immune (Hsf, NF-kB, etc.) and early gene response. In contrast,Hsp70−flies demonstrated no adaptation to training, as well as significantly impaired gene response to a single exercise bout. In conclusion, the knockout ofHsp70genes not only reduced physical performance, but also disrupted adaptation to chronic physical training, which is associated with changes in leg skeletal muscle transcriptome and impaired gene response to a single exercise bout.

New & Noteworthy

Knockout of sixHsp70genes inD. melanogasterreduced locomotion (climbing) speed that is associated with genotype-specific differences in leg skeletal muscle gene expression.

Disrupted adaptation ofHsp70−flies to chronic exercise training is associated with impaired gene response to a single exercise bout.
Noradrenergic signaling controls Alzheimer’s disease pathology via activation of microglial β2 adrenergic receptors
Authors: Le L. , Feidler A.M. , Li H. , Kara-Pabani K. , Lamantia C. , O’Banion M.K. , Majewska K. A
Published: December 2023

In Alzheimer’s disease (AD) pathophysiology, plaque and tangle accumulation trigger an inflammatory response that mounts positive feed-back loops between inflammation and protein aggregation, aggravating neurite damage and neuronal death. One of the earliest brain regions to undergo neurodegeneration is the locus coeruleus (LC), the predominant site of norepinephrine (NE) production in the central nervous system (CNS). In animal models of AD, dampening the impact of noradrenergic signaling pathways, either through administration of beta blockers or pharmacological ablation of the LC, heightened neuroinflammation through increased levels of pro-inflammatory mediators. Since microglia are the resident immune cells of the CNS, it is reasonable to postulate that they are responsible for translating the loss of NE tone into exacerbated disease pathology. Recent findings from our lab demonstrated that noradrenergic signaling inhibits microglia dynamics via β2 adrenergic receptors (β2ARs), suggesting a potential anti-inflammatory role for microglial β2AR signaling. Thus, we hypothesize that microglial β2 adrenergic signaling is progressively impaired during AD progression, which leads to the chronic immune vigilant state of microglia that worsens disease pathology. First, we characterized changes in microglial β2AR signaling as a function of amyloid pathology. We found that LC neurons and their projections degenerate early and progressively in the 5xFAD mouse model of AD; accompanied by mild decrease in the levels of norepinephrine and its metabolite normetanephrine. Interestingly, while 5xFAD microglia, especially plaque-associated microglia, significant downregulatedβ2ARgene expression early in amyloid pathology, they did not lose their responsiveness to β2AR stimulation. Most importantly, we demonstrated that specific microglial β2AR deletion worsened disease pathology while chronic β2AR stimulation resulted in attenuation of amyloid pathology and associated neuritic damage, suggesting microglial β2AR might be used as potential therapeutic target to modify AD pathology.
Contrasting Sequence with Structure: Pre-training Graph Representations with PLMs
Authors: Robinson Louis , Atkinson Timothy , Copoiu Liviu , Bordes Patrick , Pierrot Thomas , Barrett Thomas D.
Published: December 2023

Understanding protein function is vital for drug discovery, disease diagnosis, and protein engineering. While Protein Language Models (PLMs) pre-trained on vast protein sequence datasets have achieved remarkable success, equivalent Protein Structure Models (PSMs) remain underrepresented. We attribute this to the relative lack of high-confidence structural data and suitable pre-training objectives. In this context, we introduce BioCLIP, a contrastive learning framework that pre-trains PSMs by leveraging PLMs, generating meaningful per-residue and per-chain structural representations. When evaluated on tasks such as protein-protein interaction, Gene Ontology annotation, and Enzyme Commission number prediction, BioCLIP-trained PSMs consistently outperform models trained from scratch and further enhance performance when merged with sequence embeddings. Notably, BioCLIP approaches, or exceeds, specialized methods across all benchmarks using its singular pre-trained design. Our work addresses the challenges of obtaining quality structural data and designing self-supervised objectives, setting the stage for more comprehensive models of protein function. Source code is publicly available2.
Genome-wide SNP data reveal recent population structure ofHuidobria fruticosa(Loasaceae), a paleo-endemic lineage from the Atacama Desert
Authors: Merklinger Felix F. , Zheng Yichen , Böhnert Tim , Luebert Federico , Harpke Dörte , Stoll Alexandra , Wiehe Thomas , Koch Marcus , Quandt Dietmar
Published: December 2023

The Atacama Desert is a biodiversity hotspot of neo-endemic radiation, where long-term aridity and complex physiographic processes create a unique environmental setting. Current species assemblages are mainly concentrated in highly patchy loma formations, and plant populations occurring in these are often geographically isolated from each other. Despite a general consensus on long-term aridity in the Atacama, climatological and geological evidence points to repeated climate change, making the Atacama Desert an ideal system for studying population genetic processes in highly unstable habitats. We are analyzing the genetic structure within and between populations ofHuidobria fruticosa, a paleo-endemic lineage of the Atacama Desert, to shed new light on its biogeographic history and broaden our understanding of the evolution of life in extreme aridity, as well as plant evolution in response to a changing environment. To do this, we analyzed SNP data from genotyping-by-sequencing of 354 individuals from 21 populations. Our results suggest that, despite being an ancient lineage, the current population structure ofHuidobria fruticosaonly reflects changing abiotic conditions over the last 2 million years. We therefore conclude that the present distribution, together with the evolutionary processes documented here, is the result of climatic fluctuations and prolonged periods of hyperaridity during the Pleistocene. Building on this understanding, our findings contribute to a global narrative that highlights the complex interplay between climate change and evolutionary dynamics, and emphasize the importance of deserts as living laboratories for deciphering how species have historically adapted to some of the most extreme habitats on Earth.
Innate extracellular Hsp70 inflammatory properties are mediated by the interaction of Siglec-E and LOX-1 receptors
Authors: Borges Thiago J. , Lima Karina , Murshid Ayesha , Lape Isadora T. , Zhao Yunlong , Rigo Maurício M. , Lang Benjamin J. , Siddiqui Shoib S. , Hui Enfu , Riella Leonardo V. , Bonorino Cristina , Calderwood Stuart K
Published: December 2023

Innate immune responses to cell damage-associated molecular patterns induce a controlled degree of inflammation, ideally avoiding the promotion of intense unwanted inflammatory adverse events. When released by damaged cells, Hsp70 can stimulate different responses that range from immune activation to immune suppression. The effects of Hsp70 are mediated through innate receptors expressed primarily by myeloid cells, such as dendritic cells (DCs). The regulatory innate receptors that bind to extracellular mouse Hsp70 (mHsp70) are not fully characterized, and neither are their potential interactions with activating innate receptors. Here, we describe that extracellular mHsp70 interacts with a receptor complex formed by inhibitory Siglec-E and activating LOX-1 on DCs. We also find that this interaction takes place within lipid microdomains, and Siglec-E acts as a negative regulator of LOX-1-mediated innate activation upon mHsp70 or oxidized LDL binding. Thus, HSP70 can both bind to and modulate the interaction of inhibitory and activating innate receptors on the cell surface. These findings add another dimension of regulatory mechanism to how self-molecules contribute to dampening of exacerbated inflammatory responses.
Differences in stomatal sensitivity to CO2and light influences variation in water use efficiency and leaf carbon isotope composition in two genotypes of the C4plantZea mays
Authors: Crawford Joseph D , Twohey Robert J. , Pathare Varsha S. , Studer Anthony J. , Cousins Asaph B.
Published: December 2023

The ratio of net CO2uptake (Anet) and stomatal conductance (gs) is an intrinsic measurement of leaf water use efficiency (WUEi) however its measurement can be challenging for large phenotypic screens. Measurements of leaf carbon isotope composition (δ13Cleaf) may be a scalable tool to approximateWUEifor screening because it in part reflects the competing influences ofAnetandgson the CO2partial pressure (pCO2) inside the leaf over time. However, in C4photosynthesis the CO2concentrating mechanism complicates the relationship between δ13CleafandWUEi. Despite this complicated relationship, several studies have shown genetic variation in δ13Cleafacross C4plants. Yet there has not been a clear demonstration of whetherAnetorgsare the causal mechanisms controllingWUEiand δ13Cleaf. Our approach was to characterize leaf photosynthetic traits of twoZea maysrecombinant inbred lines (Z007E0067 and Z007E0150) which consistently differ for δ13Cleafeven though they have minimal confounding genetic differences. We demonstrate that these two genotypes contrasted inWUEidriven by differences in the speed of stomatal responses to changes inpCO2and light that lead to unproductive leaf water loss. These findings provide support that differences in δ13Cleafin closely related genotypes do reflect greaterWUEiand further suggests that differences in stomatal kinetic response to changing environmental conditions is a key target to improveWUEi.
Remote memory engrams are controlled by encoding-specific tau phosphorylation
Authors: Stefanoska Kristie , Prikas Emmanuel , Lin Yijun , Kosonen Renée , Ittner Arne
Published: December 2023

The engram represents the physical trace that encodes a specific memory and enables its recall1–4. Functional failure of the engram is linked to the progressive memory decline in Alzheimer’s disease5. However, it is unknown whether the microtubule-associated protein tau, a central factor in Alzheimer’s6,7, has a direct function in the engram. Here, we demonstrate that tau and encoding-associated tau phosphorylation are critical for robust remote memory engrams. Tau is required specifically during memory formation for remote, yet not proximal recall in memory paradigms in mice. Controlled expression of tau exclusively during memory entrainment is necessary and sufficient to restore remote memory deficits intauknockout mice. Tau is phosphorylated at specific sites during encoding. Gene editing to ablate site-specific phosphorylation at threonine-205 (T205) lowers precision of engram cell recruitment and precludes efficient remote recall. Vector-based engineering of engram cells reveals that T205 phosphorylation of tau is required to engrain memory for recall at remote timepoints. Notably, in the absence oftau, memory is recalled from latency by direct optogenetic activation of engram cells at distal time points but not when natural cues are used, revealing an association-specific gatekeeper function of tau during encoding. Our work delineates a physiologic role of site-specific tau phosphorylation at the inception of episodic memory to support an enduring engram and enable efficient remote recall. Thus, encoding-associated phosphorylation of tau is proximal to the elusive substrate of remote memory and may connect to the basis of amnesia in Alzheimer’s disease.
Improved Peptide Docking with Privileged Knowledge Distillation using Deep Learning
Authors: Zhang Zicong , Verburgt Jacob , Kagaya Yuki , Christoffer Charles , Kihara Daisuke
Published: December 2023

Protein-peptide interactions play a key role in biological processes. Understanding the interactions that occur within a receptor-peptide complex can help in discovering and altering their biological functions. Various computational methods for modeling the structures of receptor-peptide complexes have been developed. Recently, accurate structure prediction enabled by deep learning methods has significantly advanced the field of structural biology. AlphaFold (AF) is among the top-performing structure prediction methods and has highly accurate structure modeling performance on single-chain targets. Shortly after the release of AlphaFold, AlphaFold-Multimer (AFM) was developed in a similar fashion as AF for prediction of protein complex structures. AFM has achieved competitive performance in modeling protein-peptide interactions compared to previous computational methods; however, still further improvement is needed. Here, we present DistPepFold, which improves protein-peptide complex docking using an AFM-based architecture through a privileged knowledge distillation approach. DistPepFold leverages a teacher model that uses native interaction information during training and transfers its knowledge to a student model through a teacher-student distillation process. We evaluated DistPepFold’s docking performance on two protein-peptide complex datasets and showed that DistPepFold outperforms AFM. Furthermore, we demonstrate that the student model was able to learn from the teacher model to make structural improvements based on AFM predictions.
Soil stockpile age does not impact vegetation establishment in a cold, arid natural gas field
Authors: Curran Michael F. , Sorenson Joshua R. , Robinson Timothy J.
Published: December 2023

Land reclamation is critical to ensure surface disturbance associated with natural gas development is not permanent. Soil management is critical to reclamation success, especially in environments which are challenged by aridity. Typically, natural gas well pad construction involves stripping topsoil to allow for equipment to be on level ground and placing it into a stockpile. After well pad construction is complete, soil is respread and seeded across a large portion of the initial disturbance to initiate interim reclamation. With the advent of new extraction technologies (e.g., directional drilling), it is not always known how many individual wells will be placed on a given well pad until results from exploratory tests are examined. Previous research has shown soil disturbance during natural gas well pad construction and subsequent reclamation in cold, arid environments is highest at the stripping and respreading phases, with minimal soil activity occurring during the stockpile phase. Other research has shown that additional soil disturbances after reclamation is initiated may exacerbate soil damage, limiting revegetation potential. However, no studies have been conducted to determine if soil stockpile age impacts vegetation emergence. Here, we examine soil stockpiles which are 1-7 years old in the Jonah Infill natural gas field for vegetation emergence and vegetation cover using an image analysis software called SamplePoint. In a ten-week greenhouse experiment, we found vegetation cover across stockpile age-classes increased uniformly during the study period but that there was no significant difference in rate of vegetation cover increase or percent vegetation cover over time. These findings suggest it may be better to keep soil stockpiled in cold, arid natural gas fields when it is uncertain if additional construction activities will be required on a well pad location rather than respreading soil with a chance that redisturbance is necessary.
Inflammatory dietary potential is associated with vitamin depletion and gut microbial dysbiosis in early pregnancy
Authors: Alvernaz Suzanne A. , Wenzel Elizabeth S. , Nagelli Unnathi , Pezley Lacey B. , LaBomascus Bazil , Gilbert Jack A. , Maki Pauline M. , Tussing-Humphreys Lisa , Bernabé Beatriz Peñalver
Published: December 2023

Background

Pregnancy alters many physiological systems, including the maternal gut microbiota. Diet is a key regulator of this system and can alter the host immune system to promote inflammation. Multiple perinatal disorders have been associated with inflammation, maternal metabolic alterations, and gut microbial dysbiosis, including gestational diabetes mellitus, preeclampsia, preterm birth, and mood disorders. However, the effects of high inflammatory diets on the gut microbiota during pregnancy have yet to be fully explored.

Objective

To use a systems-based approach to characterize associations among dietary inflammatory potential, a measure of diet quality, and the gut microbiome during pregnancy.

Methods

Forty-nine pregnant persons were recruited prior to 16 weeks of gestation. Participants completed a food frequency questionnaire (FFQ) and provided fecal samples. Dietary inflammatory potential was assessed using the Dietary Inflammatory Index (DII) from FFQ data. Fecal samples were analyzed using 16S rRNA amplicon sequencing. Differential taxon abundance with respect to DII score were identified, and microbial metabolic potential was predicted using PICRUSt2.

Results

Inflammatory diets were associated with decreased vitamin and mineral intake and dysbiotic gut microbiota structure and predicted metabolism. Gut microbial compositional differences revealed a decrease in short chain fatty acid producers such asFaecalibacterium,and an increase in predicted vitamin B12 synthesis, methylglyoxal detoxification, galactose metabolism and multi drug efflux systems in pregnant individuals with increased DII scores.

Conclusions

Dietary inflammatory potential was associated with a reduction in the consumption of vitamins & minerals and predicted gut microbiota metabolic dysregulation.
Structure-based virtual screening and Molecular Dynamic Simulations identified FDA-approved molecules as potential inhibitors against the surface proteins of H1N1
Authors: Bordoloi Sukanya , Prasad Roshny , Lakshmi VS , Chandramohanadas Rajesh , Natarajan Kathiresan , Nelson-Sathi Shijulal
Published: December 2023

H1N1, a subtype of influenza A virus, remains a global concern due to its ability to cause highly contagious, and fatal infections of the respiratory tract that can lead to seasonal pandemics. Factors such as genetic reassortment and antigenic shift due to the segmented nature of its RNA genome, lead to its rapid evolution that impacts drug and vaccine interactions. Thus, there is growing interest in identifying small-molecules against H1N1 to address the challenges posed by its ever-changing nature and enhance ability to combat the virus. By targeting the surface proteins crucial in the viral life cycle and interactions with host cells, we conducted structure-based virtual screening of 2,471 FDA-approved small molecules against H1N1’s hemagglutinin (HA) and neuraminidase (NA) using molecular docking, and molecular dynamic simulations. A binding pocket for HA was identified at the interface of the three protomers, close to the fusion peptide, while in the case of NA the co-crystal ligand binding site was targeted. We identified 5 molecules, namely Econazole, Butoconazole, Miconazole, Isoconazole, and Tioconazole with higher binding affinity to HA and 4 molecules, namely Acarbose, Rutin, Paromomycin, and Idarubicin showing superior binding affinity to NA. Further molecular dynamic simulation of these molecules bound with HA and NA reaffirm the stability of the complexes. These molecules are known to have antifungal and antiviral properties. Thus, this study elucidates the importance of targeting HA and NA and paves the way for repurposing existing antivirals, antibacterials, and antifungals as inhibitors of the H1N1 viral entry into host cells.
Genetic load, eco-evolutionary feedback and extinction in metapopulations
Authors: Olusanya Oluwafunmilola , Khudiakova Ksenia , Sachdeva Himani
Published: December 2023

Habitat fragmentation poses a significant risk to population survival, causing both demographic stochasticity and genetic drift within local populations to increase, thereby increasing genetic load. Higher load causes population numbers to decline, which reduces the efficiency of selection and further increases load, resulting in a positive feedback which may drive entire populations to extinction. Here, we investigate this eco-evolutionary feedback in a metapopulation consisting of local demes connected via migration, with individuals subject to deleterious mutation at a large number of loci. We first analyse the determinants of load under soft selection, where population sizes are fixed, and then build upon this to understand hard selection, where population sizes and load co-evolve. We show that under soft selection, very little gene flow (less than one migrant per generation) is enough to prevent fixation of deleterious alleles. By contrast, much higher levels of migration are required to mitigate load and prevent extinction when selection is hard, with critical migration thresholds for metapopulation persistence increasing sharply as the genome-wide deleterious mutation rate becomes comparable to the baseline population growth rate. Moreover, critical migration thresholds are highest if deleterious mutations have intermediate selection coefficients, but lower if alleles are predominantly recessive rather than additive (due to more efficient purging of recessive load within local populations). Our analysis is based on a combination of analytical approximations and simulations, allowing for a more comprehensive understanding of the factors influencing load and extinction in fragmented populations.
Remodeling of the protein ubiquitylation landscape in the aging vertebrate brain
Authors: Marino Antonio , Fraia Domenico Di , Panfilova Diana , Sahu Amit Kumar , Ori Alessandro
Published: December 2023

Post-translational modifications (PTMs) regulate protein homeostasis and function. How aging affects the landscape of PTMs remains largely elusive. Here, we reveal changes in hundreds of protein ubiquitylation, acetylation, and phosphorylation sites in the aging brain of mice. We show that aging has a major impact on protein ubiquitylation and that 29% of the ubiquitylation sites are affected independently of protein abundance, indicating altered PTM stoichiometry. We found a subset of these sites to be also affected in the brain of the short-lived killifishNothobranchius furzeri, highlighting a conserved aging phenotype. Furthermore, we estimated that over 35% of ubiquitylation changes observed in old mouse brains derive from partial proteasome inhibition, a well-established hallmark of brain aging. Our findings provide evidence of an evolutionarily conserved ubiquitylation signature of the aging brain and establish a causal link between proteasome inhibition and age-related remodeling of the ubiquitylome.
Temporal Tracking of Plasma Cellsin vivoUsing J-chain CreERT2 Reporter System
Authors: Borbet Timothy C. , Zaldaña Kimberly , Zavitsanou Anastasia-Maria , Hines Marcus J. , Bajwa Sofia , Morrison Tate , Boehringer Thomas , Hallisey Victoria M. , Cadwell Ken , Koralov Sergei B.
Published: December 2023

Plasma cells (PCs) are essential for humoral immunity, as they are responsible for the production of antibodies and contribute to immunological memory. Despite their importance, differentiating between long-lived and short-lived PCsin vivoremains a challenge due to a lack of specific markers to distinguish these populations. Addressing this gap, our study introduces a novel J-chain CreERT2 GFP allele (IgJCreERT2) for precise genetic studies of PCs. This model takes advantage of PC-restricted expression of the J-chain gene, enabling temporal and cell-specific tracking of PCs utilizing a tamoxifen-inducible Cre recombinase. Ourin vitroandin vivovalidation studies of the inducible Cre allele confirmed the fidelity and utility of this model and demonstrated the model’s ability to trace the long-lived PC populationin vivofollowing immunization. The IgJCreERT2model allowed for detailed analysis of surface marker expression on PCs, revealing insights into PC heterogeneity and characteristics. Our findings not only validate the IgJCreERT2mouse as a reliable tool for studying PCs but also facilitate the investigation of PC dynamics and longevity, particularly in the context of humoral immunity and vaccine responses. This model represents a significant advancement for the in-depth study of PCs in health and disease, offering a new avenue for the exploration of PC biology and immunological memory.
Imaging Drug Resistance in Juvenile Myoclonic Epilepsy with MRI-derived Cortical Markers
Authors: Pimentel Bernardo Crespo , Kuchukhidze Giorgi , Xiao Fenglai , Caciagli Lorenzo , Höfler Julia , Rainer Lucas , Kronbichler Martin , Vollmar Christian , Duncan John S , Trinka Eugen , Koepp Matthias , Wandschneider Britta
Published: December 2023

Juvenile myoclonic epilepsy (JME) is the most common idiopathic generalized epilepsy (IGE) syndrome and can present a significant clinical challenge due to lack of seizure control and concomitant neuropsychological impairment. Its underlying mechanisms remain poorly understood. MRI studies have described structural changes in individuals with IGE syndromes but have so far not identified a distinct structural profile associated with drug resistant IGE. In this cross-sectional case-control neuroimaging analysis we included 79 participants with JME recruited at two European epilepsy centres, 43 of whom were drug resistant, as defined by recurrent seizures in the last 12 months despite adequate trials of at least two antiseizure medications (ASM), a drug sensitive group (n=37), and 78 healthy controls. Participants underwent T1-weighted MRI and a comprehensive neuropsychological test battery including measures within two different domains: verbal memory and executive function. We performed vertex-wise measurements of cortical thickness and neurodevelopmental cortical measures, i.e. white matter surface area and local gyrification index (LGI), through a surface-based framework with subsequent correction of scanner-related effects. Group comparisons (family-wise error (FWE) corrected atp<0.05, family-wise error corrected) showed an increase of surface area in prefrontal, cingulate and temporal regions with left-sided predominance accompanied by increased LGI in the left temporal lobe in drug-resistant compared to drug-responsive individuals with JME. Performance on executive function in participants with drug resistant JME was reduced compared to drug sensitive JME (pBonferroni<0.01) and controls (pBonferroni<0.001). Impaired executive function correlated with increased surface area in medial prefrontal and temporal cortical regions (r< -0.75,p<0.01) after adjusting for disease duration and total ASM load. In conclusion, we identified a cognitive-developmental profile in drug resistant JME characterized by left-weighted changes in surface area and cortical folding complexity, the extent of which correlates with the degree of executive dysfunction. Our results shed further light onto the pathophysiological mechanisms of JME and suggest a neurodevelopmental/network basis for both drug refractoriness and cognitive impairment.
The genetic basis of hydrocephalus: genes, pathways, mechanisms, and global impact
Authors: Hale Andrew T. , Boudreau Hunter , Devulapalli Rishi , Duy Phan Q. , Atchley Travis J. , Dewan Michael C. , Goolam Mubeen , Fieggen Graham , Spader Heather L. , Smith Anastasia A. , Blount Jeffrey P. , Johnston James M. , Rocque Brandon G. , Rozzelle Curtis J. , Chong Zechen , Strahle Jennifer M. , Schiff Steven J. , Kahle Kristopher T.
Published: December 2023

Hydrocephalus (HC) is a heterogenous disease characterized by alterations in cerebrospinal fluid (CSF) dynamics that may cause increased intracranial pressure. HC is a component of a wide array of genetic syndromes as well as a secondary consequence of brain injury (intraventricular hemorrhage (IVH), infection, etc.), highlighting the phenotypic heterogeneity of the disease. Surgical treatments include ventricular shunting and endoscopic third ventriculostomy with or without choroid plexus cauterization, both of which are prone to failure, and no effective pharmacologic treatments for HC have been developed. Thus, there is an urgent need to understand the genetic architecture and molecular pathogenesis of HC. Without this knowledge, the development of preventive, diagnostic, and therapeutic measures is impeded. However, the genetics of HC is extraordinarily complex, based on studies of varying size, scope, and rigor. This review serves to provide a comprehensive overview of genes, pathways, mechanisms, and global impact of genetics contributing to all etiologies of HC in humans.
Expression profile analysis of COVID-19 patients
Authors: Shimansky Valentin S. , Popov Oleg S. , Klochkova Tatiana G. , Apalko Svetlana V. , Sushentseva Natalya N. , Anisenkova Anna Yu. , Mosenko Sergey V. , Shcherbak Sergey G.
Published: December 2023

The course of COVID-19 is determined by various factors. Studies worldwide have shown a correlation between changes in the expression profile and the severity of the disease. Thus, an in-depth study of differentially expressed genes will allow a more detailed investigation of the metabolic changes occurring in the background of coronavirus infection. The technique of RNA sequencing and subsequent bioinformatics analysis is suitable for such research tasks. In our study, we compared groups of samples from patients with mild and severe disease course and identified a number of differentially expressed genes. These genes are involved in metabolic pathways responsible for immune response, signaling, intercellular communication, metabolism of various compounds etc. We then identified master regulators whose function and role in pathways enriched by differentially expressed genes makes them potential targets for biochemical and meta-studies.
Structural basis of anticancer drug recognition and amino acid transport by LAT1
Authors: Lee Yongchan , Jin Chunhuan , Ohgaki Ryuichi , Xu Minhui , Ogasawara Satoshi , Warshamanage Rangana , Yamashita Keitaro , Murshudov Garib , Nureki Osamu , Murata Takeshi , Kanai Yoshikatsu
Published: December 2023

LAT1 (SLC7A5) transports large neutral amino acids and their derivatives across the plasma membrane and plays pivotal roles in cancer cell proliferation, immune response and drug delivery across the blood-brain barrier. Despite recent advances in structural understanding of LAT1, how it discriminates substrates and inhibitors including the clinically relevant anticancer drugs remains elusive. Here we report six structures of LAT1, captured in three different conformations and bound with diverse bioactive ligands, elucidating its substrate transport and inhibitory mechanisms. JPH203, also known as nanvuranlat or KYT-0353 and currently in clinical trials as an anticancer drug, binds to the wide-open substrate-binding pocket of LAT1. It adopts a U-shaped conformer, with its amino-phenylbenzoxazol moiety pushing against transmembrane helix 3 (TM3), bending TM10 and arresting the transporter in the outward-facing conformation. In contrast, the physiological substrate L-Phe does not exhibit such inhibitory interactions, whereas melphalan, a slow substrate, poses steric hindrance in the pocket, explaining its inhibitory activity. Unexpectedly, the “classical” system L inhibitor BCH induces an occluded state, a key structural intermediate required for substrate transport.Transstimulation assays show that BCH facilitates transporter turnover and is therefore a transportable substrate. These findings provide a structural framework for the intricate mechanisms of substrate recognition and inhibition of LAT1, paving the way for developing more specific and effective drugs against it.
An optimised protocol for quality control of gene therapy vectors using Nanopore direct RNA sequencing
Authors: Zeglinski Kathleen , Montellese Christian , Ritchie Matthew E. , Alhamdoosh Monther , Vonarburg Cédric , Bowden Rory , Jordi Monika , Gouil Quentin , Aeschimann Florian , Hsu Arthur
Published: December 2023

Despite recent advances made towards improving the efficacy of lentiviral gene therapies, a sizeable proportion of produced vector contains an incomplete and thus potentially non-functional RNA genome. This can undermine gene delivery by the lentivirus as well as increase manufacturing costs and must be improved to facilitate the widespread clinical implementation of lentiviral gene therapies. Here, we compare three long-read sequencing technologies for their ability to detect issues in vector design and determine Nanopore direct RNA sequencing to be the most powerful. We show how this approach identifies and quantifies incomplete RNA caused by cryptic splicing and polyadenylation sites, including a potential cryptic polyadenylation site in the widely used Woodchuck Hepatitis Virus Posttranscriptional Regulatory Element (WPRE). Using artificial polyadenylation of the lentiviral RNA, we also identify multiple hairpin-associated truncations in the analysed lentiviral vectors, which account for most of the detected RNA fragments. Finally, we show that these insights can be used for optimization of lentiviral vector design. In summary, Nanopore direct RNA sequencing is a powerful tool for the quality control and optimisation of lentiviral vectors, which may help to improve lentivirus manufacturing and thus the development of higher quality lentiviral gene therapies.
AP-2α/AP-2β transcription factors are key regulators of epidermal homeostasis
Authors: Zhang Hui , Raymundo Jackelyn , Daly Kathleen E. , Zhu Wenjuan , Senapati Bill , Marneros Alexander G.
Published: December 2023

AP-2 transcription factors regulate ectodermal development but their roles for epidermal homeostasis in the adult skin are unknown. We find that AP-2α is the predominant AP-2 family member in adult epidermis, followed by AP-2β. Through inactivation of AP-2α, AP-2β, or both in keratinocytes we assessed the effects of a gradient of epidermal AP-2 activity on skin function. We find that (1) loss of AP-2β in keratinocytes is compensated for by AP-2α, (2) loss of AP-2α impairs terminal keratinocyte differentiation and hair morphogenesis, and (3) the combined loss of AP-2α/AP-2β results in more severe skin and hair abnormalities. Keratinocyte differentiation defects precede a progressive neutrophilic skin inflammation. Inducible inactivation of AP-2α/AP-2β in the adult phenocopies these manifestations. Transcriptomic analyses of epidermis lacking AP-2α or AP-2α/AP-2β in keratinocytes demonstrate a terminal keratinocyte differentiation defect with upregulation of alarmin keratins and of several immune pathway regulators. Moreover, our analyses suggest a key role of loss of AP-2α-dependent gene expression of CXCL14 and KRT15 as an early pathogenic event towards the manifestation of skin inflammation. Thus, AP-2α/AP-2β are critical regulators of epidermal homeostasis in the adult skin.