bluuebunny/crossref_metadata_2025 huggingface dataset:
Purging of highly deleterious alleles through an extreme bottleneck
Authors: Stuart Oliver P. , Cleave Rohan , Pearce Kate , Magrath Michael J.L. , Mikheyev Alexander S.
Published: July 2024

Transitions to captivity often produce population bottlenecks. On one hand, bottlenecks increase inbreeding and decrease effective population size, thus increasing extinction risk. On the other, elevated homozygosity associated with extreme bottlenecks may purge deleterious alleles. Previous studies of purging in captive breeding programs have focused on phenotypic measurements and may be confounded with environmental effects. We test the ability of natural selection to purge deleterious alleles following an extreme population bottleneck by analysing patterns of genetic diversity in wild and captive-bred populations of the Lord Howe Island stick insect (Dryococelus australis).Dryococelus australishas been bred in captivity for two decades, having passed through an extreme bottleneck – only two mating pairs with few new additions since then. The magnitude of the bottleneck, together with the fact that each female lays hundreds of eggs most of which are not recruited, set up nearly ideal conditions for the purging of deleterious alleles. As expected, captive-bred individuals had a greater number of long runs-of-homozygosity compared to wild individuals, implying strong inbreeding in captivity which would facilitate purging in the homozygous regions. Stop-codon and frameshift alleles were preferentially depleted in captivity compared to other alleles, in coding and non-coding regions. The more deleterious an allele was predicted to be, the more likely it was found outside of runs-of-homozygosity, implying that inbreeding events facilitate the expression and thus removal of deleterious alleles, even after such an extreme bottleneck and under the benign conditions of captivity. These data show that extreme inbreeding has likely decreased the deleterious mutation load of the stick insects, though loss of genetic diversity may make future adaptation more difficult.
Towards Wearable Electromyography for Personalized Musculoskeletal Trunk Models using an Inverse Synergy-based Approach
Authors: Rook Jan Willem A. , Sartori Massimo , Refai Mohamed Irfan
Published: July 2024

Electromyography (EMG)-driven musculoskeletal models (EMS) of the trunk are used for estimating lumbosacral joint moments and compressive loads during lifting tasks. These models provide personalized estimates of the parameters using information from many sensors. However, to advance technology from labs to workplaces, there is a need for sensor reduction to improve wearability and applicability. Therefore we introduce an EMG sensor reduction approach based on inverse synergy extrapolation, to reconstruct unmeasured EMG signals for different box-lifting techniques. 12 participants performed an array of tasks (squat, stoop, unilateral twist and bilateral twist) with different weights (0 kg, 7.5 kg and 15 kg). We found that two synergies were sufficient to explain the different lifting tasks (median variance accounted for of 0.91). Building upon this, we used two sensors at optimal subject-specific muscle locations to reconstruct the EMG of four unmeasured channels. Evaluation of the reconstructed and reference EMG showed median coefficients of determination (R2) between 0.70 and 0.86, with median root mean squared errors (RMSE) ranging from 0.02 to 0.04 relative to maximal voluntary contraction. This indicates that our proposed method shows promise for sensor reduction for driving a trunk EMS for ambulatory biomechanical risk assessment in occupational settings and exoskeleton control.
Characterization of three resistance-breaking isolates of sugarcane mosaic virus from Rwanda and implications for maize lethal necrosis
Authors: Wilson Jennifer R. , Willie Kristin J. , Stewart Lucy R. , Redinbaugh Margaret G. , Ohlson Erik W.
Published: July 2024

Maize lethal necrosis (MLN) is a devastating disease of maize caused by synergy between two viruses: maize chlorotic mottle virus (MCMV) and a potyvirus, most often sugarcane mosaic virus (SCMV). Throughout the 2010s, severe MLN outbreaks occurred in sub-Saharan East Africa including Kenya, Rwanda, and Ethiopia. In this study, we assessed the virulence of SCMV isolates collected from Rwanda by screening a panel of maize near isogenic lines containing different combinations of major potyvirus resistance loci. We discovered that the three Rwandan SCMV isolates tested could overcome all three potyvirus resistance loci even when used in combination, including one isolate that could asymptomatically infect all resistant lines tested. To understand how SCMV virulence may contribute to MLN, each of the three isolates were co-inoculated with MCMV on a panel of SCMV and MCMV resistant maize lines. No significant differences in MLN severity were observed for the Rwandan isolates compared to the reference SCMV isolates, indicating that increased virulence in SCMV single infection does not necessarily correlate with increased MLN severity in co-infection with MCMV. For all SCMV isolates tested, at least two potyvirus resistance loci were needed to reduce MLN severity, and maize lines with a combination of SCMV and MCMV resistance were most effective. Surprisingly, in some cases co-infection with MCMV facilitated SCMV infection of potyvirus resistant lines that SCMV could not infect alone. These results underscore the challenges of developing durable MLN resistance and highlight the importance of incorporating strong, multigenic potyvirus resistance into MLN resistance breeding programs.
Methodological approaches to derive the heartbeat evoked potential: past practices and future recommendations
Authors: Virjee Rania-Iman , Kandasamy Rohan , Garfinkel Sarah N , Carmichael David , Yogarajah Mahinda
Published: July 2024

The heartbeat-evoked potential (HEP), a cortical response time-locked to each heartbeat, is suggested as an implicit electrophysiological marker reflecting the cortical processing of heartbeats, and more broadly interoceptive processing. An increasing number of studies suggest that HEP may be a meaningful clinical measure. However, on the scalp, HEP are low amplitude signals that are mixed with direct cardiac field artefacts. Therefore, signal processing pipelines that separate the cortical HEP from cardiac field artefacts are required. With a view to establishing optimal and standardised HEP pipelines, this review aims to evaluate the current approaches to this analysis used within the literature, address gaps and inconsistencies in HEP pipelines, and highlight the impact of crucial parameter choices. To do this, a scoping review investigated current HEP processing methods and parameters used in EEG and MEG studies. Testing these processing methods on Temple University’s normal scalp EEG data (Obeid and Picone, 2016), the effect of different methods/parameters (e.g. HEP window, electrodes, filters, independent component analysis (ICA) and artefact subspace reconstruction (ASR)) on HEP extraction was explored.

EEG studies (N=101) demonstrated greater parameter variability and heterogeneity than MEG studies (N=10), although significantly more studies used EEG. ICA without cardiac field artefact and ASR at threshold 20 exhibit similar results for artefact removal. Statistical analysis revealed that the RR interval, the start and end of the HEP window and the start of the baseline correction window significantly affect HEP values in pre-frontal, frontal and centrotemporal electrodes.

Publications should report critical values for reliable HEP extraction, emphasising the need for standardised methods to enhance study comparison and reproducibility and establish a gold standard in the field.
Synthetic dysmobility screening reveals a phosphorylation-independent facet of the SLK-Ezrin-F-actin signaling cascade
Authors: Lin Hsuan-Chao , Lin Yun-Yu , Wei Ling-Ying , Zhang Jia-Ming , Tsai Pei-Ju , Lin Yu-Chiao , Chia Jean-San , Tsai Feng-Chiao
Published: July 2024

This study investigates the role of Ste20-like kinase (SLK) in cytoskeletal dynamics, focusing on its interaction with Ezrin and actin remodeling, independent of phosphorylation processes. We utilized HaCaT to explore the effects of SLK and Ezrin knockdown, as well as the application of specific inhibitors on the organization of actin structures. Our findings reveal that both SLK and Ezrin significantly influence the architecture of actin cytoskeletons with differential impacts observed between protein knockdown and dephosphorylation events. Additionally, our results suggest novel, phosphorylation-independent pathways through which Ezrin modulates actin dynamics, potentially indicating alternative, non-enzymatic roles for Ezrin in cytoskeletal integrity.
TwinEco: A Unified Framework for Dynamic Data-Driven Digital Twins in Ecology
Authors: Khan Taimur , de Koning Koen , Endresen Dag , Chala Desalegn , Kusch Erik
Published: July 2024

1.

A Digital Twin (DT) is a virtual replica of a physical object or process that is continuously updated at a certain frequency and can steer change on the physical system, enabling a seamless integration of observation, understanding, and action. Although initially applied primarily in industry, DT is emerging as a powerful tool in ecology, offering new possibilities for dynamic simulations of change in the biosphere. However, since DTs are relatively new in this field, there is currently no standard framework to guide their conceptualisation and development. Thus, DTs in ecological applications are already experiencing fragmentation in software concepts and design philosophies, leading to incompatibilities across DT implementations. This fragmentation risks undermining the progress and potential of the DT concept in ecology. A unifying framework, such as TwinEco, can address these discrepancies and establish a cohesive foundation for the effective adoption and integration of DTs across ecological domains. TwinEco is a modular framework designed to aid and harmonise ecologists’ efforts to build DTs. In doing so, TwinEco focuses on three major design goals:

Modularity, flexibility, and interoperability of DTs facilitated through distinct “components” nested within DT “layers”.

Dynamic modeling of ecological processes and states that evolve over time.

Linking ecological modelling to downstream actions or decisions made on the ecological object or process of study.

TwinEco’s architecture builds upon the feedback loops and state management strategies introduced in the Dynamic Data-Driven Application Systems (DDDAS) paradigm, which has already inspired many DTs across scientific domains. We also discuss the usefulness and ease-of-use of TwinEco by demonstrating its applicability to computational case studies and suggesting future recommendations to the community of data infrastructure builders and modellers in regards to open considerations. By introducing a shared terminology and emphasising model-data fusion, TwinEco highlights the importance of a unified framework to avoid fragmentation in the burgeoning field of ecological digital twinning.
Does Sex-Differential Gene Expression Drive Sex-Differential Selection in Humans?
Authors: Ming Matthew J. , Cheng Changde , Kirkpatrick Mark , Harpak Arbel
Published: July 2024

Sex differences in human transcriptomes have been argued to drive sex-differential natural selection (SDS). Here, we show that previous evidence supporting this hypothesis has been largely unfounded. We develop a new method to test for a genome-wide relationship between sex differences in expression and selection on expression-influencing alleles (eQTLs). We apply it across 39 human tissues and find no evidence for a general relationship. We offer possible explanations for the lack of evidence, including that it is due in part to eQTL ascertainment bias towards sites under weak selection. We conclude that the drivers of ongoing SDS in humans remain to be identified.
Use of optimized single-cell RNA flow cytometry protocol identifies monocytes as main producers of type I interferon in mouse syngeneic tumors
Authors: Lam Khiem C. , Chen Quanyi , Goldszmid Romina S.
Published: July 2024

The tumor microenvironment (TME) consists of complex interactions between cellular and extracellular components, among which the immune system is known to play an integral role in disease progression and response to therapy. Cytokines and chemokines are cell signaling proteins used by immune cells to communicate with each other as well as with other cell types in the body. These proteins control systemic and local immune responses and levels of cytokines/chemokines in the TME have been associated with tumor outcomes. However, cytokines and chemokines have varied expression across cell types, tumors, and host conditions. Therefore, approaches to effectively study the production of these proteins at the single-cell level in the TME are needed to fully elucidate the mechanisms governing the anti-cancer immune response. Here, we detail a protocol to assess the production of cytokines/chemokines across leukocyte populations in mouse tumors using RNA flow cytometry. Importantly, this method can be adapted with minimal changes to study various mouse and human tumors, other RNA analytes, and non-tumor tissues. With this approach, we characterize single-cell production ofIfnb1, Xcl1andCcl5in mouse tumors and identify monocytes and monocyte-derived macrophages as the main producers of type I interferon transcriptIfnb1consistent across 4 different syngeneic tumor models.
Concurrent assessment of neurometabolism and brain hemodynamics to comprehensively characterize the functional brain response to psychotropic drugs: an S-ketamine study
Authors: Boucherie Daphne E , Reneman Liesbeth , Booij Jan , Immink Rogier , Hollmann Markus W , Schrantee Anouk
Published: July 2024

Neuroimaging techniques are crucial for understanding pharmacological treatment effects in neuropsychiatric disorders. Here, we present a novel approach that simultaneously assesses hemodynamic and neurometabolic brain responses to psychotropic drugs using interleaved pharmacological magnetic resonance imaging (phMRI) and magnetic resonance spectroscopy (phMRS). This method was tested using a double-dose, placebo-controlled, randomized, crossover design using S-ketamine, and acquiring 7 Tesla phMRI and phMRS data to evaluate time- and dose-dependent effects in 32 healthy controls. S-ketamine elicited robust phMRI responses in the dorsal-frontal, cingulate, and insular cortices, which correlated with glutamate and opioid receptor maps and subjective dissociation scores. These hemodynamic changes were paralleled by increases in glutamate and lactate, especially at higher doses. Furthermore, accuracy in predicting received S-ketamine dose increased when combining both techniques. Here, we show for the first time that concurrent phMRI and phMRS assessments provide important complementary insights into the functional brain response to pharmacological interventions.
Molecular Dynamics of Phosphatidylcholine Model Membranes of Splenic Lymphoma Cells
Authors: Kio Michael , Lucker Joshua , Klauda Jeffery B.
Published: July 2024

In eukaryotic cell membranes, phosphatidylcholine (PC) is one of the most prevalent phospholipids. Using the CHARMM36 lipid force field, we conducted molecular dynamics (MD) simulations on phosphatidylcholine (PC) only headgroup with varied fatty acid chains. Specifically, we investigated five PC components: 1,2-diauroyl-sn-glycero-3-phospocholine (DLPC), 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC), 1,2-dipalmitoyl-sn-glycero-3- phospcholine (DPPC), 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), and 1- stearoyl-2-oleoylphosphatidylcholine (SOPC) in both pure and cancer model of PCs. We analyzed various characteristics such as lipid area, lateral compressibility, deuterium order parameter, bilayer thickness, radial distribution functions, and electron density. Our research revealed that PCs in the cancer model membrane are larger in surface area per lipid compared with pure PC membranes. This suggests that our PC model for cancer PCs may be more permeable and porous compared to pure PC membraness. In general, chain order parameter values were lower in cancer PCs compared to pure PCs. The electron density studies of cancer PCs revealed a decrease in bilayer thickness as temperature increases, indicating that cancer PCs experience thinning at higher temperatures. Overall, our results give insight into significant differences between the cellular makeup and functioning of pure PCs and cancer PCs at the molecular level.
Contrastive Learning for Graph-Based Biological Interaction Discovery: Insights from Oncologic Pathways
Authors: Nguyen Phuong-Nam
Published: July 2024

Background

Contrastive learning has emerged as a pivotal technique in representation learning, particularly for self-supervised and unsupervised tasks. Link prediction, crucial for network analysis, forecasts the formation of connections between nodes. Machine learning enhances link prediction by learning patterns from data, leading to improved performance and scalability.

Method

In this study, we propose a contrastive learning approach tailored for isomorphic graphs to uncover intrinsic interactions within biological networks. By creating data augmentations through vertex permutations, we train models to learn permutation-invariant representations.

Results

In this study, we propose a contrastive learning approach tailored for isomorphic graphs to uncover intrinsic interactions within biological networks. By creating data augmentations through vertex permutations, we train models to learn permutation-invariant representations. Our approach was validated using five cancer-targeting biomarkers:ADGRF5, TP53, BRAF, KRAS, andGNAS.

Conclusion

We discovered new connections between G-coupled receptors (GPR137B, GPR161, andGPR27) and key path-ways, interactions between cyclin-dependent kinase inhibitors (CDKN1AandCDK8) and specific biomarkers, and identifiedNFK-BIAas a central node linking all targeting biomarkers. This study highlights the potential of contrastive learning to reveal novel insights into cancer research and therapeutic targets. The implementation of this project is made available at:https://github.com/namnguyen0510/Contrastive-Learning-for-Graph-Based-Biological-Interaction-Discovery.
Induction of cytoplasmic dsDNA and cGAS-STING immune signaling after exposure of breast cancer cells to X-rays or high energetic carbon ions
Authors: Totis C. , Averbeck N. B. , Jakob B. , Schork M. , Volpi G. , Hintze D.F. , Durante M. , Fournier C. , Helm A.
Published: July 2024

Radiotherapy can trigger activation of the cGAS-STING axis via cytoplasmic dsDNA fragment induction. The activation of cGAS–STING initiates innate immune signaling mediated by interferon type-I that can contribute to eradicate the malignancy. The effect was shown to depend on the fractionation scheme employed. We hypothesized that the innate immune response can also depend on radiation quality because densely ionizing radiation, such as carbon ions, have different effects on DNA lesion quality. We show here that carbon ions induced a significantly higher yield of cytosolic dsDNA fragments per unit dose as compared to photons in anin vitro4T1 breast cancer model. The higher efficiency also translated in expression and release of interferon-β by the tumor cells. Cytoplasmic dsDNA fragments as well as interferon-β release increased with doses up to 24 Gy and no differences for a fractionation scheme (3x8 Gy) were found as compared to the single high doses of photons. In conclusion, we found that the release of interferon-β after radiation is increasing with the radiation dose up to 20 Gy and that carbon ions have the potential to elicit a strong innate immune signaling.
Effector-Specific Neural Representations of Perceptual Decisions Independent of Motor Actions and Sensory Modalities
Authors: Esmeyer Marlon F. , Schmidt Timo T. , Blankenburg Felix
Published: July 2024

Neuroscientific research has shown that perceptual decision-making occurs in effector-specific brain regions that are associated with the required motor response. Recent functional magnetic resonance imaging (fMRI) studies that dissociated decisions from coinciding processes, such as motor actions partly challenge this, indicating abstract representations that might vary across stimulus modalities. However, cross-modal comparisons have been difficult since most task designs differ not only in modality but also in effectors, motor response, and level of abstraction. Here, we describe an fMRI experiment where participants compared frequencies of two sequentially presented visual flicker stimuli in a delayed match-to-comparison task, which controlled for motor actions and stimulus sequence. Using Bayesian modelling, we estimated subjective frequency differences based on the time order effect. These values were applied in support vector regression analysis of a multi-voxel pattern whole-brain searchlight approach to identify brain regions containing information on subjective decision values. Furthermore, a conjunction analysis with data from a re-analyzed analogue vibrotactile study was conducted for a cross-modal comparison. Both analyses revealed significant activation patterns in the left dorsal (PMd) and ventral (PMv) premotor cortex as well as in the bilateral intraparietal sulcus (IPS). While previous primate and human imaging research have implicated these regions in transforming sensory information into action, our findings indicate that the IPS processes abstract decision signals while PMd and PMv represent an effector-specific, but motor response independent encoding of perceptual decisions that persists across sensory domains.
EMG1 methyltransferase activity regulates ribosome occupancy at viral uORFs
Authors: Harrington Elena M. , Murphy James C. , Aspden Julie L. , Whitehouse Adrian
Published: July 2024

Viruses do not encode their own translational machinery and rely exclusively on the translational machinery of the host cell for the synthesis of viral proteins. Viruses have evolved diverse mechanisms to redirect the cellular translation apparatus to favour viral transcripts. A unique mechanism employed by Kaposi’s sarcoma-associated herpesvirus (KSHV) involves manipulation of cellular ribosome composition, producing virus-induced specialised ribosomes. These ribosomes scan through KSHV uORFs in late lytic genes, allowing efficient translation of downstream main KSHV ORFs. Herein, we highlight the enhanced association of the ribosomal biogenesis factor EMG1 with precursor-40S ribosome complexes during KSHV lytic replication. Depletion of EMG1 results in significantly reduced expression of viral proteins and progression through the lytic cascade, culminating in a dramatic reduction of infectious virus production. We further demonstrate that the methyltransferase activity of EMG1 is required for effective regulation of translation of KSHV uORFs in late lytic genes.
Quantifying defective and wild-type viruses from high-throughput RNA sequencing
Authors: Muñoz-Sánchez Juan C. , Olmo-Uceda María J. , Oteo José-Ángel , Elena Santiago F.
Published: July 2024

Defective viral genomes (DVGs) are variants of the wild-type (wt) virus that lack the ability to complete an infectious cycle independently. However, in the presence of their parental (helper) wt virus, DVGs can interfere with the replication, encapsidation, and spread of functional genomes, acting as a significant selective force in viral evolution. DVGs also affect the host’s immune responses and are linked to chronic infections and milder symptoms. Thus, identifying and characterizing DVGs is crucial for understanding infection prognosis. Quantifying DVGs is challenging due to their inability to sustain themselves, which makes it difficult to distinguish them from the helper virus, especially using high-throughput RNA sequencing (RNA-seq). Accurate quantification is essential for understanding their interactions with their helper virus. We present a method to simultaneously estimate the abundances of DVGs and wt genomes within a sample by identifying genomic regions with significant deviations from the expected sequencing depth. Our approach involves reconstructing the depth profile through a linear system of equations, which provides an estimate of the number of wt and DVG genomes of each type. Until now,in silicomethods have only estimated the DVG-to-wt ratio for localized genomic regions. This is the first method that simultaneously estimates the proportions of wt and DVGs across RNA sequencing of the whole genome.

Availability and implementation

The Matlabcode and the synthetic datasets are freely available athttps://github.com/jmusan/wtDVGquantific.
Beyond Symptom Management: FAAH Inhibition as a Path to Mitigate Alzheimer’s Disease Progression in Mouse Models of Amyloidosis
Authors: Oddi Sergio , Scipioni Lucia , Totaro Antonio , Giacovazzo Giacomo , Ciaramellano Francesca , Tortolani Daniel , Leuti Alessandro , Businaro Rita , Armeli Federica , Bilkei-Gorzo Andras , Coccurello Roberto , Zimmer Andreas , Maccarrone Mauro
Published: July 2024

The endocannabinoidN-arachidonoylethanolamine (AEA) is a pro-homeostatic bioactive lipid known for its anti-inflammatory, anti-oxidative, immunomodulatory, and neuroprotective properties, which may contrast/mitigate Alzheimer’s disease (AD) pathology. This study explores the therapeutic potential of targeting fatty acid amide hydrolase (FAAH), the major enzyme degrading AEA, in mouse models of amyloidosis APP/PS1 and Tg2576. Enhancing AEA signaling by genetic deletion of FAAH delayed cognitive deficits in APP/PS1 mice and improved cognitive symptoms in 12-month-old AD-like mice. Chronic pharmacological FAAH inhibition fully reverted neurocognitive decline, attenuated neuroinflammation, and promoted neuroprotective mechanisms in Tg2576 mice. Additionally, pharmacological FAAH inactivation robustly suppressed β-amyloid production and accumulation, associated with decreased expression of β-site amyloid precursor protein cleaving enzyme 1 (BACE1), possibly through a cannabinoid receptor 1-dependent epigenetic mechanism. These findings improve our understanding of AEA signaling in AD pathogenesis, and provide proof-of-concept that selective targeting of FAAH activity could be a promising therapeutic strategy against AD.
SARS-CoV-2 S, M and E Structural Proteins Down-modulate HIV-1 LTR Activity and Modulate Endoplasmic Reticulum Stress Responses
Authors: Albalawi Wejdan , Thomas Jordan , Mughal Farah , Roper Kelly J , Alshehri Abdullateef , Paxton Georgios , Paxton William A
Published: July 2024

We have previously shown that the Hepatitis C Virus (HCV) E1E2 envelope glycoprotein can down-modulate HIV-1 long-terminal repeat (LTR) activity through disruption to NF-kappaB activation. This response is associated with up-regulation of the endoplasmic reticulum (ER) stress response pathway. Here we demonstrate that the SARS-CoV-2 S, M and E but not the N structural protein can perform similar down-modulation of HIV-1 LTR activation and in a dose-dependent manner in both HEK293 and lung BEAS-2B cell-lines and interpreted as a result of NF-kappaB down-modulation. The effect is highest with the SARS-CoV-2 Wuhan S strain and decreases over-time for the subsequent emerging variants of concern (VOC) with omicron providing the weakest effect. We developed pseudo-typed viral particle (PVP) molecular viral tools that allowed for the generation of cell-lines constitutively expressing separately the four SARS-CoV-2 structural proteins and utilising the VSV-g envelope protein to deliver the integrated gene construct. Differential gene expression analysis (DGEA) was performed on cells expressing S, E, M or N to determine cell activation status. It it was determined that gene expression differences were found in a number of interferon-stimulated genes (ISGs), including IF16, IFIT1, IFIT2 and ISG15 as well as for a number of heat shock protein (HSP) genes, including HSPH1, HSPA6 and HSPBP1 with all four SARS-CoV-2 structural proteins. There were also differences observed with expression patterns of transcription factors with both SP1 and MAVS upregulated in the presence of S, M and E but not the N protein. Collectively the results indicate that gene expression patterns associating with ER stress pathways can be identified with SARS-CoV-2 envelope glycoprotein expression. The results suggest the SARS-CoV-2 can modulate activation of an array of cell pathways resulting in disruption to NF-kappaB signalling hence providing alterations to multiple physiological responses of SARS-CoV-2 infected cells.
Two-factor synaptic consolidation reconciles robust memory with pruning and homeostatic scaling
Authors: Iatropoulos Georgios , Gerstner Wulfram , Brea Johanni
Published: July 2024

Memory consolidation involves a process of engram reorganization and stabilization that is thought to occur primarily during sleep through a combination of neural replay, homeostatic plasticity, synaptic maturation, and pruning. From a computational perspective, however, this process remains puzzling, as it is unclear how the underlying mechanisms can be incorporated into a common mathematical model of learning and memory. Here, we propose a solution by deriving a consolidation model that uses replay and two-factor synapses to store memories in recurrent neural networks with sparse connectivity and maximal noise robustness. The model offers a unified account of experimental observations of consolidation, such as multiplicative homeostatic scaling, task-driven synaptic pruning, increased neural stimulus selectivity, and preferential strengthening of weak memories. The model further predicts that intrinsic synaptic noise scales sublinearly with synaptic strength; this is supported by a meta-analysis of published synaptic imaging datasets.
Chromosome Numbers and Reproductive Life Cycles in Green Plants: A phylo-transcriptomic perspective
Authors: Dhakal Rijan R. , Harkess Alex , Wolf Paul G.
Published: July 2024

The strong correlation between reproductive life cycle type and chromosome numbers in green plants has been a long-standing mystery in evolutionary biology. Within green plants, the derived condition of heterosporous reproduction has emerged from the ancestral condition of homospory in disparate locations on the phylogenetic tree at least 11 times, of which 3 lineages are extant. In all green plant lineages where heterospory has emerged, there has been a significant downsizing in chromosome numbers (refer to figure 1). This dynamic has been investigated without clear answers for many decades. In this study, we combine known ideas from existing literature with novel methods, tools, and data to generate fresh insights into an old question.

Using gene family evolution models and selection analyses, we identified gene families that have undergone significant expansion, contraction, or selection in heterosporous lineages. Our results reveal both shared and lineage-specific genomic changes associated with the evolution of heterospory. We found expansions in gene families related to developmental regulation, signaling pathways, and stress responses across heterosporous groups. Notably, the MATE efflux family showed consistent expansion and evidence of selection in heterosporous lineages, suggesting a potentially conserved role in heterospory evolution. These findings highlight novel insights that may underpin the association between heterospory and reduced chromosome numbers.

The general importance of chromosome numbers, structure, and sizes in cellular biology notwithstanding, the association between the emergence of heterosporous reproduction and chromosome number reduction/genome downsizing is not fully understood. It remains unclear why there exists an association between aspects of biology at such disparate levels as reproductive life-cycles and chromosome numbers/genome size. Exploring and answering this conundrum of evolutionary biology can add to our broader understanding of life sciences and of biology at different levels. Applying the novel tools and methods emerging from ongoing progress in biotechnology and computational sciences presents an opportunity to make new inroads into this long-standing question.
Stock identification of Mediterranean horse mackerel (Trachurus mediterraneus) through the analysis of morphometric characters in the Adriatic Sea.
Authors: Vasapollo Claudio
Published: July 2024

Phenotypical differentiation among stocks of Mediterranean horse mackerel Trachurus mediterraneus in the Adriatic Sea was investigated through the analysis of several individual morphometric characters. Overall, 426 individuals of Mediterranean horse mackerels were sampled from the northern, central and southern Adriatic Sea in 2012 and 2013, and then compared using multivariate techniques (linear discriminant analysis). Discriminant analysis suggested a scarce intermingling between the northern and central Adriatic with the southern part. The former two areas showed more stable populations, overlapping both in space and time. The latter seemed to be more variable over the years. A possible hypothesis for this, to be investigated, is the flow of individuals from the Ionian and Aegean Seas populations through the Otranto Channel. When the morphometric variables were investigated, the results showed that most of the variability was associated with the head characters. In particular, the northern and central Adriatic Sea individuals had shorter and thicker heads than the southern ones. This could be due to different feeding habits: the former mainly feed on small fishes, the latter mainly on euphausiids. A short mouth could reduce the power of suction of bigger preys, while a long mouth could increase the volume of water to be filtered to feed on small planktonic crustaceans. From this study, it comes clear that the Mediterranean horse mackerel populations should not be managed as a single stock in the Adriatic Sea as it was evident that morphological two different populations are present in the basin.
Mechanism-guided engineering of a minimal biological particle for genome editing
Authors: Ngo Wayne , Peukes Julia T. , Baldwin Alisha , Xue Zhiwei Wayne , Hwang Sidney , Stickels Robert R. , Lin Zhi , Satpathy Ansuman T. , Wells James A. , Schekman Randy , Nogales Eva , Doudna Jennifer A.
Published: July 2024

The widespread application of genome editing to treat or even cure disease requires the delivery of genome editors into the nucleus of target cells. Enveloped Delivery Vehicles (EDVs) are engineered virally-derived particles capable of packaging and delivering CRISPR-Cas9 ribonucleoproteins (RNPs). However, the presence of lentiviral genome encapsulation and replication components in EDVs has obscured the underlying delivery mechanism and precluded particle optimization. Here we show that Cas9 RNP nuclear delivery is independent of the native lentiviral capsid structure. Instead, EDV-mediated genome editing activity corresponds directly to the number of nuclear localization sequences on the Cas9 enzyme. EDV structural analysis using cryo-electron tomography and small molecule inhibitors guided the removal of ∼80% of viral residues, creating a minimal EDV (miniEDV) that retains full RNP delivery capability. MiniEDVs are 25% smaller yet package equivalent amounts of Cas9 RNPs relative to the original EDVs, and demonstrated increased editing in cell lines and therapeutically-relevant primary human T cells. These results show that virally-derived particles can be streamlined to create efficacious genome editing delivery vehicles that could simplify production and manufacturing.

SIGNIFICANCE STATEMENT

Our results highlight the importance of understanding how virally-derived particles function to eliminate unnecessary viral proteins and create more efficacious and easier-to-produce delivery vehicles for therapeutic genome editing.
Proprioception impacts body perception in healthy aging – insights from a Psychophysical and Computational Approach
Authors: Risso G. , Bieri M. , Bertoni T. , Mastria G. , Allet L. , Serino A. , Bassolino M.
Published: July 2024

The experience of owning a body (body ownership, BO) and the perception of our body dimensions (metric body representation, mBR) depend on the integration of multisensory cues. As the human sensory system is subjected to a decline along the lifespan, encompassing all sensory modalities, we hypothesize that body perception may be different in older, as compared to young adults. Here, we investigate this hypothesis by comparing the multisensory processing underlying BO and mBR in healthy older (> 65 years) and young individuals. First, we applied rigorous computational and psychophysical methods to assess alterations in mBR and BO quantitatively. We then modeled the manifold relationship between the observed body misperceptions and the potential underlying sensory, motor, and cognitive factors. The results highlight significant differences between the two groups, with higher distortions in perceived arm dimensions and an increased tendency to experience BO towards a virtual hand in the aged group. These differences in both mBR and BO are explained by the reduced proprioceptive abilities of older adults, suggesting a crucial role of proprioception in driving age-dependent plasticity in body representations. Overall, our modeling and experimental approach provide new perspectives on altered body perception during aging, suggesting that they stem from the physiological proprioceptive decline occurring in older adults, and laying the groundwork to generate prevention and stimulation strategies to restore accurate body perception in aging.
Differentiation of Acute Disseminated Encephalomyelitis from Multiple Sclerosis Using a Novel Brain Lesion Segmentation and Classification Pipeline
Authors: Radi Osama , Huang Aiden , Murakami Kira
Published: July 2024

Multiple Sclerosis (MS) is a chronic autoimmune disease affecting the central nervous system, while Acute Disseminated Encephalomyelitis (ADEM) is a sudden, often monophasic inflammatory condition of the brain and spinal cord. Only 17% of ADEM cases are correctly diagnosed on the first visit due to overlapping clinical and radiological presentations with Multiple Sclerosis (MS) [1]. Both ADEM and MS are demyelinating diseases, meaning they cause brain lesions by damaging the myelin sheath, leading to scar tissue that disrupts nerve signals [2]. Previous machine learning pipelines have differentiated Neuromyelitis Optica Spectrum Disorder (NMOSD) (a different demyelinating disease) from MS and ADEM from NMOSD based on MRI imagery with varying accuracies [3, 4]. Our novel Classifier for Demyelinating Disease (CDD) pipeline is the first to differentiate ADEM from MS using MRI imagery. It does this in two stages: a segmentation stage which creates segmentation masks of the lesions and a classification stage to classify them as either ADEM or MS. Additionally, we introduce a novel ADEM dataset from open-access medical case reports. The CDD pipeline achieves an accuracy of 90.0% on our validation dataset, making it a potentially viable diagnostic tool in the future. All data and code is available here.2
Sequencing 1206 genomes reveals origin and movement ofAedes aegyptidriving increased dengue risk
Authors: Crawford Jacob E. , Balcazar Dario , Redmond Seth , Rose Noah H. , Youd Henry A. , Lucas Eric R. , Sudirman Made Ali Rusdiyah , Alnazawi Ashwaq , Badolo Athanase , Chen Chun-Hong , Cosme Luciano V. , Henke Jennifer A. , Hung Kim Y. , Kluh Susanne , Liu Wei-Liang , Maringer Kevin , Micieli María Victoria , Pless Evlyn , Sombié Aboubacar , Surendran Sinnathamby N. , Wahid Isra , Armbruster Peter A. , Weetman David , McBride Carolyn S. , Gloria-Soria Andrea , Powell Jeffrey R. , White Bradley J.
Published: July 2024

The number of dengue cases worldwide has increased ten-fold over the past decade asAedes aegypti, the primary vector of this disease, thrives and expands its distribution, revealing limitations to current control methods. To better understand howAe. aegyptievolved from a forest dwelling, generalist species to a highly anthropophilic urban species and the impact of contemporary gene flow on the future of dengue control, we sequenced 1,206 genomes from mosquitoes collected at 74 locations around the globe. Here we show that after evolving a preference for humans in the Sahel region of West Africa, the origin of the fully domesticated, anthropophilic subspeciesAe. aegypti aegypti(Aaa) occurred in the Americas during the Atlantic Slave Trade era and was followed by its explosive expansion around the globe. In recent decades,Aaahas invaded coastal Africa, the ancestral home range, introducing insecticide resistance mutations and an affinity for human hosts. Evidence of back-to-Africa migration is found in regions with recent dengue outbreaks, raising concern that global movement ofAaacould increase transmission risk of arboviruses including dengue in urban Africa. These data provide a platform to further study this important mosquito vector species and underscore developing complexity in the fight to limit the spread of dengue, Zika, and chikungunya diseases.
The Structural Logic of Dynamic Signaling in theEscherichia coliSerine Chemoreceptor
Authors: Reyes Georgina I. , Flack Caralyn E. , Parkinson John S.
Published: July 2024

The experimental challenges posed by integral membrane proteins hinder molecular understanding of transmembrane signaling mechanisms. Here, we exploited protein crosslinking assays in living cells to follow conformational and dynamic stimulus signals in Tsr, theEscherichia coliserine chemoreceptor. Tsr mediates serine chemotaxis by integrating transmembrane serine-binding inputs with adaptational modifications of a methylation helix bundle to regulate a signaling kinase at the cytoplasmic tip of the receptor molecule. We created a series of cysteine replacements at Tsr residues adjacent to hydrophobic packing faces of the bundle helices and crosslinked them with a cell-permeable, bifunctional thiol-reagent. We identified an extensively crosslinked dynamic junction midway through the methylation helix bundle that seemed uniquely poised to respond to serine signals. We explored its role in mediating signaling shifts between different packing arrangements of the bundle helices by measuring crosslinking in receptor molecules with apposed pairs of cysteine reporters in each subunit and assessing their signaling behaviors with an in vivo kinase assay. In the absence of serine, the bundle helices evinced compact kinase-ON packing arrangements; in the presence of serine, the dynamic junction destabilized adjacent bundle segments and shifted the bundle to an expanded, less stable kinase-OFF helix-packing arrangement. An AlphaFold 3 model of kinase-active Tsr showed a prominent bulge and kink at the dynamic junction that might antagonize stable structure at the receptor tip. Serine stimuli probably inhibit kinase activity by shifting the bundle to a less stably-packed conformation that relaxes structural strain at the receptor tip, thereby freezing kinase activity.

SIGNIFICANCE

This study used in vivo protein crosslinking to follow stimulus-induced signals through Tsr, a bacterial transmembrane receptor for chemotaxis to serine. Our experiments distinguished Tsr conformations that activate or inhibit its signaling kinase partner and showed how those signals reach the receptor’s kinase-controlling cytoplasmic tip. A dynamic junction in the Tsr molecule triggers stimulus responses by propagating a less stable helix-packing arrangement to flanking structural elements, thereby reducing structural stresses at the receptor tip. An AlphaFold model indicated that the dynamic junction might cause a structural distortion that destabilizes the receptor tip in the absence of a serine stimulus. This model and experimental approach could help to elucidate the signaling logic and mechanisms in other transmembrane chemoreceptor proteins.
The spread of antibiotic resistance is driven by plasmids amongst the fastest evolving and of broadest host range
Authors: Coluzzi Charles , Rocha Eduardo P. C.
Published: July 2024

Microorganisms endure novel challenges for which other microorganisms in other biomes may have already evolved solutions. This is the case of nosocomial bacteria under antibiotic therapy because antibiotics are of ancient natural origin and resistances to them have previously emerged in environmental bacteria. In such cases, the rate of adaptation crucially depends on the acquisition of genes by horizontal transfer of plasmids from distantly related bacteria in different biomes. We hypothesized that such processes should be driven by plasmids amongst the most mobile and evolvable. We confirmed these predictions by showing that plasmid families encoding antibiotic resistance are very mobile, have broad host ranges, while showing higher rates of homologous recombination and faster turnover of gene repertoires than the other plasmids. These characteristics remain outstanding when we remove resistance plasmids from our dataset, suggesting that antibiotic resistance genes are preferentially acquired and carried by plasmid families that are intrinsically very mobile and plastic. Evolvability and mobility facilitate the transfer of antibiotic resistance, and presumably of other phenotypes, across distant taxonomic groups and biomes. Hence, plasmid families, and possibly those of other mobile genetic elements, have differentiated and predictable roles in the spread of novel traits.
Examining the Central Auditory Processing Using a Multi-Feature ERP Paradigm to Phonetic, Prosodic and Acoustic Features
Authors: Ioanna Zavogianni Maria , Kelić Maja , Honbolygó Ferenc
Published: July 2024

Previous studies have shown that multi-feature paradigms can be used for the investigation of the central auditory processing. In this study, we developed a speech multi-feature paradigm with phonetic, prosodic, and acoustic changes. Our aim was to examine the participants’ involuntary discrimination of the changes of speech sound features while they were watching a movie without any sound or subtitles. All five deviant conditions (vowel, consonant, stress, intensity, frequency) elicited statistically significant MMN ERP responses which varied in amplitude depending on the condition; stress was also connected with the occurrence of the LDN component. With vowel, consonant and stress among the conditions that received the most statistically significant ERPs, we could suggest that the current multi-feature paradigm can be used to successfully elicit the MMN ERP component and potentially to assess phonological processing in children and adults.
A postzygoticGNA13variant upregulates the RHOA/ROCK pathway and alters melanocyte function in a mosaic skin hypopigmentation syndrome
Authors: Masri Rana El , Iannuzzo Alberto , Kuentz Paul , Tacine Rachida , Vincent Marie , Barbarot Sébastien , Morice-Picard Fanny , Boralevi Franck , Oillarburu Naia , Mazereeuw-Hautier Juliette , Duffourd Yannis , Faivre Laurence , Sorlin Arthur , Vabres Pierre , Delon Jérôme
Published: July 2024

The genetic bases of mosaic pigmentation disorders have increasingly been identified, but these conditions remain poorly characterised, and their pathophysiology is unclear. Here, we report in four unrelated patients that a recurrent postzygotic mutation inGNA13is responsible for a recognizable syndrome with hypomelanosis of Ito associated with developmental anomalies.GNA13encodes Gα13, a subunit of αβγ heterotrimeric G proteins coupled to specific transmembrane receptors known as G-protein coupled receptors. In-depth functional investigations revealed that this R200K mutation provides a gain of function to Gα13. Mechanistically, we show that this variant hyperactivates the RHOA/ROCK signalling pathway that consequently increases actin polymerisation and myosin light chains phosphorylation, and promotes melanocytes rounding. Our results also indicate that R200K Gα13hyperactivates the YAP signalling pathway. All these changes appear to affect cell migration and adhesion but not the proliferation. Our results suggest that hypopigmentation can result from a defect in melanosome transfer to keratinocytes due to cell shape alterations. These findings highlight the interaction between heterotrimeric G proteins and the RHOA pathway, and their role in melanocyte function.