bluuebunny/crossref_metadata_2025 huggingface dataset:
Fe–Zn alloy, a new biodegradable material capable of reducing ROS and inhibiting oxidative stress
Authors: Yang Shuaikang , Wang Weiqiang , Xu Yanan , Yuan Yonghui , Hao Shengzhi
Published: January 2024

Fe-based biodegradable materials have attracted significant attention due to their exceptional mechanical properties and favorable biocompatibility. Currently, research on Fe-based materials mainly focuses on regulating the degradation rate. However, excessive release of Fe ions during material degradation will induce the generation of reactive oxygen species (ROS), leading to oxidative stress and ferroptosis. Therefore, the control of ROS release and the improvement of biocompatibility for Fe-based materials are very important. In this study, new Fe–Zn alloys were prepared by electrodeposition with the intention of using Zn as an antioxidant to reduce oxidative damage during alloy degradation. Initially, the impact of three potential degradation ions (Fe2+, Fe3+, Zn2+) from the Fe–Zn alloy on human endothelial cell (EC) activity and migration ability was investigated. Subsequently, cell adhesion, cell activity, ROS production and DNA damage were assessed at various locations surrounding the alloy. Finally, the influence of different concentrations of Zn2+ in the medium on cell viability and ROS production was evaluated. High levels of ROS exhibited evident toxic effects on ECs and promoted DNA damage. As an antioxidant, Zn2+ effectively reduced ROS production around Fe and improved the cell viability on its surface at a concentration of 0.04 mmol/l. These findings demonstrate that Fe–Zn alloy can attenuate the ROS generated from Fe degradation thereby enhancing cytocompatibility.
Risk of cardiovascular disease associated with long-term use of non-steroidal anti-inflammatory drugs in ankylosing spondylitis
Authors: Kim Ji-Won , Yoon Jun Sik , Park Sojeong , Kim Hasung , Kim Bo young , Lee Hwajeong , Park Sung-Hoon , Kim Seong-Kyu , Choe Jung-Yoon
Published: January 2024

Objective

To examine the risk of cardiovascular disease associated with long-term use of NSAIDs in a large real-world AS cohort.

Methods

This nationwide population-based cohort study used data from the Korean National Health Insurance Database. Patients aged ≥18 years old who were newly diagnosed with AS without prior cardiovascular disease between January 2010 and December 2018 were included in this study. Controls without AS were randomly selected by age, sex and index year. The primary outcome was cardiovascular disease, a composite outcome of ischaemic heart disease, stroke or congestive heart failure. Long-term use of NSAIDs was defined as use of NSAIDs for >365 cumulative defined daily doses. The association between long-term use of NSAIDs and incident cardiovascular disease was examined in both AS and non-AS populations.

Results

Among 19 775 patients with AS and 59 325 matched controls without AS, there were 1663 and 4308 incident cases of cardiovascular disease, showing an incidence of 16.9 and 13.8 per 1000 person-years, respectively. Long-term use of NSAIDs was associated with increased risk of cardiovascular disease in non-AS controls [adjusted hazard ratio (aHR) 1.64; 95% CI 1.48–1.82]. In contrast, long-term use of NSAIDs did not increase the risk of cardiovascular disease in AS patients (aHR 1.06; 95% CI 0.94–1.20; adjusted for age, sex, socioeconomic status, BMI, smoking status, hypertension, diabetes, hyperlipidemia and TNF inhibitor use).

Conclusion

Prolonged NSAID treatment in AS patients may not be as harmful as in the general population regarding cardiovascular risk.
Predictors of renal flares in systemic lupus erythematosus: a post-hoc analysis of four phase III clinical trials of belimumab
Authors: Jägerback Sandra , Gomez Alvaro , Parodis Ioannis
Published: January 2024

Objective

The objective of this study was to identify predictors of renal flares in patients with SLE treated for active extra-renal disease.

Methods

Data from four clinical trials of belimumab in SLE (BLISS-52, NCT00424476; BLISS-76, NCT00410384; BLISS-NEA, NCT01345253; BLISS-SC, NCT01484496) were used. Patients were assigned to belimumab or placebo on top of standard therapy. We investigated the performance of predictors of renal flares through weeks 52–76 using proportional hazards regression analysis.

Results

Of 3225 participants, 192 developed at least one renal flare during follow-up, with the first occurring after a median time of 197 days. Current/former renal involvement [hazards ratio (HR): 15.4; 95% CI: 8.3–28.2; P < 0.001], low serum albumin levels (HR 0.9; 95% CI: 0.8–0.9; P < 0.001), proteinuria (HR: 1.6; 95% CI: 1.5–1.7; P < 0.001), and low C3 levels (HR: 2.9; 95% CI: 2.1–4.1; P < 0.001) at baseline appeared robust determinants of impending renal flares. Anti-dsDNA positivity yielded an increased hazard for renal flares (HR: 2.1; 95% CI: 1.4–3.2; P < 0.001), which attenuated after adjustments. Anti-Sm positivity was associated with renal flares in the placebo (HR: 3.7; 95% CI: 2.0–6.9; P < 0.001) but not in the belimumab subgroup, whereas anti-ribosomal P positivity was associated with renal flares in the belimumab subgroup only (HR: 2.8; 95% CI: 1.5–5.0; P = 0.001).

Conclusion

A history of renal involvement, high baseline proteinuria, hypoalbuminaemia, and C3 consumption were robust determinants of impending renal flares. In addition to anti-dsDNA, anti-Sm and anti-ribosomal P protein antibody positivity may have value in surveillance of renal SLE.
Disease activity trajectories in juvenile dermatomyositis from childhood to adulthood
Authors: Nozawa Tomo , Pullenayegum Eleanor M , Bell-Peter Audrey , Marcuz Jo-Anne , Whitney Kristi , Vinik Ophir , Shupak Rachel , Dover Saunya , Feldman Brian M
Published: January 2024

Objectives

To assess whether there are identifiable subgroups of disease activity trajectory in a population of JDM patients—followed throughout childhood and into adulthood—and determine factors that predict those trajectory groupings.

Methods

This is a retrospective, longitudinal inception cohort of patients with idiopathic inflammatory myopathies, largely JDM. We sought to identify baseline factors that predict membership into different groups (latent classes) of disease activity trajectory.

Results

A total of 172 patients (64% females), with median age at diagnosis of 7.7 years, were analysed. We studied 4725 visits (1471 patient-years). We identified three latent classes of longitudinal disease activity, as measured by the modified DAS (DASm), with distinct class trajectories predicted by DASm at baseline, and by the changes of DASm from either baseline to 3 months or baseline to 6 months (early response to therapy). In the analysis in which DASm at baseline and the changes of DASm from baseline to 6 months are included as predictors, Class 1 (10%) has persistently high disease activity, Class 2 (34%) is characterized by moderate disease activity and Class 3 (56%) is characterized by individuals with a high early disease activity but an apparently good response to treatment and long-term low disease activity.

Conclusion

High early disease activity, and treatment resistance in the first few months, predict a more chronic longitudinal course of JDM.
First-time orgasm in a young man with lifelong anorgasmia after flibanserin use: a case report
Authors: Saffati Gal , Naeem Taher , Kaaki Basil , Khera Mohit
Published: January 2024

Introduction

Anorgasmia is a poorly understood phenomenon defined as either a lifelong or acquired consistent inability to achieve ejaculation. Despite the prevalence of anorgasmia, there is currently no established treatment for the condition.

Aims

To report a unique case of a patient with lifelong anorgasmia who was able to achieve his first orgasm with off-label use of flibanserin.

Methods

The present case study relies on the patient’s self-report and a review of the relevant literature. The patient provided written informed consent.

Results

A 28-year-old male presented to our office with complaints of lifelong anorgasmia, without any signs of erectile dysfunction. He reported good libido and energy levels and denied any urinary symptoms or history of depression. The patient failed medical management with numerous off-label medications, including bupropion and bremelanotide. Despite having received 4 or 5 sex therapy sessions over 3 months, the patient reported that this treatment approach was not effective. Off-label use of flibanserin was then initiated, and after 28 to 32 doses over 4 weeks, he achieved his first orgasm. Notably, the patient experienced nocturia and insomnia. The follow-up International Index of Erectile Function score marginally improved by 2 points without any improvement in the overall satisfaction subdomain.

Conclusion

This case highlights the challenges of managing anorgasmia and anejaculation in a young male patient. A stepwise approach involving pharmacotherapy and sex therapy was not successful. However, the off-label use of flibanserin ultimately resulted in the patient achieving his first orgasm, albeit with some side effects. Further studies are needed to evaluate the efficacy and safety of flibanserin in men for this indication.
A propensity score–matched analysis of intra- and postoperative penile prosthetic complications in the solid organ transplant population
Authors: Johnson John C , Venna Rahul , Alzweri Laith
Published: January 2024

Introduction

Solid organ transplant (SOT) has an anticipated higher risk of penile prosthesis (PP) complications related to immunosuppression and surgical approach post-SOT. It is still not determined if PP surgery in the SOT population incurs these same higher risks.

Objectives

To observe differences in intra- and postoperative PP complications between SOT and non-SOT cases from the TriNetX US Collaborative Network, a large real-world database of deidentified patient data from 56 health care organizations within the United States.

Methods

We used the TriNetX database to perform a propensity score–matched cohort study comparing 10-year outcomes between patients with and without a SOT (kidney, heart, lung, liver, pancreas, and intestine) who underwent a PP procedure. Cohorts were matched on age, race/ethnicity, history of pelvic and abdominal surgery, overweight and obesity status, type 2 diabetes mellitus, atherosclerosis, substance use disorders, socioeconomic difficulties, anticoagulant/antiplatelet medications, and spinal cord injury. Outcomes included intra- and perioperative complications as well as prosthetic complications (mechanical malfunction, fibrosis, displacement, hemorrhage, pain, stenosis, removal with or without replacement, and complex [all postoperative complications]).

Results

There were 233 patients in each group after matching (SOT and non-SOT). The mean ± SD age at the prosthesis procedure was 59.7 ± 9.89 years, and 44% of patients were White (P > .05). There was no significant difference for incidence of intra- and perioperative complications (2.62% vs 2.19%, P = .76). The SOT group did not have a higher 10-year incidence of complex complications (30.58% vs 27.51%, P = .11) or mechanical malfunction (10.35% vs 11.62%, P = .25) when compared with the non-SOT group. No difference was found for other prosthetic-related complications (P > .05).

Conclusion

In our analysis, patients with a SOT were not more likely to experience long-term complications related to PP. Surgeons performing PP surgery in the SOT population may consider this procedure a potentially safe and viable option for restoring erectile function.
Human immunodeficiency virus dynamics in secondary lymphoid tissues and the evolution of cytotoxic T lymphocyte escape mutants
Authors: Chung Wen-Jian , Connick Elizabeth , Wodarz Dominik
Published: January 2024

In secondary lymphoid tissues, human immunodeficiency virus (HIV) can replicate in both the follicular and extrafollicular compartments. Yet, virus is concentrated in the follicular compartment in the absence of antiretroviral therapy, in part due to the lack of cytotoxic T lymphocyte (CTL)–mediated activity there. CTLs home to the extrafollicular compartment, where they can suppress virus load to relatively low levels. We use mathematical models to show that this compartmentalization can explain seemingly counter-intuitive observations. First, it can explain the observed constancy of the viral decline slope during antiviral therapy in the peripheral blood, irrespective of the presence of CTL in Simian Immunodeficiency Virus (SIV)-infected macaques, under the assumption that CTL-mediated lysis significantly contributes to virus suppression. Second, it can account for the relatively long times it takes for CTL escape mutants to emerge during chronic infection even if CTL-mediated lysis is responsible for virus suppression. The reason is the heterogeneity in CTL activity and the consequent heterogeneity in selection pressure between the follicular and extrafollicular compartments. Hence, to understand HIV dynamics more thoroughly, this analysis highlights the importance of measuring virus populations separately in the extrafollicular and follicular compartments rather than using virus load in peripheral blood as an observable; this hides the heterogeneity between compartments that might be responsible for the particular patterns seen in the dynamics and evolution of the HIV in vivo.
SARS-CoV-2 lineage assignments using phylogenetic placement/UShER are superior to pangoLEARN machine-learning method
Authors: de Bernardi Schneider Adriano , Su Michelle , Hinrichs Angie S , Wang Jade , Amin Helly , Bell John , Wadford Debra A , O’Toole Áine , Scher Emily , Perry Marc D , Turakhia Yatish , De Maio Nicola , Hughes Scott , Corbett-Detig Russ
Published: January 2024

With the rapid spread and evolution of SARS-CoV-2, the ability to monitor its transmission and distinguish among viral lineages is critical for pandemic response efforts. The most commonly used software for the lineage assignment of newly isolated SARS-CoV-2 genomes is pangolin, which offers two methods of assignment, pangoLEARN and pUShER. PangoLEARN rapidly assigns lineages using a machine-learning algorithm, while pUShER performs a phylogenetic placement to identify the lineage corresponding to a newly sequenced genome. In a preliminary study, we observed that pangoLEARN (decision tree model), while substantially faster than pUShER, offered less consistency across different versions of pangolin v3. Here, we expand upon this analysis to include v3 and v4 of pangolin, which moved the default algorithm for lineage assignment from pangoLEARN in v3 to pUShER in v4, and perform a thorough analysis confirming that pUShER is not only more stable across versions but also more accurate. Our findings suggest that future lineage assignment algorithms for various pathogens should consider the value of phylogenetic placement.
Oxaloacetic acid induces muscle energy substrate depletion and fatigue by JNK‐mediated mitochondrial uncoupling
Authors: Yin Cong , Qin Rui , Ma Zewei , Li Fan , Liu Jiao , Liu Hong , Shu Gang , Xiong Hairong , Jiang Qingyan
Published: January 2024

Fatigue is a common phenomenon closely related to physical discomfort and numerous diseases, which is severely threatening the life quality and health of people. However, the exact mechanisms underlying fatigue are not fully characterized. Herein, we demonstrate that oxaloacetic acid (OAA), a crucial tricarboxylic acid cycle intermediate, modulates the muscle fatigue. The results showed that serum OAA level was positively correlated with fatigue state of mice. OAA‐treated induced muscle fatigue impaired the exercise performance of mice. Mechanistically, OAA increased the c‐Jun N‐terminal kinase (JNK) phosphorylation and uncoupling protein 2 (UCP2) levels in skeletal muscle, which led to decreased energy substrate and enhanced glycolysis. On the other hand, OAA boosted muscle mitochondrial oxidative phosphorylation uncoupled with energy production. In addition, either UCP2 knockout or JNK inhibition totally reversed the effects of OAA on skeletal muscle. Therein, JNK mediated UCP2 activation with OAA‐treated. Our studies reveal a novel role of OAA in skeletal muscle metabolism, which would shed light on the mechanism of muscle fatigue and weakness.
Immunothrombolytic monocyte-neutrophil axes dominate the single-cell landscape of human thrombosis
Authors: Pekayvaz Kami , Joppich Markus , Brambs Sophia , Knottenberg Viktoria , Eivers Luke , Martinez-Navarro Alejandro , Kaiser Rainer , Meißner Nina , Kilani Badr , Stockhausen Sven , Janjic Aleksandar , Polewka Vivien , Wendler Franziska , Droste zu Senden Augustin , Leunig Alexander , Voelkl Michael , Engelmann Bernd , Hernandez Petzsche Moritz R , Boeckh-Behrens Tobias , Liebig Thomas , Dichgans Martin , Enard Wolfgang , Zimmer Ralf , Tiedt Steffen , Massberg Steffen , Nicolai Leo , Stark Konstantin
Published: January 2024

Abstract

Thrombotic diseases remain the major cause of death and disability worldwide with insufficient preventive and therapeutic strategies available. In the last decades a prominent inflammatory component has been identified as a key driver in the initiation and propagation of thrombosis – named thromboinflammation. However, a comprehensive investigation of the human immune system in thromboinflammation, beyond histological quantification, is lacking, which is essential for the development of novel therapeutic approaches. We therefore mapped the trajectories, functional states, and intercommunication of immune cells in stroke thrombi, retrieved by thrombectomy, at single-cell resolution. We reveal distinct leukocyte subpopulations with prothrombotic and, surprisingly, prominent fibrinolytic properties characterized by aberrant activation of intracellular host defense as well as hypoxia induced pathways. A prominent thrombolytic PLAUhigh, PLAURhigh, THBDhighthrombus neutrophil subset, also expressing high levels of pro-recanalizing VEGFA and VEGFB, dominated the thrombus neutrophil environment. On the other hand CD16highNR4A1highnon-classical monocytes with strong CXCL8, CXCL2, CXCL1 and CXCL16 mediated neutrophil- attracting and PLAU, PLAUR, THBD and TFPI mediated thrombolytic properties defined the thrombus monocyte environment. These thrombus monocyte subsets were characterized by high expression of TIMP1 and TREM1. These novel innate immune- cell subsets provide insights into the thrombogenic and pro-resolving properties of innate immune-cells. To provide mechanistic insight into these multi-omic findings, we utilized reverse translation approaches.In vitroas well as murinein vivothrombosis models underlined the causal relevance of these immune-cell axes for thrombolysis: NR4A1highthrombus monocytes acquired a neutrophil-chemoattractive transcriptomic phenotype, neutrophils continuously infiltrated established murine thrombiin vivoand acquired a HIF1α-mediated thrombolytic phenotypein vitro. A depletion of NR4A1highthrombus monocytes reduced thrombus neutrophil influx and exacerbated thrombosisin vivo.

Together, this unravels cross-communicating monocyte and neutrophil subsets with thrombus-resolving properties and provide a publicly accessible immune-landscape of thrombosis. This provides a valuable resource for future research on thrombo- inflammation and might pave the way for novel immune-modulatory approaches for prevention or resolution of thrombosis.
Spiking Neuron-Astrocyte Networks for Image Recognition
Authors: Lorenzo Jhunlyn , Rico-Gallego Juan-Antonio , Binczak Stéphane , Jacquir Sabir
Published: January 2024

From biological and artificial network perspectives, researchers have started acknowledging astrocytes as computational units mediating neural processes. Here, we propose a novel biologically-inspired neuron-astrocyte network model for image recognition, one of the first attempts at implementing astrocytes in Spiking Neuron Networks (SNNs) using a standard dataset. The architecture for image recognition has three primary units: the pre-processing unit for converting the image pixels into spiking patterns, the neuron-astrocyte network forming bipartite (neural connections) and tripartite synapses (neural and astrocytic connections), and the classifier unit. In the astrocyte-mediated SNNs, an astrocyte integrates neural signals following the simplified Postnov model. It then modulates the Integrate-and-Fire (IF) neurons via gliotransmission, thereby strengthening the synaptic connections of the neurons within the astrocytic territory. We develop an architecture derived from a baseline SNN model for unsupervised digit classification. The Spiking Neuron-Astrocyte Networks (SNANs) display better network performance with an optimal variance-bias trade-off than SNN alone. We demonstrate that astrocytes promote faster learning, support memory formation and recognition, and provide a simplified network architecture. Our proposed SNAN can serve as a benchmark for future researchers on astrocyte implementation in artificial networks, particularly in neuromorphic systems, for its simplified design.
Dynamic coexistence driven by physiological transitions in microbial communities
Authors: Narla Avaneesh V. , Hwa Terence , Murugan Arvind
Published: January 2024

Abstract

Microbial ecosystems are commonly modeled by fixed interactions between species in steady exponential growth states. However, microbes often modify their environments so strongly that they are forced out of the exponential state into stressed or non-growing states. Such dynamics are typical of ecological succession in nature and serial-dilution cycles in the laboratory. Here, we introduce a phenomenological model, the Community State model, to gain insight into the dynamic coexistence of microbes due to changes in their physiological states. Our model bypasses specific interactions (e.g., nutrient starvation, stress, aggregation) that lead to different combinations of physiological states, referred to collectively as “community states”, and modeled by specifying the growth preference of each species along a global ecological coordinate, taken here to be the total community biomass density. We identify three key features of such dynamical communities that contrast starkly with steady-state communities: increased tolerance of community diversity to fast growth rates of species dominating different community states, enhanced community stability through staggered dominance of different species in different community states, and increased requirement on growth dominance for the inclusion of late-growing species. These features, derived explicitly for simplified models, are proposed here to be principles aiding the understanding of complex dynamical communities. Our model shifts the focus of ecosystem dynamics from bottom-up studies based on idealized inter-species interaction to top-down studies based on accessible macroscopic observables such as growth rates and total biomass density, enabling quantitative examination of community-wide characteristics.
Idiosyncratic pupil regulation in autistic children
Authors: Bleimeister Isabel , Avni Inbar , Granovetter Michael , Meiri Gal , Ilan Michal , Michaelovski Analya , Menashe Idan , Behrmann Marlene , Dinstein Ilan
Published: January 2024

Recent neuroimaging and eye tracking studies have suggested that children with autism spectrum disorder (ASD) may exhibit more variable and idiosyncratic brain responses and eye movements than typically developing (TD) children. Here we extended this research for the first time to pupillometry recordings. We successfully completed pupillometry recordings with 103 children (66 with ASD), 4.5-years-old on average, who viewed three 90 second movies, twice. We extracted their pupillary time-course for each movie, capturing their stimulus evoked pupillary responses. We then computed the correlation between the time-course of each child and those of all others in their group. This yielded an average inter-subject correlation value per child, representing how similar their pupillary responses were to all others in their group. ASD participants exhibited significantly weaker inter-subject correlations than TD participants, reliably across all three movies. Differences across groups were largest in responses to a naturalistic movie containing footage of a social interaction between two TD children. This measure enabled classification of ASD and TD children with a sensitivity of 0.82 and specificity of 0.73 when trained and tested on independent datasets. Using the largest ASD pupillometry dataset to date, we demonstrate the utility of a new technique for measuring the idiosyncrasy of pupil regulation, which can be completed even by young children with co-occurring intellectual disability. These findings reveal that a considerable subgroup of ASD children have significantly more unstable, idiosyncratic pupil regulation than TD children, indicative of more variable, weakly regulated, underlying neural activity.
Prospective validation of a seizure diary forecasting falls short
Authors: Goldenholz Daniel M. , Eccleston Celena , Moss Robert , Westover M. Brandon
Published: January 2024

OBJECTIVE

Recently, a deep learning AI model forecasted seizure risk using retrospective seizure diaries with higher accuracy than random forecasts. The present study sought to prospectively evaluate the same algorithm.

METHODS

We recruited a prospective cohort of 46 people with epilepsy; 25 completed sufficient data entry for analysis (median 5 months). We used the same AI method as in our prior study. Group-level and individual-level Brier Skill Scores (BSS) compared random forecasts and simple moving average forecasts to the AI.

RESULTS

The AI had an AUC of 0.82. At the group level, the AI outperformed random forecasting (BSS=0.53). At the individual level, AI outperformed random in 28% of cases. At the group and individual level, the moving average outperformed the AI. If pre-enrollment (non-verified) diaries (with presumed under-reporting) were included, the AI significantly outperformed both comparators. Surveys showed most did not mind poor quality LOW-RISK or HIGH-RISK forecasts, yet 91% wanted access to these forecasts.

SIGNIFICANCE

The previously developed AI forecasting tool did not outperform a very simple moving average forecasting this prospective cohort, suggesting that the AI model should be replaced.

Key points

A previously developed e-diary based AI seizure forecasting tool was prospectively tested. Although by some metrics the tool was successful, the overall AI performance was unacceptably low.

It was much easier to outperform a random forecast; it was much harder to outperform a moving average forecast.

Using unverified diaries can skew forecasting metrics in favor of underperforming tools.
Neural Network-Assisted Humanization of COVID-19 Hamster scRNAseq Data Reveals Matching Severity States in Human Disease
Authors: Friedrich Vincent D , Pennitz Peter , Wyler Emanuel , Adler Julia M , Postmus Dylan , Alves Luiz Gustavo Teixeira , Prigann Julia , Pott Fabian , Vladimirova Daria , Hoefler Thomas , Goekeri Cengiz , Landthaler Markus , Goffinet Christine , Saliba Antoine-Emmanuel , Scholz Markus , Witzenrath Martin , Trimpert Jakob , Kirsten Holger , Nouailles Geraldine
Published: January 2024

Translating findings from animal models to human disease is essential for dissecting disease mechanisms, developing and testing precise therapeutic strategies. The coronavirus disease 2019 (COVID-19) pandemic has highlighted this need, particularly for models showing disease severity-dependent immune responses. Single-cell transcriptomics (scRNAseq) is well poised to reveal similarities and differences between species at the molecular and cellular level with unprecedented resolution. However, computational methods enabling detailed matching are still scarce. Here, we provide a structured scRNAseq-based approach that we applied to scRNAseq from blood leukocytes originating from humans and hamsters affected with moderate or severe COVID-19. Integration of COVID-19 patient data with two hamster models that develop moderate (Syrian hamster,Mesocricetus auratus) or severe (Roborovski hamster,Phodopus roborovskii) disease revealed that most cellular states are shared across species. A neural network-based analysis using variational autoencoders quantified the overall transcriptomic similarity across species and severity levels, showing highest similarity between neutrophils of Roborovski hamsters and severe COVID-19 patients, while Syrian hamsters better matched patients with moderate disease, particularly in classical monocytes. We further used transcriptome-wide differential expression analysis to identify which disease stages and cell types display strongest transcriptional changes. Consistently, hamster’s response to COVID-19 was most similar to humans in monocytes and neutrophils. Disease-linked pathways found in all species specifically related to interferon response or inhibition of viral replication. Analysis of candidate genes and signatures supported the results. Our structured neural network-supported workflow could be applied to other diseases, allowing better identification of suitable animal models with similar pathomechanisms across species.

Key Points

Neural networks can successfully match disease states between animal models and humans using single-cell data as shown for COVID-19

Moderately diseased patients best matched Syrian hamster cells; severely diseased patients best matched Roborovski hamster neutrophils
Analgesic targets identified in mouse sensory neuron somata and terminal pain translatomes
Authors: Bangash M. Ali , Cubuk Cankut , Iseppon Federico , Haroun Rayan , Luiz Ana P. , Arcangeletti Manuel , Gossage Samuel J. , Santana-Varela Sonia , Cox James J. , Lewis Myles J. , Wood John N. , Zhao Jing
Published: January 2024

The relationship between transcription and protein expression is complex. We identified polysome-associated RNA transcripts in the somata and central terminals of mouse sensory neurons in control, painful (+ Nerve Growth Factor (NGF)) and pain-free conditions (Nav1.7 null mice). The majority (98%) of translated transcripts are shared between male and female mice in both the somata and terminals. Some transcripts are highly enriched in the somata or terminals. Changes in the translatome in painful and pain-free conditions include novel and known regulators of pain pathways. Antisense knockdown of selected somatic and terminal polysome-associated transcripts that correlate with pain states diminished pain behaviour. Terminal-enriched transcripts encoding synaptic proteins (e.g. Synaptotagmin), non-coding RNAs, transcription factors (e.g. Znf431), proteins associated with trans-synaptic trafficking (HoxC9), GABA generating enzymes (Gad1 and Gad2) and neuropeptides (Penk). Thus, central terminal translation may well be a significant regulatory locus for peripheral input from sensory neurons.
EMG-to-torque models for exoskeleton assistance: a framework for the evaluation ofin situcalibration
Authors: Quesada Lucas , Verdel Dorian , Bruneau Olivier , Berret Bastien , Amorim Michel-Ange , Vignais Nicolas
Published: January 2024

In the field of robotic exoskeleton control, it is critical to accurately predict the intention of the user. While surface electromyography (EMG) holds the potential for such precision, current limitations arise from the absence of robust EMG-to-torque model calibration procedures and a universally accepted model. This paper introduces a practical framework for calibrating and evaluating EMG-to-torque models, accompanied by a novel nonlinear model. The framework includes anin situprocedure that involves generating calibration trajectories and subsequently evaluating them using standardized criteria. A comprehensive assessment on a dataset with 17 participants, encompassing single-joint and multi-joint conditions, suggests that the novel model outperforms the others in terms of accuracy while conserving computational efficiency. This contribution introduces an efficient model and establishes a versatile framework for EMG-to-torque model calibration and evaluation, complemented by a dataset made available. This further lays the groundwork for future advancements in EMG-based exoskeleton control and human intent detection. This work has been submitted to the IEEE for possible publication. Copyright may be transferred without notice, after which this version may no longer be accessible.
Response-locked theta dissociations reveal potential feedback signal following successful retrieval
Authors: Smith Devyn E. , Wheelock Justin R. , Long Nicole M.
Published: January 2024

Successful memory retrieval relies on memory processes to access an internal representation and decision processes to evaluate and respond to the accessed representation, both of which are supported by fluctuations in theta (4-8Hz) activity. However, the extent to which decision making processes are engaged following a memory response is unclear. Here, we recorded scalp electroencephalography (EEG) while human participants performed a recognition memory task. We focused on response-locked data, allowing us to investigate the processes that occur prior to and following a memory response. We replicate previous work and find that prior to a memory response theta power is greater for identification of previously studied items (hits) relative to rejection of novel lures (correct rejections; CRs). Following the memory response, the theta power dissociation ‘flips’ whereby theta power is greater for CRs relative to hits. We find that the post-response ‘flip’ is more robust for hits that are committed quickly, potentially reflecting a positive feedback signal for strongly remembered experiences. Our findings suggest that there are potentially distinct processes occurring before and after a memory response that are modulated by successful memory retrieval.
Erroneous compensation for long-latency feedback delays as origin of Essential Tremor Running title: Erroneous delay compensation as origin of ET
Authors: Blondiaux Florence , Colmant Lise , Lebrun Louisien , Hanseeuw Bernard , Crevecoeur Frédéric
Published: January 2024

Essential tremor (ET), a movement disorder characterized by involuntary oscillations of the limbs during movement, remains to date not well understood. It has been recently suggested that the tremor originates from impaired delay compensation, affecting movement representation and online control. Here we tested this hypothesis directly with ET patients (N=24) and neurologically intact (NI) volunteers (N=28) in an upper limb postural perturbation task. After maintaining their hand in a visual target, participants experienced perturbations of unpredictable direction and magnitude, and were instructed to counter the perturbation and steer their hand back to the starting position. In comparison with NI volunteers, ET patients’ early muscular responses (Short and Long-Latency Responses, 20-50 ms and 50-100 ms respectively) were preserved or even slightly increased. However, they exhibited perturbation-dependent deficits when stopping and stabilizing their hand in the final target supporting the hypothesis that the tremor was generated by the feedback controller. We show in a computational model that errors in delay compensation accumulating over time produced the same small increase in initial feedback response followed by oscillations that scaled with the perturbation magnitude as observed in ET population. Our experimental results therefore validate the computational hypothesis that inaccurate delay compensation in long-latency pathways could be the origin of the tremor.

Significance Statement

Essential Tremor origin remains poorly understood. In the present study, we focused on motor impairments associated with feedback control. Following a mechanical perturbation applied to their arm, patients’ short and initial long-latency stretch responses were preserved. However, we observed clear impairments during the stabilization phase that scaled with the perturbation magnitude. These results were reproduced in a computational model where delay compensation was inaccurate, suggesting that the origin of the tremor may lie in an underestimation of the delays impacting the internal monitoring of the motor commands.

Conflict of interest

The authors declare no competing financial interests.
Subtle, but Perceptible, Sexual Dichromatism and Disassortative Mating Based on Plumage Reflectance in Black Terns (Chlidonias niger)
Authors: Baldassarre Daniel T. , Davis Kristina M. , Shealer David A.
Published: January 2024

In birds, sexual selection on plumage often leads to sexual dichromatism and male ornamentation. However, even in drab species with no obvious sexual dichromatism, both sexes may still use plumage for mate choice. A previous study found weak sexual size dimorphism in North American Black Terns (Chlidonias niger surinamensis), but no assortative mating based on morphology. However, the relevance of plumage variation to mate choice is yet untested. Here, using reflectance spectrometry and avian visual modeling revealed that Black Tern males and females exhibited a subtle but significant difference in brightness (males darker). Importantly, the achromatic contrast between the sexes should be perceptible during mate choice. Moreover, there was evidence of disassortative mating for plumage color, but not brightness: more black and saturated birds paired with more gray and unsaturated birds. There was no relationship between plumage color or brightness and body mass. This finding suggests that visual signals unrelated to body condition may be relevant to Black Tern mate choice. The pattern of disassortative mating was unexpected, and potential benefits of choosing a mate dissimilar from oneself are discussed. This study highlights the importance of considering the avian visual system when studying plumage variation elusive to human observers.
RiboGraph: An interactive visualization system for ribosome profiling data at read length resolution
Authors: Chacko Jonathan , Ozadam Hakan , Cenik Can
Published: January 2024

Ribosome profiling is a widely-used technique for measuring ribosome occupancy at nucleotide resolution. However, the need to analyze this data at nucleotide resolution introduces unique challenges in data visualization and analyses. In this study, we introduce RiboGraph, a dedicated visualization tool designed to work with .ribo files, a specialized and efficient format for ribosome occupancy data. Unlike existing solutions that rely on large alignment files and time-consuming preprocessing steps, RiboGraph operates on a purpose designed compact file type and eliminates the need for data preprocessing. This efficiency allows for interactive, real-time visualization at ribosome-protected fragment length resolution. By providing an integrated toolset, RiboGraph empowers researchers to conduct comprehensive visual analysis of ribosome occupancy data.

Availability and Implementation

Source code, step-by-step installation instructions and links to documentation are available on GitHub:https://github.com/ribosomeprofiling/ribograph. On the same page, we provide test files and a step-by-step tutorial highlighting the key features of RiboGraph.
Timing and Amplitude of Catch-up Saccades to Accelerating Targets
Authors: Doré Sydney , Coutinho Jonathan , Brooks Emma , Khan Aarlenne Z , Lefèvre Philippe , Blohm Gunnar
Published: January 2024

To track moving targets, humans move their eyes using both saccades and smooth pursuit. If pursuit eye movements fail to accurately track the moving target, catch-up saccades are initiated to rectify the tracking error. It is well known that retinal position and velocity errors determine saccade timing and amplitude, but the extent to which retinal acceleration error influences these aspects is not well quantified. To test this, 13 adult human participants performed an experiment where they pursued accelerating / decelerating targets. During ongoing pursuit, we introduced a randomly sized target step to evoke a catch-up saccade and analyzed its timing and amplitude. We observed that retinal acceleration error was a statistically significant predictor of saccade amplitude and timing. A multiple linear regression supported our hypothesis that retinal acceleration errors influence saccade amplitude in addition to the influence of retinal position and velocity errors. We also found that saccade latencies were shorter when retinal acceleration error increased the tracking error and vice versa. In summary, our findings support a model in which retinal acceleration error is used to compute a predicted position error ∼100ms into the future to trigger saccades and determine saccade amplitude.

Significance statement

When visually tracking object motion, humans combine smooth pursuit and saccadic eye movements to maintain the target image on the fovea. Retinal position and velocity errors are known to determine catch-up saccade amplitude and timing, however it is unknown if retinal acceleration error is also used to predict future target position. This study provides evidence of a small but statistically significant contribution of retinal acceleration error in determining saccade amplitude and timing.
A mass cytometry approach to track the evolution of T cell responses during infection and immunotherapy by paired T cell receptor repertoire and T cell differentiation state analysis
Authors: Castillo Jesse Garcia , DeBarge Rachel , Mende Abigail , Tenvooren Iliana , Marquez Diana M. , Straub Adrian , Busch Dirk H. , Spitzer Matthew H. , DuPage Michel
Published: January 2024

T cell receptor (TCR) recognition followed by clonal expansion is a fundamental feature of adaptive immune responses. Here, we developed a mass cytometric (CyTOF) approach combining antibodies specific for different TCR Vα– and Vβ-chains with antibodies against T cell activation and differentiation proteins to identify antigen-specific expansions of T cell subsets and assess aspects of cellular function. This strategy allowed for the identification of expansions of specific Vβ and Vα chain expressing CD8+and CD4+T cells with varying differentiation states in response toListeria monocytogenes, tumors, and respiratory influenza infection. Expanded Vβ chain expressing T cells could be directly linked to the recognition of specific antigens fromListeria, tumor cells, or influenza. In the setting of influenza infection, we showed that the common therapeutic approaches of intramuscular vaccination or convalescent serum transfer altered the clonal diversity and differentiation state of responding T cells. Thus, we present a new method to monitor broad changes in TCR specificity paired with T cell differentiation during adaptive immune responses.
Incorporating temporal information during feature engineering bolsters emulation of spatio-temporal emergence
Authors: Cain Jason Y. , Evarts Jacob I. , Yu Jessica S. , Bagheri Neda
Published: January 2024

Motivation

Emergent biological dynamics derive from the evolution of lower-level spatial and temporal processes. A long-standing challenge for scientists and engineers is identifying simple low-level rules that give rise to complex higher-level dynamics. High-resolution biological data acquisition enables this identification and has evolved at a rapid pace for both experimental and computational approaches. Simultaneously harnessing the resolution and managing the expense of emerging technologies—e.g. live cell imaging, scRNAseq, agent-based models—requires a deeper understanding of how spatial and temporal axes impact biological systems. Effective emulation is a promising solution to manage the expense of increasingly complex high-resolution computational models. In this research, we focus on the emulation of a tumor microenvironment agent-based model to examine the relationship between spatial and temporal environment features, and emergent tumor properties.

Results

Despite significant feature engineering, we find limited predictive capacity of tumor properties from initial system representations. However, incorporating temporal information derived from intermediate simulation states dramatically improves the predictive performance of machine learning models. We train a deep-learning emulator on intermediate simulation states and observe promising enhancements over emulators trained solely on initial conditions. Our results underscore the importance of incorporating temporal information in the evaluation of spatio-temporal emergent behavior. Nevertheless, the emulators exhibit inconsistent performance, suggesting that the underlying model characterizes unique cell populations dynamics that are not easily replaced.

Availability

All source codes for the agent-based model, emulation, and analyses are publicly available atgithub.com/bagherilab/ARCADE,github.com/bagherilab/emulation, andgithub.com/bagherilab/emulation_analysis, respectively.

Contact

nbagheri@uw.edu
Secreted Particle Information Transfer (SPIT) – A Cellular Platform forIn VivoGenetic Engineering
Authors: Charlesworth Carsten T. , Homma Shota , Suchy Fabian , Wang Sicong , Bhadhury Joydeep , Amaya Anais K. , Camarena Joab , Zhang Jinyu , Tan Tze Kai , Igarishi Kyomi , Nakauchi Hiromitsu
Published: January 2024

A multitude of tools now exist that allow us to precisely manipulate the human genome in a myriad of different ways. However, successful delivery of these tools to the cells of human patients remains a major barrier to their clinical implementation. Here we introduce a new cellular approach forin vivogenetic engineering,SecretedParticleInformationTransfer (SPIT) that utilizes human cells as delivery vectors forin vivogenetic engineering. We demonstrate the application of SPIT for cell-cell delivery of Cre recombinase and CRISPR-Cas9 enzymes, we show that genetic logic can be incorporated into SPIT and present the first demonstration of human cells as a delivery platform forin vivogenetic engineering in immunocompetent mice. We successfully applied SPIT to genetically modify multiple organs and tissue stem cellsin vivoincluding the liver, spleen, intestines, peripheral blood, and bone marrow. We anticipate that by harnessing the large packaging capacity of a human cell’s nucleus, the ability of human cells to engraft into patients’ long term and the capacity of human cells for complex genetic programming, that SPIT will become a paradigm shifting approach forin vivogenetic engineering.