bluuebunny/crossref_metadata_2025 huggingface dataset:
A Comparative assessment of T-Cell response of Healthy donors and Acute Graft-versus-Host-Disease Patients: Customizing immune monitoring platform
Authors: Mendiratta Mohini , Mendiratta Meenakshi , Rai Sandeep , Gupta Ritu , Bakhshi Sameer , Aggarwal Mukul , Gupta Aditya Kumar , Prakash Hridayesh , Mohanty Sujata , Sahoo Ranjit Kumar
Published: September 2024

Background

T-cell activation and proliferation are critical for understanding immune responses in both healthy and pathological conditions such as acute graft-versus-host disease (aGVHD). Phytohemagglutinin (PHA) and interleukin-2 (IL-2) are commonly used in in vitro assays to study T-cell responses. In view of the discrete response of T cells from aGvHD patient’s cohorts, our study optimized PHA / IL-2 based T-cell response among healthy individuals versus aGVHD patients.

Methods

Peripheral blood was collected from age- and sex-matched healthy individuals (n=10) and aGVHD patients (n=10). CD3+T-cell were isolated and stimulated with varying concentrations of PHA (1-10μg/ml) and IL-2 (50-500 IU/ml). Cell proliferation was assessed using MTS and CFSE assays, while their apoptosis was evaluated with Annexin V/7-AAD staining.

Results

We observed enhanced proliferation of healthy individuals at higher PHA concentrations (5-10μg/ml), whereas aGVHD patients exhibited heightened proliferation even at lower PHA concentrations (1-2.5μg/ml) at 48 hours. Prolonged exposure of T cells from GvHD patients to PHA led to decreased proliferation while it increased in the T cells from healthy donors.IL-2 supplementation (50 IU/ml) of T-cells from healthy donors significantly enhanced their proliferation and survival, with the optimal concentration supporting robust proliferation over extended culture periods.

Conclusion

Our study optimized PHA and IL-2 concentrations required for T-cell proliferation studies among healthy individuals and aGVHD patients. and underscored experimental conditions required for studying T-cell behavior/dysregulation in aGVHD condition.

GRAPHICAL ABSTRACT

Highlights of the study

Lower doses of PHA (1.0μg/ml) and IL-2 (50IU/ml) are optimum conditions for aGVHD patients derived CD3+ T-cell proliferation underin vitroconditions.

The maximum T-cell proliferation in healthy individuals occurs with 7.5μg/ml PHA and 50IU/ml IL-2.

Higher doses of PHA induce cytotoxicity in both cohorts.

IL-2 significantly enhances T-cell survival, with 50IU/ml maintaining robust proliferation over extended periods.
Environmental Impacts of Serum-free Food-grade and Complex Culture Medium Production for Cultivated Meat
Authors: Takenaka Natsufumi , Hong-Mitsui Kimiko , Kunimasa Kazuhiro , Kawajiri Kotaro , Kayo Chihiro , Yoshikawa Naoki
Published: September 2024

Cultivated meat is an alternative meat produced via cell culture. The culture medium accounts for most of the environmental impact of cultivated meat production. This study quantitatively evaluated and analyzed the environmental impact of serum-free food-grade and complex culture medium production for cultivated meat by performing a life cycle assessment (LCA) based on activity data at the laboratory scale. In addition, specific measures were proposed to reduce the environmental impact further. LCAs were performed at current and future production scales. This study also evaluated the impact of multiple electricity sources on the environmental impact of culture-medium production. Expendables at the current scale, as well as electricity and animal-derived materials at both scales, are hotspots in the environmental impact of this culture-medium production. Among these components, the production of serum substitutes accounts for most of the environmental impact. As the scale shifts, the environmental impacts are expected to decrease by 11.3%–93.2% in all impact categories. As the composition of electricity sources changed, the impact on certain categories decreased. However, as the share of renewable energy increased, the impact on land use also increased significantly. This study promotes the practical application of new culture media for low-cost and low-environment-impact cultivated meat.

Graphical abstract

SYNOPSIS. This study evaluates the environmental impact of culture-medium production for cultivated meat and reports that electricity, animal-derived materials, and expendables are hotspots of this impact.
Discovery of novel 1,4-dicarbonylthiosemicarbazides as DNA gyrase inhibitors for the treatment of MRSA infection
Authors: Zhang Gao , Liang Jiaxin , Wen Gang , Yao Mingli , Jia Yuqing , Feng Bo , Li Jishun , Han Zunsheng , Liu Qingxin , Li Tianlei , Zhang Wenxuan , Jin Hongwei , Xia Jie , Peng Liang , Wu Song
Published: September 2024

Antibiotic resistance has become a serious threat to public health, thus novel antibiotics are urgently needed to combat drug-resistant bacteria including MRSA (methicillin-resistantS. aureus). The 1,4-dicarbonylthiosemicarbazide is an interesting chemotype that could exhibit antibacterial activity. However, the currently available compounds are not as potent as clinical antibiotics. Herein, we adopted the computer-aided drug design strategy, substructure search, to retrieve antibacterial 1,4-dicarbonylthiosemicarbazide derivatives, and identified compoundB5(Specs ID: AG-690/15432331) from the Specs chemical library that exhibited moderate activity (minimum inhibitory concentration (MIC): 6.25 µg/mL) againstS. aureus(ATCC 29213). Based on that compound, we further designed and synthesized 45 derivatives, and evaluated their antibacterial activity. Eight derivatives were more potent than or equivalent to vancomycin (MIC: 1.56 µg/mL). We compared the three most potent ones for their cytotoxicity to HepG2 and HUVEC cells and selected compound1bas our lead compound for comprehensive biological evaluation. As a result, compound1bexhibited a bacteriostatic mode, and was active against a panel of gram-positive bacteria strains, metabolically stable, and effective to protect the mice from MRSA infection. More importantly, we applied 2D similarity calculation and reverse docking to predict potential targets of compound1b. Through experimental validation and molecular dynamics simulation, we were able to confirm that compound1binhibitedS. aureusDNA gyrase (IC50: 1.81 µM) and DNA supercoiling, potentially by binding to the ATPase domain, where ASP81, GLU58 and GLN91 formed key hydrogen bonds. Taken together, we have discovered a new class of DNA gyrase inhibitors represented by compound1bfor the treatment of MRSA infection, through the design, synthesis, and biological evaluation of novel 1,4-dicarbonylthiosemicarbazides.

Graphic Abstract

Highlights

An interesting 1,4-dicarbonylthiosemicarbazide derivativeB5with moderate antibacterial activity forS. aureuswas discovered by substructure search.

Based onB5, 45 new 1,4-dicarbonylthiosemicarbazides were designed, synthesized and biologically evaluated, which led to the discovery of a promising lead compound1b.

Compound1bexhibited good antibacterial activity for a panel of gram-positive bacteria strains, and was effective to protect mice from MRSA infection.

The 1,4-dicarbonylthiosemicarbazides represented by compound1bwere discovered as a new class of DNA gyrase inhibitors, by target prediction and experimental validation.
Comparative analysis of transcriptomic and proteomic expression between two non-small cell lung cancer subtypes
Authors: Nicholas Ben , Bailey Alistair , McCann Katy J , Johnson Peter , Elliott Tim , Ottensmeier Christian , Skipp Paul
Published: September 2024

Non-small cell lung cancer (NSCLC) is frequently diagnosed at an advanced stage and has poor survival. NSCLC subtypes require different treatment regimes, hence there are extensive efforts to find more precise and non-invasive differential diagnostics tools. Complementing these efforts, we examined two NSCLC subtypes for differences that may inform treatment options and identify potential novel therapeutic pathways.

Here we present a comparative analysis of transcriptomic and proteomic expression in tumours from a cohort of 22 NSCLC patients: 8 squamous cell carcinoma (LUSC), 14 adenocarcinoma (LUAD). We examined differential gene and differential protein expression between LUSC and LUAD, and between NSCLC subtypes and either PBMCs or normal adjacent lung tissue (NAT).

We found that both NSCLC subtypes shared common differences in gene expression to PBMC relating to developmental and structural changes, and common protein expression differences to NAT relating to protein translation and RNA related processing and splicing.

Between NSCLC subtypes we found differential gene expression relating to cell differentiation for LUSC and cellular structure and immune response regulation for LUAD. Differential protein expression between NSCLC subtypes related to extracellular structure for LUSC and metabolic processes, including glucose metabolism for LUAD.

Many of our observations of differentially expressed genes and proteins between NSCLC subtypes support and inform existing observations, aiding both basic and clinical research seeking to identify subtype biomarkers or druggable targets.
Uncertainty in cardiovascular digital twins despite non-normal errors in 4D flow MRI: identifying reliable biomarkers such as ventricular relaxation rate
Authors: Tunedal Kajsa , Ebbers Tino , Cedersund Gunnar
Published: September 2024

Cardiovascular digital twins and mechanistic models can be used to obtain new biomarkers from patient-specific hemodynamic data. However, such model-derived biomarkers are only clinically relevant if the variation between timepoints/patients is smaller than the uncertainty of the biomarkers. Unfortunately, this uncertainty is challenging to calculate, as the uncertainty of the underlying hemodynamic data is largely unknown and has several sources that are not additive or normally distributed. This violates normality assumptions of current methods; implying that also biomarkers have an unknown uncertainty. To remedy these problems, we herein present a method, with attached code, for uncertainty calculation of model-derived biomarkers using non-normal data. First, we estimated all sources of uncertainty, both normal and non-normal, in hemodynamic data used to personalize an existing model; the errors in 4D flow MRI-derived stroke volumes were 5-20% and the blood pressure errors were 0±8 mmHg. Second, we estimated the resulting model-derived biomarker uncertainty for 100 simulated datasets, sampled from the data distributions, by: 1) combining data uncertainties 2) parameter estimation, 3) profile-likelihood. The true biomarker values were found within a 95% confidence interval in 98% (median) of the cases. This shows both that our estimated data uncertainty is reasonable, and that we can use profile-likelihood despite the non-normality. Finally, we demonstrated that e.g. ventricular relaxation rate has a smaller uncertainty (∼10%) than the variation across a clinical cohort (∼40%), meaning that these biomarkers have clinical usefulness. Our results take us one step closer to the usage of model-derived biomarkers for cardiovascular patient characterization.

Highlights

Digital twin models provide physiological biomarkers using e.g. 4D-flow MRI data

However, the data has several non-normal uncertainty components

For this reason, we do not know which biomarkers are reliable and clinically useful

New method for data uncertainty and for calculation of biomarker uncertainty

We identified several reliable biomarkers: e.g. ventricular relaxation rate

Graphical abstract
Time-on-task-related decrements in performance in the rodent continuous performance test are not caused by physical disengagement from the task
Authors: Li Ye , van Kralingen Thomas , Masi Megan , Villaneuva Sanchez Brandon , Mitchell Beyonca , Johnson Joshua , Miranda-Barrientos Jorge , Rehg Jason J , Martinowich Keri , Carr Gregory V
Published: September 2024

Attention deficits, a hallmark of many neuropsychiatric disorders, significantly impair quality of life and functional outcome for patients. Continuous Performance Tests (CPTs) are widely used to assess attentional function in clinical settings and have been adapted for mice as the rodent Continuous Performance Test (rCPT). In this study, we combined traditional analyses of rCPT performance with markerless pose estimation using DeepLabCut and visual field analysis (VFA) to objectively measure the orientation of mice toward stimuli during rCPT sessions. Additionally, we extended session lengths to assess performance decrements over time. Our findings show that extending rCPT sessions from 45 to 90 minutes results in a significant decline in performance in male mice, which aligns with performance decrements observed in clinical research. Importantly, physical engagement with the task remained relatively stable throughout the session, even as performance deteriorated. This suggests that the performance decline specifically reflects a time-on-task (TOT)-dependent vigilance decrement rather than physical disengagement. We also investigated the effects of amphetamine, an FDA-approved treatment for attention-deficit/hyperactivity disorder (ADHD), on rCPT performance. Amphetamine significantly improved rCPT performance in male mice by reducing false alarms without modulating orientation or physical engagement with the task stimuli. Collectively, these findings validate a behavioral tracking platform for objectively measuring physical engagement in the rCPT and a task modification that accentuates TOT-dependent performance decrements, enhancing the translational value of the rCPT for studies related to human neuropsychiatric disorders.
A trans-synaptic IgLON adhesion molecular complex directly contacts and clusters a nicotinic receptor
Authors: Mialon Morgane , Patrash Liubov , Weinreb Alexis , Özkan Engin , Bessereau Jean-Louis , Pinan-Lucarre Berangere
Published: September 2024

The localization and clustering of neurotransmitter receptors at appropriate postsynaptic sites is a key step in the control of synaptic transmission. Here, we identify a novel paradigm for the synaptic localization of an ionotropic acetylcholine receptor (AChR) based on the direct interaction of its extracellular domain with a cell adhesion molecule of the IgLON family. Our results show that RIG-5 and ZIG-8, which encode the sole IgLONs inC. elegans,are tethered in the pre- and postsynaptic membranes, respectively, and interactin vivothrough their first immunoglobulin-like (Ig) domains. In addition, ZIG-8 traps ACR-16 via a directcis-interaction between the ZIG-8 Ig2 domain and the base of the large extracellular AChR domain. Such mechanism has never been reported, but all these molecules are conserved during evolution. Similar interactions may directly couple Ig superfamily adhesion molecules and members of the large family of Cys-loop ionotropic receptors, including AChRs, in the mammalian nervous system, and may be relevant in the context of IgLON-associated brain diseases.
Engineered chitosan-derived nanocarrier for efficient siRNA delivery to peripheral and central neurons
Authors: Spencer Ana P. , Vilaça Adriana , Xavier Miguel , Santos Rafael , Ionescu Ariel , Lázaro María , Leiro Victoria , Perlson Eran , Guimarães Sofia C. , Maoz Ben M. , Pêgo Ana P.
Published: September 2024

Gene therapy using small interfering RNA (siRNA) holds promise for treating neurological disorders by silencing specific genes, such as the phosphatase and tensin homolog (PTEN) gene, which restricts axonal growth. Yet, delivering siRNA to neurons efficiently is challenging due to premature degradation and unspecific delivery. Chitosan-based delivery systems have shown great potential due to their well-established biocompatibility. However, their limited transfection efficiency and lack of neuronal tropism require further modification. Building on our previous successes with neuron-targeted DNA delivery using chitosan, a novel approach for siRNA delivery aimed at PTEN downregulation is proposed. This involves using thiolated trimethyl chitosan (TMCSH)-based siRNA nanoparticles functionalized with the neurotropic C-terminal fragment of the tetanus neurotoxin heavy chain (HC) for efficient delivery to both peripheral and central neurons. These polyplexes demonstrated suitable physicochemical properties, biocompatibility, and no adverse effects on neuronal electrophysiology. Diverse neuronal models, including 3Dex vivocultures and microfluidics, confirmed polyplexes’ efficiency and neurospecificity. HC targeting significantly enhanced nanoparticle neuronal binding, and live cell imaging revealed five times faster retrograde transport along axons. Furthermore, siRNA delivery targeting PTEN promoted axonal outgrowth in embryonic cortical neurons. Thus, these polyplexes represent a promising platform for siRNA delivery, offering potential for clinical translation and therapeutic applications.
Genetic determinants of distinct CD8+ α/β-TCR repertoires in the genusMus
Authors: Peters Moritz A , Soltys Volker , Su Dingwen , Kučka Marek , Chan Yingguang Frank
Published: September 2024

The adaptive immune system's efficacy relies on the diversity of T cell receptors and the ability to distinguish between self and foreign antigens. Analysis of the paired heterodimeric αβ-TCR chains of individual T cells requires single-cell resolution, but existing single-cell approaches offer limited coverage of the vast TCR repertoire diversity. Here we introduce CITR-seq, a novel, instrument-free, high-throughput method for single-cell TCR sequencing with >88% αβ-TCR pairing precision. We analyzed the TCR repertoires of CD8+ T cells originated from 32 inbred mice using CITR-seq, comprising four evolutionary divergent sister species and their F1 hybrids. Overall, we identified more than 5 million confidently paired TCRs. We found that V(D)J gene usage patterns are highly specific to the genotype and that Vβ-gene usage is strongly impacted by thymic selection. Using F1 hybrids, we show that differences in gene segment usage across species are likely caused bycis-acting factors prior to thymic selection, which imposed strong allelic biases. At the greatest divergence, this led to increased rates of TCR depletion through rejection of particular Vβ-genes. TCR repertoire overlap analysis across all mice revealed that sharing of identical paired CDR3 amino acid motifs is four times more frequent than predicted by random pairing of TCRα and TCRβ chains, with significantly increased sharing rates among related individuals. Collectively, we show that beyond the stochastic nature of TCR repertoire generation, genetic factors contribute significantly to the shape of an individual's repertoire.
Increasing prevalence of plant-fungal symbiosis across two centuries of environmental change
Authors: Fowler Joshua C. , Moutouama Jacob , Miller Tom E.X.
Published: September 2024

Species' distributions and abundances are shifting in response to climate change. Most species harbor microbial symbionts that have the potential to influence these responses. Mutualistic microbial symbionts may provide resilience to environmental change by protecting their hosts from increasing stress. However, environmental change that disrupts these interactions may lead to declines in hosts or symbionts. Microbes preserved within herbarium specimens offer a unique opportunity to quantify changes in microbial symbiosis across broad temporal and spatial scales. We asked how the prevalence of seed-transmitted fungal symbionts of grasses (Epichloe endophytes), which can protect hosts from abiotic stress, have changed over time in response to climate change, and how these changes vary across host species' ranges. Specifically, we analyzed 2,346 herbarium specimens of three grass host species collected over the last two centuries (1824 -- 2019) for the presence or absence of endophyte symbiosis, and evaluated spatial and temporal trends in endophyte prevalence. We found that endophytes increased in prevalence over the last two centuries from ca. 25% prevalence to ca. 75% prevalence, on average, across three host species. We also found that changes in prevalence were associated with observed changes in seasonal climate drivers; notably increasing precipitation corresponding to each host species' peak growing season and changes in off-peak season variability in precipitation. Our analysis performed favorably in an out-of-sample predictive test with contemporary data, however we identified greater local-scale variability in endophyte prevalence in contemporary data compared to historic data, suggesting that model fusion may be an important step moving forward. Our results provide novel evidence for a cryptic biological response to climate change that may contribute to the resilience of host-microbe symbiosis through context-dependent benefits that confer a fitness advantage to symbiotic hosts under environmental change.
The patient voice: valproate, topiramate and MHRA regulation
Authors: Hanna Jane , Waddams Faye , Jones Sarah L , Arkell Rachel , Angus-Leppan Heather
Published: September 2024

Valproate and topiramate use are increasingly restricted by government regulations, such as those of the MHRA. The views of people with epilepsy and their families affected by these have been little studied. This qualitative study examines 19 people with epilepsy and their views on the restrictions, and examines the thematic outcomes of these views, in terms of direct damage of avoiding valproate or topiramate (including SUDEP), missed opportunities and disruption of belief systems. Recommendations to align the regulations to human rights and true informed decision making are made.
Inpatient Hospitalizations for COVID-19 Among Patients with Prader-Willi Syndrome: a National Inpatient Sample Analysis
Authors: Luccarelli James , Strong Theresa V. , Rubin Emily B. , McCoy Thomas H.
Published: September 2024

Background

Prader-Willi syndrome (PWS) is a genetic disorder associated with baseline respiratory impairment caused by multiple contributing etiologies. While this may be expected to increase the risk of severe COVID-19 infections in PWS patients, survey studies have suggested paradoxically low disease severity. To better characterize the course of COVID-19 infection in patients with PWS, this study analyzes the outcomes of hospitalizations for COVID-19 among patients with and without PWS.

Methods

The National Inpatient Sample, an all-payors administrative claims database of hospitalizations in the United States, was queried for patients with a coded diagnosis COVID-19 in 2020 and 2021. Hospitalizations for patients with PWS compared to those for patients without PWS using Augmented Inverse Propensity Weighting (AIPW).

Results

There were 295 (95% CI: 228 to 362) COVID-19 hospitalizations for individuals with PWS and 4,112,400 (95% CI: 4,051,497 to 4,173,303) for individuals without PWS. PWS patients had a median age of 33 years compared to 63 for those without PWS. Individuals with PWS had higher baseline rates of obesity (47.5% vs. 28.4%). AIPW models show that PWS diagnosis is associated with increased hospital length of stay by 7.43 days, hospital charges by $80,126, and the odds of mechanical ventilation and in-hospital death (odds ratios of 1.79 and 1.67, respectively).

Conclusions

PWS patients hospitalized with COVID-19 experienced longer hospital stays, higher charges, and increased risk of mechanical ventilation and death. PWS should be considered a risk factor for severe COVID-19, warranting continued protective measures and vaccination efforts. Further research is needed to validate coding for PWS and assess the impact of evolving COVID-19 variants and population immunity on this vulnerable population.
Development and validation of domain-specific clinical prediction models of post-stroke cognitive impairment
Authors: Kusec Andrea , Snell Kym IE , Demeyere Nele
Published: September 2024

Background

Post-stroke cognitive impairment (PSCI) is highly prevalent across multiple cognitive domains. Individualised PSCI prognosis has mainly been researched using global cognitive outcomes. Here, we develop and externally validate clinical prediction models for overall and domain-specific PSCI, including language, memory, attention, executive function, numeracy, and praxis.

Methods

N=430 stroke survivors completed the Oxford Cognitive Screen (OCS) in acute care and at 6-month follow-up (binarized outcome; impaired vs unimpaired). Logistic regression models were fitted comprising both mandatory clinically-relevant (age, sex, stroke severity, education, stroke hemisphere, acute PSCI) and data-driven (acute mood difficulties, length of stay in acute care, multimorbidity) predictors using backward elimination (p< 0.10) on multiply imputed data. Internal validation used bootstrapping to obtain optimism-adjusted performance estimates. External validation used the optimism-adjusted C-Slope as a uniform shrinkage factor.

Results

Compared to the overall PSCI model (C-Statistic=0.76 [95% CI=0.71–0.80]), comparable or improved optimism-adjusted performance was observed in models of language (C-Statistic=0.77 [95% CI=0.72–0.81]) memory (C-Statistic=0.72 [95% CI=0.65–0.75]), and attention (C-Statistic=0.74 [0.69–0.78]). Numeracy (C-Statistic=0.69 [95% CI=0.63–0.74]), executive function (C-Statistic=0.71 [95% CI=0.65–0.76]), and praxis (C-Statistic=0.60 [95% CI=0.53–0.65]) models showed weaker performance. In external validation, the overall PSCI model was comparable to development data (C-Statistic=0.74 [95% CI=0.67–0.79]).

Conclusions

Domain-specific prediction models have the potential to offer more meaningful PSCI prognoses compared to overall PSCI models. External performance of overall PSCI models show promise in different stroke severity cohorts. Future recalibration of memory, numeracy, executive function, and praxis models would be beneficial.
CD300f immune receptor is a microglial tissue damage sensor and regulates efferocytosis after brain damage
Authors: Negro-Demontel María Luciana , Evans Frances , Cawen Andrés , Fitzpatrick Zach , Mason Hannah D. , Alí Daniela , Peluffo Hugo
Published: September 2024

Microglia, the resident phagocytes of the central nervous system (CNS), continuously monitor the parenchyma and surrounding borders and are the primary responders to brain damage. CD300f is a lipid-sensing immunoreceptor present in the microglial cell membrane, which binds to phosphatidylserine and other lipid mediators. Defining the functional microglial sensome is critical to understand their function and cell state determination. Using intravital two-photon microscopy we show that microglia lacking the CD300f receptor fail to detect environmental damage cues after a laser ablation injury. After a mild traumatic brain injury or after the intracortical injection of apoptotic cells, CD300f-/-microglia showed reduced capacity for detecting and phagocytosing dyeing cells, leading to the accumulation of dead cells in the neural parenchyma. Moreover, at later timepoints, increased accumulation of dyeing cells was found inside CD300f-/-microglia in vivo and in bone marrow-derived macrophages in vitro, suggesting that these cells display a reduced capacity for metabolizing phagocytosed cells. Finally, CD300f deficiency increased functional compromise after a contusive traumatic brain injury, associated to increased conservation of brain tissue. Collectively, these results suggest that CD300f function as a damage-associated molecular pattern (DAMP) receptor that coordinates microglial process reaction towards tissue debris and highlights its central role in microglial sensome machinery and in the modulation of in vivo microglial efferocytosis.
A physiologically inspired hybrid CPG/Reflex controller for cycling simulations that generalizes to walking
Authors: Severini Giacomo , Muñoz David
Published: September 2024

Predictive simulations based on explicit, physiologically inspired, control policies, can be used to test theories on motor control and to evaluate the effect of interventions on the different components of control. Several control architectures have been proposed for simulating locomotor tasks, based on fully feedback, reflex-based, controllers, or on feedforward architectures mimicking the Central Pattern Generators. Recently, hybrid architectures integrating both feedback and feedforward components have been shown to represent a viable alternative to fully feedback or feedforward controllers. Current literature on controller-based simulations, however, almost exclusively presents task-specific controllers that do not generalize across different tasks. The task-specificity of current controllers limits the generalizability of the neurophysiological principles behind such controllers. Here we propose a hybrid controller for predictive simulations of cycling based where the feedforward component is based on a well-known theoretical model, the Unit Burst Generation model, and the feedback component includes a limited set of reflex pathways, expected to be active during submaximal steady cycling. We show that this controller can simulate physiological cycling patterns at different desired speeds. We also show that the controller can generalize to walking behaviors by just adding an additional control component for accounting balance needs. The controller here proposed, although simple in design, represent an instance of physiologically inspired generalizable controller for cyclical lower limb tasks.

Author Summary

Predictive simulations allow to synthesize human movements and their associated biomechanical quantities without using experimental data. Such simulations can help understand how humans may perform movement tasks in different scenarios and could provide useful information in fields like rehabilitation. One of the methodologies used for developing predictive simulations is based on creating models of the neural control architectures that generate the activation of the muscles. In this work we propose the first neural control architecture for cycling behaviors. We show that our architecture can be used to develop predictive simulations of cycling at different speeds and that the associated biomechanical quantitites are consistent with experimental data. Moreover, we show that our control architecture can also replicate walking behaviors with minimal modifications.
Behavioral Interactions in Two Ant Species in The Southeast United States and Evidence for a Native Supercolony
Authors: Kanwar Shreyas , Nowicki Renee , Mavourneen Isabella R.E. , Gibson Joshua D.
Published: September 2024

Ants vary extensively in their colony structure, ranging from occupying single nests to tremendous supercolonies that occupy territories spanning large areas. Fewer than 1% of ants are known to produce supercolonies, yet they are disproportionately overrepresented in highly invasive ants. A broader understanding of supercolonial ants in their native range, therefore, may provide key insights into the factors that allow some ants to become invasive. Here, we show the results of behavioral assays of two native species of ants,Dorymyrmex bureniandD. smithi(Hymenoptera: Formicidae: Dolichoderinae) across geographically separated sites in southeastern Georgia, USA. We show thatD. smithihas extremely low incidence of aggression in ants from sites up to 35 km apart, indicating that this may be a supercolonial species. In contrast, we show thatD. bureniexhibits high levels of aggression between nest sites.Dorymyrmex smithiis also a temporary social parasite ofD. bureniand these two species form mixed nests with no apparent interspecific aggression between workers, but we show that both species interact aggressively in assays within and between sites when the workers are derived from pure species nests. These findings represent an important addition to our knowledge of supercolonial species, and they also lay the groundwork for further studies of the parasitic relationship between these species.
Prolonged thermal stress enhances mosquito tolerance to viral infection
Authors: Perdomo Hugo D. , Khorramnejad Ayda , Cham Nfamara M. , Kropf Alida , Sogliani Davide , Bonizzoni Mariangela
Published: September 2024

How and to what extent mosquito-virus interaction is influenced by climate change is a complex question of ecological and epidemiological relevance. We worked at the intersection between thermal biology and vector immunology and studied shifts in tolerance and resistance to the cell fusing agent virus (CFAV), a prominent component of the mosquito virome know to contribute to shaping mosquito vector competence, in warm-acclimated and warm-evolvedAedes albopictusmosquitoes. We show that the length of the thermal challenge influences the outcome of the infection with warm-evolved mosquitoes being more tolerant to CFAV infection, while warm-acclimated mosquitoes being more resistant and suffering from extensive fitness costs. These results highlight the importance of considering fluctuations in vector immunity in relation to the length of a thermal challenge to understand natural variation in vector response to viruses and frame realistic transmission models.
An RNA binding regulatory cascade controls the switch from proliferation to differentiation in theDrosophilamale germ cell lineage
Authors: Harris Devon E. , Kim Jongmin J. , Stern Sarah R. , Vicars Hannah M. , Matias Neuza R. , Gallicchio Lorenzo , Baker Catherine C. , Fuller Margaret T.
Published: September 2024

The switch from precursor cell proliferation to onset of differentiation in adult stem cell lineages must be carefully regulated to produce sufficient progeny to maintain and repair tissues, yet prevent overproliferation that may enable oncogenesis. In theDrosophilamale germ cell lineage, spermatogonia produced by germ line stem cells undergo a limited number of transit amplifying mitotic divisions before switching to the spermatocyte program that sets up meiosis and eventual spermatid differentiation. The number of transit amplifying divisions is set by accumulation of thebag-of-marbles(Bam) protein to a critical threshold. Inbammutants, spermatogonia proliferate through several extra rounds of mitosis then die without becoming spermatocytes. Here we show that a key role of Bam for the mitosis to differentiation switch is repressing expression of Held Out Wings (how), homolog of mammalian Quaking. Knockdown ofhowin germ cells was sufficient to allow spermatogonia mutant forbamor its partnerbenign gonial cell neoplasm(bgcn) to differentiate, while forced expression of nuclear-targeted How protein in spermatogonia wild-type forbamresulted in continued proliferation at the expense of differentiation. Our findings suggest that Bam targetshowRNA for degradation by acting as an adapter to recruit the CCR4-NOT deadenylation complex via binding its subunit, Caf40. As How is itself an RNA binding protein with roles in RNA processing, our findings reveal that the switch from proliferation to meiosis and differentiation in theDrosophilamale germ line adult stem cell lineage is regulated by a cascade of RNA-binding proteins.
Reversible Transcriptomic Age Shifts from Physiological Stress in Whole Blood
Authors: An Kyungwhan , Kwon Yoonsung , Bhak Jihun , Ryu Hyojung , Jeon Sungwon , Nam Dougu , Bhak Jong
Published: September 2024

We developed a genome-wide transcriptomic clock for predicting chronological age using whole blood samples from 463 healthy individuals. Our findings reveal profound age acceleration, up to 24.47 years, under perturbed homeostasis in COVID-19 patients, which reverted to baseline upon recovery. This study demonstrates that the whole blood transcriptome can track reversible changes in biological age induced by stressors in real physiological time, suggesting a potential role for anti-aging interventions in disease management.
The causal role of thyroid hormones in bipolar disorders: a two-sample Mendelian Randomization study
Authors: Li James L.
Published: September 2024

Introduction

Bipolar disorder is a complex psychiatric condition with distinctions between clinical subtypes including Type 1 and 2 disorders. Several studies have proposed thyroid hormones may be involved in the etiology of bipolar disorders.

Methods

This study employed a two-sample Mendelian Randomization (MR) approach to investigate the causal relationships between six thyroid hormone metrics (TSH, FT4, FT3, TT3, FT3/FT4, and TT3/FT4) and bipolar disorder, and Type 1 and 2 disorders, separately. Genome-wide association (GWAS) data from the Thyroidomics Consortium (up to 271,040 individuals of European ancestry) were used for thyroid function metrics. Bipolar disorder GWAS data included 41,917 cases and 371,549 controls (25,060 Type 1 and 6,781 Type 2 cases). We applied inverse variance weighted (IVW) methods for primary MR analysis, with MR Egger, weighted median, and weighted mode for sensitivity. Additional tests assessed horizontal pleiotropy and heterogeneity.

Results

Higher FT4 levels showed a protective causal effect against bipolar disorder (OR: 0.92, 95% CI: 0.86-0.97, p=4.58×10−3) and a suggestive effect on Type 1 disorders (OR: 0.92, 95% CI: 0.86-0.99, p=3.21×10−2). Elevated FT3 (OR: 1.18, 95% CI: 1.03-1.35, p=1.55×10−2) and FT3/FT4 ratio (OR: 1.97, 95% CI: 1.02-3.82, p=4.46×10−2) had suggestive harmful effects on Type 1 disorders. Sensitivity analyses showed consistent effects, with no significant horizontal pleiotropy or heterogeneity.

Conclusions

These findings highlight the protective role of FT4 and the potentially harmful effect of elevated FT3 in Type 1 bipolar disorder, highlighting the need for further research on thyroid hormone levels as a potential treatment strategy for Type 1 bipolar disorder.
Evaluation of the diagnostic accuracy and analytical sensitivity of the novel Xpert® Mpox (Cepheid®) and STANDARD™ M10 MPX/OPX (SD Biosensor) molecular point-of-care assays for the detection of Mpox virus in skin lesion swabs and upper-respiratory swab samples
Authors: Romero-Ramirez Alessandra , Somasundaran Anushri , Kontogianni Konstantina , Parkes Jacob , Hussain Yusra , Gould Susan , Williams Christopher T , Wooding Dominic , Body Richard , Hardwick Hayley E , Kenneth Baillie J , Dunning Jake , Semple Malcom G ,   CONDOR steering group,   ISARIC CCP UK investigators, Fletcher Tom E , Edwards Thomas , Emperador Devy , Cubas-Atienzar Ana I
Published: September 2024

Objectives

Evaluation of diagnostic accuracy of two point-of-care (POC) molecular diagnostic tests for the detection of monkeypox virus (MPXV): Xpert® Mpox (Cepheid, Inc., USA) and STANDARD™ M10 MPX/OPX (SD Biosensor, Inc., Korea).

Methods

Diagnostic accuracy of both platforms was evaluated using 53 upper-respiratory swabs (URS) and 32 skin lesions swabs (SS) collected from mpox and COVID-19 patients in the UK against the Sansure (Sansure Biotech Inc.) and the CDC reference qPCR tests. The analytical sensitivity of both platforms was assessed using a viral isolate from the lineage II, B.1.

Results

The limit of detection was 1×101pfu/ml for both tests. The overall sensitivity and specificity of the Xpert® Mpox was 97.67% [95% CI 87.71–99.94%] and 88.57% [95% CI 73.26–96.80%] and 97.44% [95% CI 86.52–99.94%] and 74.42% [95% CI 58.83–86.48%] comparing the Sansure and CDC qPCR, respectively and for the M10 MPX/OPX was 87.80% [95% CI 73.80–95.92%] and 76.60% [95% CI 61.97–87.70%] and 94.29% [95% CI 80.84–99.30%] and 86.67% [95% CI 73.21–94.95%] with the Sansure and CDC qPCR.

Conclusion

The Xpert® Mpox had good diagnostic accuracy for both sample types while the M10 MPX/OPX clinical accuracy was deficient with URS. Our data supports the use of URS during the first 3 days of symptoms onset for mpox diagnosis.

Highlights

The Xpert® Mpox detected Monkeypox virus (MPXV) DNA in more samples than the M10 MPX/OPX, CDC qPCR and Sansure qPCR suggesting higher sensitivity at lower viral loads.

Xpert® Mpox fulfilled the performance requirements recommended in the World Health Organisation (WHO) target product profile (TPP) using upper-respiratory swabs (URS) and skin lesion swabs (SS) but M10 MPX/OPX performance was only met when using SS.

MPXV DNA was reliably detectable in SS up to 5 days after onset of symptoms. with all PCR tests

The use of URS for mpox diagnosis is not recommended for use more than 3 days after onset of symptoms.
Role ofBAG3protein interactions in cardiomyopathies
Authors: Qu Hui-Qi , Wang JuFang , Rosa-Campos Alexandre , Hakonarson Hakon , Feldman Arthur M.
Published: September 2024

Background

Bcl-2-associated athanogene 3 (BAG3) plays an important function in cellular protein quality control (PQC) maintaining proteome stability. Mutations in the BAG3 gene result in cardiomyopathies. Due to its roles in cardiomyopathies and the complexity of BAG3-protein interactions, it is important to understand these protein interactions given the importance of the multifunctional cochaperone BAG3 in cardiomyocytes, using an in vitro cardiomyocyte model.

Methods

The experimental assay was done using high pressure liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) in the human AC16 cardiomyocyte cell line with the BioID technology.

Results

Proteins with BAG3-interaction were identified in all the 28 hallmark gene sets enriched in idiopathic cardiomyopathies and/or ischemic disease. Among the 24 hallmark gene sets enriched in both idiopathic cardiomyopathies and ischemic disease, 15 gene sets had at least 3 proteins with BAG3-interaction.

Conclusions

This study highlights BAG3 protein interactions, unveiling the key gene sets affected in cardiomyopathies, which help to explain the molecular mechanisms of the cardioprotective effects of BAG3. In addition, this study also highlighted the complexity of proteins with BAG3 interactions, implying unwanted effects of BAG3.
Excessive Corneal Endothelial Single Cell Loss Following Endothelial Injuries
Authors: Fu Yuan Kai , Lin Matthew , Hung Kuo-Hsuan , Yeh Lung-Kun , Tan Hsin-Yuan
Published: September 2024

Corneal endothelial dysfunction is the main cause for more than 50% of corneal transplantations. Human corneal endothelial cells are generally viewed as non-proliferativein vivo. Any injury that results in endothelial loss exceeding the critical threshold can cause irreversible endothelial functional decompensation, leading to corneal edema and vision loss. Currently, the mainstay treatment for irreversible corneal dysfunction is corneal transplantation. In this work, using well-established imaging technique of specular microscopy, we revisited the endothelial damage following three common corneal endothelial injury scenarios: post-cataract surgery, endothelial dystrophy, and corneal penetrating injury. We identified unexpected, stochastic single-cell loss in the corneal endothelium following primary injuries, persisting well beyond the expected wound healing period, a phenomenon that has not been previously highlighted. This finding offers a potential explanation for the chronic endothelial cell loss following a primary injury. Further investigation could provide valuable insights for improving clinical management strategies for corneal endothelial dysfunction.
Letter: Cancer-independent, second somaticNF1mutation of normal tissues in neurofibromatosis type 1
Authors: Oliver Thomas R. W. , Lawson Andrew R. J. , Lee-Six Henry , Tollit Anna , Jung Hyunchul , Hooks Yvette , Sanghvi Rashesh , Young Matthew D. , Butler Timothy M. , Nicola Pantelis , Treger Taryn D. , Amos Burke G. A. , Aquilina Kristian , Löbel Ulrike , Cortes-Ciriano Isidro , Hargrave Darren , Jorgensen Mette , Jessop Flora A. , Coorens Tim H. H. , Flanagan Adrienne M. , Allinson Kieren , Martincorena Inigo , Jacques Thomas S. , Behjati Sam
Published: September 2024

INTRODUCTION

Cancer predisposition syndromes mediated by recessive cancer genes generate tumours via somatic variants (second hits) in the unaffected allele. Second hits may or may not be sufficient for neoplastic transformation. Here, we performed whole genome and exome sequencing on 479 tissue biopsies from a child with neurofibromatosis type 1, a multi-system cancer-predisposing syndrome mediated by constitutive monoallelicNF1inactivation. We identified multiple independentNF1driver variants in histologically normal tissues, but not in 610 biopsies from two non-predisposed children. We corroborated this finding using targeted duplex sequencing, including a further nine adults with the same syndrome. Overall, truncatingNF1mutations were under positive selection in normal tissues from individuals with neurofibromatosis type 1. We demonstrate that normal tissues in neurofibromatosis type 1 commonly harbour second hits inNF1, the extent and pattern of which may underpin the syndrome’s cancer phenotype.
Kinbiont: From time series to ecological and evolutionary responses in microbial systems
Authors: Angaroni Fabrizio , Peruzzi Alberto , Alvarenga Edgar Z. , Pinheiro Fernanda
Published: September 2024

Microbial behavior is quantitatively characterized by observables inferred from kinetics experiments. Growth rate and biomass yield, for example, are used to map response patterns across different conditions including antibiotic growth inhibition and yield dependence on substrate. As microbial kinetics datasets grow, there is immense potential to advance our understanding of ecological and evolutionary processes. But how can we turn these data into actionable insights about microbial responses? Here we introduce Kinbiont – an ecosystem of numerical methods integrating advanced ordinary differential equation solvers, non-linear optimization, signal processing, and interpretable machine learning algorithms. Kinbiont offers a model-based data analysis pipeline covering all aspects of microbial kinetics, from pre-processing to result interpretation. We demonstrate Kinbiont’s performance using synthetic and real datasets, including bacterial growth, diauxic curves, phage-bacteria co-cultures, and ecotoxicological responses. Kinbiont can aid biological discovery through data-driven generation of hypotheses that can be tested in targeted experiments.
How a pathogenic mutation impairs Hsp60 functional dynamics from monomeric to fully assembled states
Authors: Torielli Luca , Guarra Federica , Shao Hao , Gestwicki Jason E. , Serapian Stefano A. , Colombo Giorgio
Published: September 2024

Heat Shock Protein 60 kDa (Hsp60) is a mitochondrial chaperonin that cooperates with Hsp10 to drive the correct folding of client proteins. MonomersMof Hsp60 (featuring equatorial, intermediate, and apical domains) first assemble into 7-meric Single rings (S), then pairs ofSinterface equatorially to form 14-meric Double rings (D) that accommodate clients into their lumen. Recruitment of 7 Hsp10 molecules per pole turnsDinto a 28-meric Football-shaped complex (F). Sequential hydrolysis of ATP present in each Hsp60 unit ofFfinally drives client folding andFdisassembly. Equatorial domain mutation V72I occurs in SPG13, a form of hereditary spastic paraplegia: while distal to the active site, this severely impairs the chaperone cycle and stability. To understand the molecular bases of this impairment we have run atomistic molecular dynamics (MD) simulations ofM,S,D, andFfor both WT and mutant Hsp60, with two catalytically relevant Hsp60 aspartates inDandFmodelled in three different protonation states. Additionally,Din one protonation state was modelled post-hydrolysis (total production time: 36 µs). By combining complementary experimental and computational approaches for the analysis of functional dynamics and allosteric mechanisms, we consistently find that mutation V72I significantly rewires allosteric routes present in WT Hsp60 across its complexes, from isolatedMunits right up toF, rigidifying them—as observed experimentally—by introducing a direct allosteric link between equatorial and apical Hsp60 domains that bypasses the ATP binding site (wherein we observe the alteration of mechanisms driving reactivity). Our results reveal a multiscale complexity of functional mechanisms for Hsp60 and its pathogenic mutant, and may lay the foundation for the design of experiments to fully understand both variants.