bluuebunny/crossref_metadata_2025 huggingface dataset:
Anabolic sensitivity in healthy, lean, older men is associated with higher expression of amino acid sensors and mTORC1 activators
Authors: Horwath Oscar , Moberg Marcus , Hodson Nathan , Edman Sebastian , Johansson Mats , Andersson Eva , van Hall Gerrit , Rooyackers Olav , Philp Andrew , Apró William
Published: June 2024

Background

Sarcopenia is thought to be underlined by age-associated anabolic resistance and dysregulation of intracellular signalling pathways. However, it is unclear whether these phenomena are driven by ageingper seor other confounding factors.

Methods

Lean and healthy young (n=10, 22 ± 3 yrs, BMI; 23.4 ± 0.8 kg/m2) and old men (n=10, 70 ± 3 yrs, BMI; 22.7 ± 1.3 kg/m2) performed unilateral resistance exercise followed by intake of essential amino acids (EAA). Muscle biopsies were collected from the rested and the exercised leg before, immediately after, as well as 60 and 180 minutes after EAA intake. Muscle samples were analyzed for amino acid concentrations, muscle protein synthesis (MPS) and associated anabolic signaling.

Results

Following exercise, peak plasma levels of EAA and leucine were similar between groups, but the area under the curve was ∼11% and ∼28% lower in Young (p<0.01). Absolute levels of muscle EAA and leucine peaked 60 min after exercise, with ∼15 and ∼21 % higher concentrations in the exercising leg (p<0.01) but with no difference between groups. MPS increased in both the resting (∼ 0.035%·h-1to 0.056%·h-1, p<0.05) and exercising leg (∼ 0.035%·h-1to 0.083%·h-1, p<0.05) with no difference between groups. Phosphorylation of S6K1Thr389increased to a similar extent in the exercising leg in both groups but was 2.8-fold higher in the resting leg of Old at the 60 min timepoint (p<0.001). Phosphorylation of 4E-BP1Ser65increased following EAA intake and exercise, but differences between legs were statistically different only at 180 min (p<0.001). However, phosphorylation of this site was on average 78% greater across all timepoints in Old (p<0.01). Phosphorylation of eEF2Thr56was reduced (∼ 66 and 39%) in the exercising leg at both timepoints after EAA intake and exercise, with no group differences (p<0.05). However, phosphorylation at this site was reduced by ∼ 27% also in the resting leg at 60 min, an effect that was only seen in Old (p<0.01). Total levels of Rheb (∼ 45%), LAT1 (∼ 31%) and Rag B (∼ 31%) were higher in Old (p<0.001).

Conclusion

Lean and healthy old men do not manifest AR as evidenced by potent increases in MPS and mTORC1 signalling following EAA intake and exercise. Maintained anabolic sensitivity with age appears to be a function of a compensatory increase in basal levels of proteins involved in anabolic signalling. Therefore, our results suggest that ageper sedoes not appear to cause AR in human skeletal muscle.
Is ChatGPT smarter than Otolaryngology trainees? A comparison study of board style exam questions
Authors: Patel J , Robinson PZ , Illing EA , Anthony BP
Published: June 2024

Objectives

This study compares the performance of the artificial intelligence (AI) platform Chat Generative Pre-Trained Transformer (ChatGPT) to Otolaryngology trainees on board style exam questions.

Methods

We administered a set of 30 Otolaryngology board style questions to medical students (MS) and Otolaryngology residents (OR). 31 MSs and 17 ORs completed the questionnaire. The same test was administered to ChatGPT version 3.5, five times. Comparisons of performance were achieved using a one-way ANOVA with Tukey Post Hoc test, along with a regression analysis to explore the relationship between education level and performance.

Results

The average scores increased each year from MS1 to PGY5. A one-way ANOVA revealed that ChatGPT outperformed trainee years MS1, MS2, and MS3 (p = <0.001, 0.003, and 0.019, respectively). PGY4 and PGY5 otolaryngology residents outperformed ChatGPT (p = 0.033 and 0.002, respectively). For years MS4, PGY1, PGY2, and PGY3 there was no statistical difference between trainee scores and ChatGPT (p = .104, .996, and 1.000, respectively).

Conclusion

ChatGPT can outperform lower-level medical trainees on Otolaryngology board-style exam but still lacks the ability to outperform higher-level trainees. These questions primarily test rote memorization of medical facts; in contrast, the art of practicing medicine is predicated on the synthesis of complex presentations of disease and multilayered application of knowledge of the healing process. Given that upper-level trainees outperform ChatGPT, it is unlikely that ChatGPT, in its current form will provide significant clinical utility over an Otolaryngologist.
Predicting different dimensions of fatigue from speech data: a longitudinal study in shift workers
Authors: Norbury Agnes , Georgescu Alexandra Livia , Molimpakis Emilia , Goria Stefano , Cummins Nicholas
Published: June 2024

Background

Shift work, or working outside of normal circadian cycles, is associated with both experience of fatigue and poorer long-term physical and mental health. However, current methods for assessing fatigue present several barriers to building understanding of how these risks develop over time within individuals.

Objective

Here, we explore the potential of momentary speech activity-based fatigue measurement in a large, multi-lingual cohort of shift workers, using an intensive longitudinal study design (twice-daily measurement over two weeks inN=1,197 individuals from six different countries).

Methods

Paralinguistic speech features were used to predict different aspects of acute and chronic fatigue at each study time-point, with performance assessed in unseen (held-out) data. Results are reported both across the dataset as a whole, and for user-specific prediction models.

Findings

In the cross-sectional analysis, good (close to or exceeding current state-of-the-art) performance was achieved for both current sleep deprivation and self-reported sleepiness levels. The within-user analysis revealed robust increases in performance, yielding the ability to detect more subjective aspects of fatigue such as pervasive physical and mental exhaustion.

Conclusions

These findings offer preliminary support for the utility of using brief momentary speech samples as a low-burden, acceptable, and reliable measure of different aspects of fatigue in high-risk populations such as shift workers.

Clinical Implications

Developing brief, accessible measures of different dimensions of fatigue is an important step towards building understanding of how risks for poorer health outcomes develop over time within individuals exposed to significant circadian disruption.

What is already known on this topic

Previous studies have indicated that speech data may be a promising source of information about fatigue: however to date these have primarily been carried out in small, unrepresentative samples and in non-naturalistic settings, making results hard to generalize.

What this study adds

Here, we present evidence from a large international study where participants both provided momentary speech activity data and reported levels of different aspects of fatigue, as they went about their usual working lives. Importantly, we use a modelling framework that explicitly takes into account potential influences of factors such as age, sex, and language on speech features and target fatigue measures, as well as assessing potential biases and reliability of model output.

How this study might affect research, practice or policy

If individuals who are at heightened risk of fatigue-related health problems are able to monitor their fatigue levels regularly and in real-time, this may yield the opportunity to intervene prior to transitioning into less tractable states of poor physical and mental health.
Frontotemporal Dementia Subtyping using Machine Learning, Multivariate Statistics, and Neuroimaging
Authors: Metz Amelie , Zeighami Yashar , Ducharme Simon , Villeneuve Sylvia , Dadar Mahsa
Published: June 2024

Frontotemporal Dementia (FTD) is a prevalent form of early-onset dementia characterized by progressive neurodegeneration. It encompasses a group of heterogeneous disorders, including behavioral variant frontotemporal dementia (bvFTD), nonfluent variant primary progressive aphasia (nfvPPA), and semantic variant primary progressive aphasia (svPPA). Due to disease heterogeneity and overlapping symptoms, diagnosis of FTD and its subtypes still poses a challenge. Magnetic-resonance imaging (MRI) is commonly used to support the diagnosis of FTD. Using machine learning and multivariate statistics, we tested whether brain atrophy patterns are associated with severity of cognitive impairment, whether this relationship differs between the phenotypic subtypes, and whether we could use these brain patterns to classify patients according to their FTD variant.

A total of 136 patients (70 bvFTD, 36 svPPA, 30 nfvPPA) from the frontotemporal lobar degeneration neuroimaging initiative (FTLDNI) database underwent brain MRI and clinical and neuropsychological examination. Deformation-based morphometry (DBM), which offers increased sensitivity to subtle local differences in structural image contrasts was used to estimate regional cortical and subcortical atrophy. Atlas-based associations between DBM values and performance across different cognitive tests were assessed using partial least squares (PLS). We then applied linear regression models to discern the group differences regarding the relationship between atrophy and cognitive decline in the three FTD phenotypes. Lastly, we assessed whether the combination of neural and behavioral patterns in the latent variables identified in the PLS analysis could be used as features in a machine-learning model to predict FTD subtypes in patients.

Results revealed four significant latent variables that combined accounted for 86% of the shared covariance between cognitive and brain atrophy measures. PLS-based atrophy and behavioral patterns predicted the FTD phenotypes with a cross-validated accuracy of 89.12%, with high specificity (91.46-97.15%) and sensitivity (84.19-93.56%). When using only MRI measures and two behavioral tests in the PLS and classification algorithm, ensuring clinical feasibility, our model was similarly precise (83.62%, specificity 86.38-93.51%, sensitivity 76.17-87.50%). Here, including only atrophy or behavior patterns in the analysis led to prediction accuracies of 69.76% and 76.38%, respectively, highlighting the increased value of combining MRI and clinical measures in subtype classification.

We demonstrate that the combination of brain atrophy and clinical characteristics, and multivariate statistical methods can serve as an imaging biomarker for early disease phenotyping in FTD, whereby inclusion of DBM measures adds to the classification precision in the absence of extensive clinical testing.
Spatial Clustering Analysis with Spectral Imaging-based Single-Step Multiplex Immunofluorescence (SISS-mIF)
Authors: Nakamura Tomohiko , Kaneko Noe , Taguchi Towako , Ikeda Kenji , Sakata Moe , Inoue Miori , Kuwayama Tetsuro , Tatsuta Hirokazu , Onishi Iichiroh , Kurata Morito , Nakagawa Kazuhiro
Published: June 2024

Precision medicine, anchored in spatial biology, is essential for the accurate diagnosis of cancer and prediction of drug responses. We have introduced the Spectral Imaging-based Single-Step Multiplex Immunofluorescence (SISS-mIF) technique, which leverages hyperspectral imaging to simultaneously capture fluorescence spectra. This approach automatically optimizes tissue autofluorescence spectra for each image, facilitating the use of fluorescent direct-labeled antibodies for multicolor staining in a single step. Unlike conventional methods, images are outputted as antibody counts rather than fluorescence intensity, allowing for consistent comparisons under different imaging conditions. We demonstrate that this technique allows for identical cell detection of CD3, CD5, and CD7 in T-cell lymphoma on a single slide. The utilization of fluorescent direct-labeled antibodies enables the triple staining of CD3, CD5, and CD7 without cross-reactivity, maintaining the same intensity as single stains. Moreover, we developed a joint Non-Negative Matrix Factorization-based Spatial Clustering Analysis (jNMF-SCA) with a modified spectral unmixing system, highlighting its potential as a supportive diagnostic tool for T-cell lymphoma.
TRIM7 ubiquitinates SARS-CoV-2 membrane protein to limit apoptosis and viral replication
Authors: Gonzalez-Orozco Maria , Tseng Hsiang-chi , Hage Adam , Xia Hongjie , Behera Padmanava , Afreen Kazi , Peñaflor-Tellez Yoatzin , Giraldo Maria I. , Huante Matthew , Puebla-Clark Lucinda , van Tol Sarah , Odle Abby , Crown Matthew , Teruel Natalia , Shelite Thomas R , Menachery Vineet , Endsley Mark , Endsley Janice J. , Najmanovich Rafael J. , Bashton Matthew , Stephens Robin , Shi Pei-Yong , Xie Xuping , Freiberg Alexander N. , Rajsbaum Ricardo
Published: June 2024

SARS-CoV-2 is a highly transmissible virus that causes COVID-19 disease. Mechanisms of viral pathogenesis include excessive inflammation and viral-induced cell death, resulting in tissue damage. We identified the host E3-ubiquitin ligase TRIM7 as an inhibitor of apoptosis and SARS-CoV-2 replication via ubiquitination of the viral membrane (M) protein.Trim7-/-mice exhibited increased pathology and virus titers associated with epithelial apoptosis and dysregulated immune responses. Mechanistically, TRIM7 ubiquitinates M on K14, which protects cells from cell death. Longitudinal SARS-CoV-2 sequence analysis from infected patients revealed that mutations on M-K14 appeared in circulating variants during the pandemic. The relevance of these mutations was tested in a mouse model. A recombinant M- K14/K15R virus showed reduced viral replication, consistent with the role of K15 in virus assembly, and increased levels of apoptosis associated with the loss of ubiquitination on K14. TRIM7 antiviral activity requires caspase-6 inhibition, linking apoptosis with viral replication and pathology.
Structural robustness and temporal vulnerability of the starvation-responsive metabolic network in liver of healthy and obese mice
Authors: Morita Keigo , Hatano Atsushi , Kokaji Toshiya , Sugimoto Hikaru , Tsuchiya Takaho , Ozaki Haruka , Egami Riku , Li Dongzi , Terakawa Akira , Ohno Satoshi , Inoue Hiroshi , Inaba Yuka , Suzuki Yutaka , Matsumoto Masaki , Takahashi Masatomo , Izumi Yoshihiro , Bamba Takeshi , Hirayama Akiyoshi , Soga Tomoyoshi , Kuroda Shinya
Published: June 2024

Adaptation to starvation is a multi-molecular and temporally ordered process, that could be impaired in obesity. To elucidate how the healthy liver regulates various molecules in a temporally ordered manner during starvation and how obesity disrupts this process, we measured time course multiomic data in the liver of wild-type (WT) and leptin-deficient obese (ob/ob) mice during starvation. Using the measured data, we constructed a starvation-responsive metabolic network, that is a transomic network including responsive molecules and their regulatory relationships during starvation, and analyzed the structure of the network. In WT mice, ATP and AMP, the energy indicators, regulated various metabolic reactions in the network as the hub molecules, both of which were not responsive inob/obmice. However, the structural properties of the network were maintained inob/obmice. In WT mice, the molecules in the network were temporally ordered through metabolic process coordinated by the hub molecules including ATP and AMP and were positively or negatively co-regulated. By contrast, both temporal order and co-regulation were disrupted inob/obmice. Taken together, the starvation-responsive metabolic network is structurally robust, but temporally vulnerable by the loss of responsiveness of the hub molecules in obesity. In addition, we proposed a potential therapeutic target to treat the negative effects of obesity on intermittent fasting to extend lifespan.

One Sentence Summary

Hub molecules activate or inhibit various molecules in a temporally ordered manner in healthy liver, and the regulatory network is structurally robust but temporally vulnerable to obesity.
Exploring the functional, protective, and transcriptomic effects of GIP on cytokine-exposed human pancreatic islets and EndoC-βH5 cells
Authors: Henriksen Kristine , Jørgensen Anne , Kaur Simranjeet , Gerwig Rebekka , Svane Cecilie Amalie Brøgger , Knop Filip K. , Størling Joachim
Published: June 2024

Immune-mediated beta-cell destruction and lack of alpha-cell responsiveness to hypoglycaemia are hallmarks of type 1 diabetes pathology. The incretin hormone glucose-dependent insulinotropic polypeptide (GIP) may hold therapeutic potential for type 1 diabetes due to its insulinotropic and glucagonotropic effects, as well as its beta-cell protective effects shown in rodent islets. Here, we examined the functional, protective, and transcriptomic effects of GIP treatment upon diabetogenic cytokine exposure to interleukin (IL)-1β ± interferon (IFN)-γ in human EndoC-βH5 beta cells and isolated human islets, respectively.

GIP dose-dependently augmented glucose-stimulated insulin secretion from EndoC-βH5 cells and increased insulin and glucagon secretion from human islets during high and low glucose concentrations, respectively. The insulinotropic effect of GIP in EndoC-βH5 cells was abrogated by KN-93, an inhibitor of calcium/calmodulin-dependent protein kinase 2 (CaMK2). GIP did not prevent cytokine-induced apoptosis or cytokine-induced functional impairment of human EndoC-βH5 cells. GIP also did not prevent cytokine-induced apoptosis in human islets. GIP treatment of human islets with or without cytokines for 24 hours did not significantly impact the transcriptome. GIP potentiated cytokine-induced secretion of IL-10 and c-c motif chemokine ligand (CCL)-2 from human islets while decreasing the secretion of c-x-c motif chemokine ligand (CXCL)-8. In EndoC-βH5 cells, GIP reduced IFN-γ-induced secretion of tumor necrosis factor (TNF)-α, IL-2, IL-6, and IL-10 but increased the secretion of CXCL8, CCL2, CCL4, and CCL11.

In conclusion, our results suggest that the insulinotropic effect of GIP is CaMK2-dependent. Furthermore, our results indicate that GIP does not provide substantial cytoprotective effects against diabetogenic cytokine challenge or significantly modulate the transcriptome of human islets when applied at a supraphysiological level. GIP may, however, still exert selective inflammation-modulatory effects upon diabetogenic cytokine exposure.
Stability of four carbapenem antibiotics in discs used for antimicrobial susceptibility testing
Authors: Shahab Selvi N. , Bexkens Michiel L. , Kempenaars Nikita , Rijfkogel Amber , Karuniawati Anis , Vos Margreet C. , Goessens Wil H.F. , Severin Juliëtte A.
Published: June 2024

In low-to middle-income countries, microbiological laboratories often use disc diffusion for antimicrobial susceptibility testing (AST). Reliable AST of carbapenem antibiotics is crucial for treatment decisions and surveillance purposes. Transport and storage conditions of materials used for AST are critical and may be challenging in some settings, where temperature cannot always be controlled. This study aimed to test the stability of four carbapenems in discs for AST under unfavourable conditions,i.e., at room temperature and 35°C for up to 72 hours. Imipenem, meropenem, ertapenem, and doripenem discs from three brands, Oxoid, Becton Dickinson, and HiMedia, containing 10 μg of antibiotic were included. Discs were exposed to six unfavourable conditions and the recommended storage-condition as control. Subsequently, disc diffusion testing following the EUCAST guidelines was performed with four well-defined strains ofEscherichia coliwith different susceptibility profiles to carbapenems. The inhibition zone diameters were measured after 16-18 hours of incubation at 35±2°C. All experiments were executed in triplicate. In parallel, the carbapenems’ degradation was observed using a spectrophotometric method. Our study revealed that carbapenem discs were generally stable for AST although the concentration of most carbapenem antibiotics in discs decreased over time. Overall, imipenem (Oxoid and Becton Dickinson) discs were the most stable. Meropenem discs were less stable when exposed to 35°C than at room temperature. Concentrations of carbapenems in HiMedia discs were higher than those in Oxoid and Becton Dickinson. For carbapenem AST using disc diffusion in a rural area, we recommend using imipenem discs from Oxoid or Becton Dickinson.

GRAPHICAL ABSTRACT

HIGHLIGHTS

In remote areas, transportation conditions of AST discs may be challenging

Discs with four carbapenems from three brands were tested using six conditions

Carbapenem discs were generally stable for AST

In unfavourable conditions, concentrations in the discs degraded over time

Imipenem (Oxoid and Becton Dickinson) discs were the most stable
Transcutaneous delivery of disease specific PI3K/Akt/mTOR inhibitor based hybrid nanoparticles in hydrogel system for the management of psoriasis: Insights from in vivo studies
Authors: keshari Roshan , Bagale Rupali , Rath Sulagna , De Abhijit , Banerjee Rinti , Sen Shamik , Srivastava Rohit
Published: June 2024

We have reported robust and scalable lipid polymeric conjugated hybrid nanoparticles comprised of phospholipid shell and polymeric core that combine the benefit of both polymeric and lipid nanoparticles. Rapamycin, a PI3K/Akt/mTORC1 inhibitor, was encapsulated inside the lipid-polymeric conjugated spherical-shaped hybrid nanoparticles (RPMN), having an encapsulation efficiency of ≈ 83% and particle size ≈ 277.6 nm. Further, RPMN was converted into the carpool-based hydrogel system (RPMNGel), which enhanced release kinetics, long-term stability and skin residence time. Specifically, in an in-vivo imiquimod-induced psoriatic model, RPMNGel showed high accumulation and deeper penetration inside the epidermis and slowly diffusing away inside the psoriatic skin without causing any side effect to normal skin. This leads to longer and sustained retention over more than three days without being affected by sweat, humidity or wiping due to adherence between the stratum corneum and epidermis. Similarly, the cumulative PASI score was also reduced from 10.25 to 1.75 on day 7 in the group treated with RPMNGel. Overall, RPMNGel has a potential role in treating and managing psoriasis.
Disruption of the CRF1receptor eliminates morphine-induced sociability deficits and firing of oxytocinergic neurons in male mice
Authors: Piccin Alessandro , Allain Anne-Emilie , Baufreton Jérôme , Bertrand Sandrine S. , Contarino Angelo
Published: June 2024

Substance-induced social behavior deficits dramatically worsen the clinical outcome of substance use disorders; yet, the underlying mechanisms remain poorly understood. Herein, we investigated the role for the corticotropin-releasing factor receptor 1 (CRF1) in the acute sociability deficits induced by morphine and the related activity of oxytocin (OXY)-and arginine-vasopressin (AVP)-expressing neurons of the paraventricular nucleus of the hypothalamus (PVN). For this purpose, we used both the CRF1receptor-preferring antagonist compound antalarmin and the genetic mouse model of CRF1receptor-deficiency. Antalarmin completely abolished sociability deficits induced by morphine in male, but not in female, C57BL/6J mice. Accordingly, genetic CRF1receptor-deficiency eliminated morphine-induced sociability deficits in male mice.Ex vivoelectrophysiology studies showed that antalarmin also eliminated morphine-induced firing of PVN neurons in male, but not in female, C57BL/6J mice. Likewise, genetic CRF1receptor-deficiency reduced morphine-induced firing of PVN neurons in a CRF1gene expression-dependent manner. The electrophysiology results consistently mirrored the behavioral results, indicating a link between morphine-induced PVN activity and sociability deficits. Interestingly, in male mice antalarmin abolished morphine-induced firing in neurons co-expressing OXY and AVP, but not in neurons expressing only AVP. In contrast, in female mice antalarmin did not affect morphine-induced firing of neurons co-expressing OXY and AVP or only OXY, indicating a selective sex-specific role for the CRF1receptor in opiate-induced PVN OXY activity. The present findings demonstrate a major, sex-linked, role for the CRF1receptor in sociability deficits and related brain alterations induced by morphine, suggesting new therapeutic strategy for opiate use disorders.
Consistent neural representation of valence in watching and recall conditions
Authors: Kim Hyeonjung , Kim Jongwan
Published: June 2024

Recall is an act of elicitation of emotions similar to those emotions previously experienced. Unlike the past experiences where external sensory stimuli triggered emotions, recall does not require external sensory stimuli. This difference is pertinent to the key debate in affective representation, addressing whether the representation of valence is consistent across modalities (modality-general) or dependent on modalities (modality-specific). This study aimed to verify neural representations of valence irrespective of the presence of external sensory stimuli. Using neuroimaging data from video watching and recall (Chen et al., 2017) and behavioral data for valence ratings (Kim et al., 2020), a searchlight analysis was conducted with cross-participant regression-based decoding across the presence and absence of external stimuli. Multidimensional scaling was employed as a validation analysis of the results. The searchlight analysis revealed the right middle temporal and inferior temporal gyrus as well as the left fusiform gyrus. The validation analysis further exhibited significant consistent neural representations of valence in the inferior temporal gyrus and the left fusiform gyrus. This study identified the brain regions where valence is consistently represented, regardless of the presence of external sensory stimuli. These findings contribute to debate in affective representations, by comparing conditions utilized little in prior, suggesting the inferior temporal gyrus is related to representations of valence irrespective of the presence and absence of external visual stimuli.
A Cell-Permeable Fluorescent Probe Reveals Temporally Diverse PI(4,5)P2 Dynamics Evoked by Distinct GPCR Agonists in Neurons
Authors: Kundu Rajasree , Mondal Samsuzzoha , Kapadia Akshay , Banerjee Antara A. , Kucherak Oleksandr A. , Klymchenko Andrey S. , Koushika Sandhya P. , Venkatramani Ravindra , Vaidya Vidita A. , Datta Ankona
Published: June 2024

Lipids, key constituents of cell-membranes, are the first responders to cell signals. At the crux of spatiotemporal dynamics of lipid-signaling response are phosphoinositides. Indeed, phosphoinositides like phosphatidylinositol-(4,5)-bisphosphate (PI(4,5)P2), present in the inner-leaflet of eukaryotic cell-membranes, form the link between signal reception and downstream signal-transmission. In this backdrop, reversible fluorescent probes that can track live PI(4,5)P2 dynamics on a seconds time-scale will afford key insights into lipid-mediated signaling. However, realizing cell-permeable PI(4,5)P2-selective sensors for imaging dynamics remains a challenge due to the presence of structurally similar lipids and low levels of PI(4,5)P2. We report a computationally-designed, rapid-response, reversible, photo-stable, fluorescent sensor that permeates living cells, neurons, and a multicellular organism within few min of direct incubation and distinctly visualizes PI(4,5)P2 pools. We used the sensor to interrogate the role of PI(4,5)P2 in driving heterogeneity of signaling responses and contrasting behavioral effects that ensue upon binding of distinct ligands to the same G protein-coupled receptor. Specifically, we asked whether probing PI(4,5)P2 dynamics using our novel sensor could uncover the earliest of signaling differences evoked by hallucinogenic versus non-hallucinogenic ligands at the serotonin2A (5-HT2A) receptor. Our results reveal that a hallucinogenic ligand at the 5-HT2Areceptor leads to a slower rate of PI(4,5)P2-depletion when compared to a non-hallucinogenic ligand, within the initial seconds of ligand addition, but has a sustained effect. The ability of our designer chemical probe in timing early seconds-minute timescale lipid-dynamics in living cells opens avenues for tracking early time-point molecular events in neuronal response to chemical and physical stimuli.
Comparative Nephro-Hepatoprotective Effects of Herbal Teas fromHibiscus sabdariffa, Moringa oleifera, Zingiber officinale, and Azadirachta indicain Alloxan-Induced Diabetic Male Wistar Rats: A Preclinical Study
Authors: Numonde Emieseimokumo , Momoh Isaac Sokoato , Sheneni Victor Duniya , Okosesi Ebunoluwa Ajibike , Ibrahim Micheal Omeyiza
Published: June 2024

Diabetes, a silent killer, ravages the kidney and liver, leaving a trail of destruction in its wake. Studies have suggested a linkconnectingdysfunctional liver and renalactivity along side glucotoxicretinopathy in patients of type 2 diabetes mellitus. Against this background, our preclinical study unveils the remarkable nephro-hepatoprotective effects of herbal teas fromHibiscus sabdariffa, Moringa oleifera, Zingiber officinale, and Azadirachta indicain diabetic male Wistar rats induced with alloxan.Diabetes of artificial source was administered through a one-time interperitonealadministeration of about seven categorieshaving 6 rats in the individual group.control (glycemic), diabetic groupthat is made up of alloxan treatment + Zobo (100+400 mg/kg)., alloxan + moringa (100 +200 mg/kg), alloxan + ginger (100+500 mg/kg), alloxan + Dogoyaro (100+250 mg/kg), and lastly, the alloxan +glibenclamide(100+5mg/kg) were orally given for 28 days.Reduction of tissue weight was observed upon administration of alloxan which was ameliorated upon treatment with the selected herbal teas. Also, elevated levels of liver and kidney biomakersinduced by alloxan were reversed upon administration of the Herbal teas. Furthermore, the Herbal teas decreased fasting blood glucose, which was initially significantly increased byalloxan (p<0.05). Consequently, given to their antihyperglycemic and nephro-hepatoprotective prowess, these selected herbal teas offer a beacon of hope for the millions afflicted not just with diabetes but also diabetes-related kidney and liver diseases.
Diversifying selection and adaptive introgression of carotenoid-processing genes underlie the evolution of bill color in the long-tailed finch
Authors: Hooper Daniel M. , McDiarmid Callum S. , Powers Matthew J. , Justyn Nicholas M. , Kučka Marek , Hart Nathan S. , Hill Geoffrey E. , Andolfatto Peter , Chan Yingguang Frank , Griffith Simon C.
Published: June 2024

Carotenoid pigmentation produces the yellow and red coloration of birds and other vertebrates, but our understanding of the genetic architecture of carotenoid ornamentation is largely limited to studies of novel color variants observed in captively bred populations. The complexity of carotenoid-based color evolution in nature remains poorly characterized. Here, we examine the long-tailed finchPoephila acuticauda, an Australian songbird with two hybridizing subspecies that differ in bill coloration: yellow in western subspeciesacuticaudaand red in eastern subspecieshecki. We characterize the carotenoid composition of each subspecies and find that yellow bills can be explained by the loss of C(4)-oxidation, thus blocking yellow dietary pigments from being metabolized to red. Combining linked-read genomic sequencing and reflectance spectrophotometry measurements of bill color collected from wild-sampled finches and laboratory crosses, we identify four loci that together explain 53% of variance in this trait. The two loci of largest effect contain the genesCYP2J19, an essential enzyme for the ketolation via C(4)-oxidation of dietary carotenoids, andTTC39B, an enhancer of ketocarotenoid production. Evolutionary genealogy reconstruction indicates that the red-billed phenotype is ancestral and yellow alleles at bothCYP2J19andTTC39Barose and fixed inacuticaudaapproximately 100 kya. Yellow alleles then introgressed intoheckiless than 5 kya. Across all four loci,acuticaudaderived variants show evidence of selective sweeps, implying that yellow bill coloration has been favored by natural selection. Our study suggests that the frequent adaptive evolutionary transitions between red and yellow ornamentation in nature can have a simple genetic basis.

Significance

We studied variation in carotenoid ornamentation of an Australian songbird with two hybridizing subspecies that differ in bill color: one yellow and the other red. We identified a single metabolic process, C(4)-oxidation, underlying the distinct carotenoid composition of these two bill colors. Genetic association mapping revealed four major effect loci that explained most of the observed variation the trait, including the oxidative ketolation enzymeCYP2J19and the carotenoid ketolation enhancer geneTTC39B. Evolutionary reconstruction indicates that yellow alleles are derived, ancient (~100 kya), and under positive selection. This has driven their recent (<5 kya) adaptive introgression across the hybrid zone. These findings have important implications for understanding the role of natural selection in phenotypic evolution in natural systems.
Modulation ofSaprolegnia parasiticagrowth with copper and ionophores
Authors: Ogunwa Tomisin Happy , Thornhill Madison Grace , Ledezma Daniel , Peterson Ryan Loren
Published: June 2024

Saprolegnia parasiticais an oomycete pathogen responsible for saprolegniasis diseases that result in large production losses in the catfish and salmon aquaculture industry. The use of copper sulfate as an anti-Saprolegnia treatment has been reported as an alternative to malachite green, formaldehyde and hydrogen peroxide treatment methods. The current study investigates a new strategy to inhibitSaprolegnia parasiticagrowth by combining copper and ionophores at low levels. The chemical agents tetraethylthiuram disulfide (TDD), ciclopirox olamine (CLP), 2-mercaptopyridine N-oxide (MPO), 5-chloro-8-hydroxy-7-iodoquinoline (CHI), 5,7-dichloro-8-hydroxyquinoline (DHQ) and 8-Quinolinol (8QN) were identified to inhibitS. parasiticagrowth in a copper-dependent manner. At concentrations below the lethal dose of individual ionophore, increasing copper concentrations resulted in synergeticS. parasiticagrowth inhibition. The addition of the exogenous copper chelator bathocuproine sulfate (BCS), reversed the inhibition ofS. parasiticagrowth by TDD, CLP, MPO, and 8QN but not CHI and DHQ. Our data demonstrates that ionophores, in combination with low levels of copper, can effectively limitS. parasiticagrowth both in a liquid and solid support growth environment. Investigations into the underlying mechanism of Cu-ionophore toxicity are discussed.
Extensive location bias of the GPCR-dependent translatome via site-selective activation of mTOR
Authors: Klauer Matthew J , Jagla Caitlin AD , Tsvetanova Nikoleta G
Published: June 2024

G protein-coupled receptors (GPCRs) modulate various physiological functions by re-wiring cellular gene expression in response to extracellular signals. Control of gene expression by GPCRs has been studied almost exclusively at the transcriptional level, neglecting an extensive amount of regulation that takes place translationally. Hence, little is known about the nature and mechanisms of gene-specific post-transcriptional regulation downstream of receptor activation. Here, we apply an unbiased multiomics approach to delineate an extensive translational regulatory program initiated by the prototypical beta2-adrenergic receptor (β2-AR) and provide mechanistic insights into how these processes are orchestrated. Using ribosome profiling (Ribo-seq), we identify nearly 120 novel gene targets of adrenergic receptor activity which expression is exclusively regulated at the level of translation. We next show that all translational changes are induced selectively by endosomal β2-ARs. We further report that this proceeds through activation of the mammalian target of rapamycin (mTOR) pathway. Specifically, within the set of translational GPCR targets we discover significant enrichment of genes with 5’ terminal oligopyrimidine (TOP) motifs, a gene class classically known to be translationally regulated by mTOR. We then demonstrate that endosomal β2-ARs are required for mTOR activation and subsequent mTOR-dependent TOP mRNA translation. Together, this comprehensive analysis of drug-induced translational regulation establishes a critical role for location-biased GPCR signaling in fine-tuning the cellular protein landscape.
Systemic delivery of murine SOD2 mRNA to experimental abdominal aortic aneurysm mitigates expansion and rupture
Authors: Yan Huimin , Hu Ying , Lyu Yang , Akk Antonina , Hirbe Angela C. , Wickline Samuel A. , Pan Hua , Roberson Elisha D.O. , Pham Christine T.N.
Published: June 2024

Background

Oxidative stress is implicated in the pathogenesis and progression of abdominal aortic aneurysm (AAA). Antioxidant delivery as a therapeutic for AAA is of substantial interest although clinical translation of antioxidant therapy has met with significant challenges due to limitations in achieving sufficient antioxidant levels at the site of AAA. We posit that nanoparticle-based approaches hold promise to overcome challenges associated with systemic administration of antioxidants.

Methods

We employed a peptide-based nanoplatform to overexpress a key modulator of oxidative stress, superoxide dismutase 2 (SOD2). The efficacy of systemic delivery of SOD2 mRNA as a nanotherapeutic agent was studied in two different murine AAA models. Unbiased mass spectrometry-enabled proteomics and high-dimensional bioinformatics were used to examine pathways modulated by SOD2 overexpression.

Results

The murine SOD2 mRNA sequence was mixed with p5RHH, an amphipathic peptide capable of delivering nucleic acidsin vivoto form self-assembled nanoparticles of ∼55 nm in diameter. We further demonstrated that the nanoparticle was stable and functional up to four weeks following self-assembly when coated with hyaluronic acid. Delivery of SOD2 mRNA mitigated the expansion of small AAA and largely prevented rupture. Mitigation of AAA was accompanied by enhanced SOD2 protein expression in aortic wall tissue. Concomitant suppression of nitric oxide, inducible nitric oxide synthase expression, and cell death was observed. Proteomic profiling of AAA tissues suggests that SOD2 overexpression augments levels of microRNAs that regulate vascular inflammation and cell apoptosis, inhibits platelet activation/aggregation, and downregulates mitogen-activated protein kinase signaling. Gene set enrichment analysis shows that SOD2 mRNA delivery is associated with activation of oxidative phosphorylation, lipid metabolism, respiratory electron transportation, and tricarboxylic acid cycle pathways.

Conclusions

These results confirm that SOD2 is key modulator of oxidative stress in AAA. This nanotherapeutic mRNA delivery approach may find translational application in the medical management of small AAA and the prevention of AAA rupture.
ER-phagy Receptor’s Intrinsically Disordered Modules Drive ER Fragmentation and ER-phagy
Authors: Rudinskiy Mikhail , Galli Carmela , Raimondi Andrea , Molinari Maurizio
Published: June 2024

Membrane remodeling leading to fragmentation is crucial for autophagy programs that control capture by phagophores or endolysosomes of portions of organelles to be removed from cells. It is driven by membrane-bound autophagy receptors that display cytoplasmic intrinsically disordered modules (IDRs) engaging Atg8/LC3/GABARAP (LC3). Studies on endoplasmic reticulum (ER)-phagy receptors of the FAM134 family revealed the importance of sequential FAM134 proteins phosphorylation, ubiquitylation and clustering for execution of the ER-phagy programs. In this model, ER fragmentation is promoted/facilitated by the membrane-remodeling function of FAM134 reticulon homology domains (RHDs). However, RHDs are not conserved in ER-phagy receptors. The question that we tackle in this work is if activation of ER-phagy receptors anchored at the ER membrane with conventional membrane spanning domains, i.e., most of the ER-phagy receptors known to date, eventually trigger ER remodeling and fragmentation, and how. Here, we show that the membrane-tethering modules of ER-phagy receptors (RHDs for FAM134B, single/multi spanning transmembrane domains for TEX264 and SEC62) determine the sub-compartmental distribution of the receptors but are dispensable for ER fragmentation, regardless of their propensity to remodel the ER membrane. Rather, ER fragmentation is promoted by the ER-phagy receptors intrinsically disordered region (IDR) modules that are a conserved feature of all ER-phagy receptors exposed at the cytoplasmic face of the ER membrane. Since cytoplasmic IDRs with net negative charge are conserved in autophagy receptors at the limiting membrane of other organelles, we anticipate that conserved mechanisms of organelle fragmentaVon driven by cytoplasmic exposed IDRs could operate in eukaryoVc cells.
Exact counterdiabatic driving in finite topological lattice models
Authors: Duncan Callum W.
Published: June 2024

Adiabatic protocols are often employed in state preparation schemes but require the system to be driven by a slowly varying Hamiltonian so that transitions between instantaneous eigenstates are exponentially suppressed. Counterdiabatic driving is a technique to speed up adiabatic protocols by including additional terms calculated from the instantaneous eigenstates that counter diabatic excitations. However, this approach requires knowledge of the full eigenspectrum meaning that the exact analytical form of counterdiabatic driving is only known for a subset of problems, e.g., the harmonic oscillator and transverse field Ising model. We extend this subset of problems to include the general family of one-dimensional noninteracting lattice models with open boundary conditions and arbitrary onsite potential, tunneling terms, and lattice size. We will derive a general analytical form for the counterdiabatic term for all states of lattice models, including bound and in-gap states which appear, e.g., in topological insulators. We also derive the general analytical form of targeted counterdiabatic driving terms which are tailored to enforce the dynamical state to remain in a specific state. As an example of the use of the derived analytical forms, we consider state transfer using the topological edge states of the Su-Schrieffer-Heeger model. The derived analytical counterdiabatic driving Hamiltonian can be utilized to inform control protocols in many-body lattice models or to probe the nonequilibrium properties of lattice models.

Published by the American Physical Society
2024
Exact solution to the quantum and classical dimer models on the spectre aperiodic monotiling
Authors: Singh Shobhna , Flicker Felix
Published: June 2024

The decades-long search for a shape that tiles the plane only aperiodically under translations and rotations recently ended with the discovery of the “spectre” aperiodic monotile. In this setting we study the dimer model, in which dimers are placed along tile edges such that each vertex meets precisely one dimer. The complexity of the tiling combines with the dimer constraint to allow an exact solution to the model. The partition function is Z=2Nmystic+1 where Nmystic is the number of “mystic” tiles. We exactly solve the quantum dimer (Rokhsar-Kivelson) model in the same setting by identifying an eigenbasis at all interaction strengths V/t. We find that test monomers, once created, can be infinitely separated at zero energy cost for all V/t, constituting a deconfined phase in a (2+1)-dimensional bipartite quantum dimer model.

Published by the American Physical Society
2024
Single production of an exotic vectorlike
Y
quark at future high energy
pp
colliders
Authors: Shang Liangliang , Yan Yuxiao , Moretti Stefano , Yang Bingfang
Published: June 2024

Vectorlike quarks have been predicted in various new physics scenarios beyond the Standard Model. In a simplified modelling of a (B,Y) doublet including a vectorlike quark Y, with charge −43e, there are only two free parameters: the Y coupling κY and mass mY. In the five flavor scheme, we investigate the single production of the

Y

state decaying into Wb at the Large Hadron Collider (LHC) run-III and High-Luminosity LHC (HL-LHC) operating at s=14  TeV, the possible High-Energy LHC (HE-LHC) with s=27  TeV as well as the Future Circular Collider in hadron-hadron mode (FCC-hh) with s=100  TeV. Through detailed signal-to-background analyses and detector simulations, we assess the exclusion capabilities of the Y state at the different colliders. We find that this can be improved significantly with increasing collision energy, especially at the HE-LHC and FCC-hh, both demonstrating an obvious advantage with respect to the HL-LHC in the case of high mY. Assuming a 10% systematic uncertainty on the background event rate, the exclusion capabilities are summarized as follows: (1) the LHC run-III can exclude the correlated regions of κY∈[0.06,0.5] and mY∈[1500  GeV,3800  GeV] with integrated luminosity L=300  fb−1; (2) the HL-LHC can exclude the correlated regions of κY∈[0.05,0.5] and mY∈[1500  GeV,3970  GeV] with L=3  ab−1; (3) the HE-LHC can exclude the correlated regions of κY∈[0.06,0.5] and mY∈[1500  GeV,6090  GeV] with L=3  ab−1; (4) the FCC-hh can exclude the correlated regions of κY∈[0.08,0.5] and mY∈[1500  GeV,10080  GeV] with L=3  ab−1.

Published by the American Physical Society
2024
Field independent additive constant in Wilson actions
Authors: Pagani Carlo , Sonoda Hidenori
Published: June 2024

We discuss the field independent additive constant in Wilson actions carefully within the exact renormalization group formalism. The additive constant does not affect the correlation functions of fields normalized by the partition function, and for that reason it is often ignored. But it is an essential part of the partition function, and in the limit where the UV cutoff goes to zero, the constant gives a renormalized vacuum energy density. We discuss some concrete examples: the massless and massive Gaussian theory for a single component scalar field and a Dirac fermion and the linear sigma model in the large N limit.

Published by the American Physical Society
2024
A strategic process to manage the right value proposition with retailers in the B2C sector
Authors: Baidya Mehir , Maity Bipasha
Published: June 2024

Purpose

In the past, there have been few studies that shed light on the process of how to maintain the right value proposition with retailers. This research aims to examine the factors that play a significant role in the process of keeping the right value proposition with retailers in the B2C sector through a firm-retailer dependency lens.

Design/methodology/approach

Longitudinal data was gathered from 700 retailers who deal with the products of two of India’s firms in the B2C sector. Three data sets were created, and an econometric model was fitted to each data set separately.

Findings

The findings revealed that the firm-centric and retailer-centric variables had positive impacts, whereas competitor-centric variables negatively impacted the value proposition. Furthermore, the intensity of the impact on the value proposition of all types of drivers varied from “quiet-quitting retailers” to “active retailers.”

Practical implications

This study’s findings should assist managers in framing a value-sharing strategy to maintain a “win-win” relationship with retailers.

Originality/value

Using real-world data and a panel regression model, this research extends the theory on the relationship between value proposition and its drivers in the B2C sector and, hence, enriches the literature on the interface between business process management, retailing, and marketing.