Unveiling the ecotoxicological effects of azoxystrobin-based fungicides at realistic concentrations on the land snail, Theba pisana.

The ecotoxicological consequences of azoxystrobin on land snails have not yet been addressed. Therefore, the present study aims to provide novel data on the threat of a commercial grade azoxystrobin (AMISTAR) at two environmentally relevant concentrations (0.3 µg/ml) and tenfold (3 µg/ml) on the model species, Theba pisana by physiological, biochemical, and histopathological markers for 28 days. Our results showed a reduction in animal food consumption and growth due to exposure to both azoxystrobin concentrations. It also induced oxidative stress and led to a significant decrease in lipid peroxidation (LPO) levels after 7 days of exposure, while the opposite effect occurred after 28 days. Except for the 7-day exposure, all treated snails had significantly reduced glutathione (GSH) content and increased catalase (CAT) activity at all-time intervals. Glutathione peroxidase (GPx), glutathione-S-transferase (GST) activities, and protein content (PC) were elevated in treated snails at all-time intervals. Moreover, alterations in acetylcholinesterase (AChE) activity between a decrease and an increase were noticed. Additionally, azoxystrobin exerted changes in T. pisana hepatopancreas architecture. Our study suggests that azoxystrobin may have negative ecological consequences for T. pisana and highlights its potential risks to the natural environment.

The functional role of conscious sensation of movement.

This paper proposes a new framework for investigating neural signals sufficient for a conscious sensation of movement and their role in motor control. We focus on signals sufficient for proprioceptive awareness, particularly from muscle spindle activation and from primary motor cortex (M1). Our review of muscle vibration studies reveals that afferent signals alone can induce conscious sensations of movement. Similarly, studies employing peripheral nerve blocks suggest that efferent signals from M1 are sufficient for sensations of movement. On this basis, we show that competing theories of motor control assign different roles to sensation of movement. According to motor command theories, sensation of movement corresponds to an estimation of the current state based on afferent signals, efferent signals, and predictions. In contrast, within active inference architectures, sensations correspond to proprioceptive predictions driven by efferent signals from M1. The focus on sensation of movement provides a way to critically compare and evaluate the two theories. Our analysis offers new insights into the functional roles of movement sensations in motor control and consciousness.

Insulin receptor isoform B is required for efficient proinsulin processing in pancreatic ß cells.

The insulin receptor (INSR, IR) has two isoforms, IRA and IRB, through alternative splicing. However, their distinct functions in vivo remain unclear. Here we generated ß cell-specific IRB knockout (KO) mice (ßIRBKO). The KO mice displayed worsened hyperinsulinemia and hyperproinsulinemia in diet-induced obesity due to impaired proinsulin processing in ß cells. Mechanistically, loss of IRB suppresses eukaryotic translation initiation factor 4G1 (eIF4G1) by stabilizing the transcriptional receptor sterol-regulatory element binding protein 1 (SREBP1). Moreover, excessive autocrine proinsulin in ßIRBKO mice enhances the activity of extracellular signal-regulated kinase (ERK) through the remaining IRA to further stabilize nuclear SREBP1, forming a feedback loop. Collectively, our study paves the way to dissecting the isoform-specific function of IR in vivo and highlights the important roles of IRB in insulin processing and protecting ß cells from lipotoxicity in obesity.

Chaos control in cardiac dynamics: terminating chaotic states with local minima pacing.

Current treatments of cardiac arrhythmias like ventricular fibrillation involve the application of a high-energy electric shock, that induces significant electrical currents in the myocardium and therefore involves severe side effects like possible tissue damage and post-traumatic stress. Using numerical simulations on four different models of 2D excitable media, this study demonstrates that low energy pulses applied shortly after local minima in the mean value of the transmembrane potential provide high success rates. We evaluate the performance of this approach for ten initial conditions of each model, ten spatially different stimuli, and different shock amplitudes. The investigated models of 2D excitable media cover a broad range of dominant frequencies and number of phase singularities, which demonstrates, that our findings are not limited to a specific kind of model or parameterization of it. Thus, we propose a method that incorporates the dynamics of the underlying system, even during pacing, and solely relies on a scalar observable, which is easily measurable in numerical simulations.

Prediction of adverse drug reactions in geriatric patients admitted to intensive care units. / [Artículo traducido] Predicción de reacciones adversas a medicamentos en pacientes geriátricos ingresados en unidades de cuidados intensivos.

INTRODUCTION: Intensive Care Units (ICUs) pose challenges in managing critically-ill patients with polypharmacy, potentially leading to Adverse Drug Reactions (ADRs), particularly in the elderly. OBJECTIVE: To evaluate whether the severity and clinical prognosis scores used in ICUs correlate with the prediction of ADRs in aged patients admitted to an ICU. METHODS: A cohort study was conducted in a Brazilian University Hospital ICU. APACHE II and SAPS 3 assessed clinical prognosis, while GerontoNet ADR Risk Score and BADRI evaluated ADR risk at ICU admission. Severity of the patients' clinical conditions was evaluated daily based on the SOFA score. Adverse Drug Reaction (ADR) screening was performed daily through the identification of ADR triggers. RESULTS: 1295 triggers were identified (median 30 per patient, IQR = 28), with 15 suspected ADRs. No correlation was observed between patient severity and ADRs at admission (p=0.26), during hospitalization (p=0.91), or at follow-up (p=0.77). There was also no association between death and ADRs (p=0.28) or worse prognosis and ADRs (p>0.05). Higher BADRI scores correlated with more ADRs (p=0.001). CONCLUSIONS: The data suggest that employing the severity and clinical prognosis scores used in Intensive Care Units is not sufficient to direct active pharmacovigilance efforts, which are therefore indicated for critically ill patients.

Differential changes in end organ immune cells and inflammation in salt-sensitive hypertension: effects of lowering blood pressure.

We reported that salt-sensitive hypertension (SSHTN) is associated with increased pro-inflammatory immune cells, inflammation, and inflammation-associated lymphangiogenesis in the kidneys and gonads of male and female mice. However, it is unknown whether these adverse end organ effects result from increased blood pressure (BP), elevated levels of salt, or both. We hypothesized that pharmaceutically lowering BP would not fully alleviate the renal and gonadal immune cell accumulation, inflammation, and lymphangiogenesis associated with SSHTN. SSHTN was induced in male and female C57BL6/J mice by administering nitro-L-arginine methyl ester hydrochloride (L-NAME; 0.5 mg/ml) in their drinking water for 2 weeks, followed by a 2-week washout period. Subsequently, the mice received a 3-week 4% high salt diet (SSHTN). The treatment group underwent the same SSHTN induction protocol but received hydralazine (HYD; 250 mg/L) in their drinking water during the diet phase (SSHTN+HYD). Control mice received tap water and a standard diet for 7 weeks. In addition to decreasing systolic BP, HYD treatment generally decreased pro-inflammatory immune cells and inflammation in the kidneys and gonads of SSHTN mice. Furthermore, the decrease in BP partially alleviated elevated renal and gonadal lymphatics and improved renal and gonadal function in mice with SSHTN. These data demonstrate that high systemic pressure and salt differentially act on end organ immune cells, contributing to the broader understanding of how BP and salt intake collectively shape immune responses and highlight implications for targeted therapeutic interventions.

Metabolomics and transcriptomics combined with physiology reveal key metabolic pathway responses in tobacco roots exposed to NaHS.

Hydrogen sulfide (H2S) has emerged as a novel endogenous gas signaling molecule, joining the ranks of nitric oxide (NO) and carbon monoxide (CO). Recent research has highlighted its involvement in various physiological processes, such as promoting root organogenesis, regulating stomatal movement and photosynthesis, and enhancing plant growth, development, and stress resistance. Tobacco, a significant cash crop crucial for farmers' economic income, relies heavily on root development to affect leaf growth, disease resistance, chemical composition, and yield. Despite its importance, there remains a scarcity of studies investigating the role of H2S in promoting tobacco growth. This study exposed tobacco seedlings to different concentrations of NaHS (an exogenous H2S donor) - 0, 200, 400, 600, and 800 mg/L. Results indicated a positive correlation between NaHS concentration and root length, wet weight, root activity, and antioxidant enzymatic activities (CAT, SOD, and POD) in tobacco roots. Transcriptomic and metabolomic analyses revealed that treatment with 600 mg/L NaHS significantly effected 162 key genes, 44 key enzymes, and two metabolic pathways (brassinosteroid synthesis and aspartate biosynthesis) in tobacco seedlings. The addition of exogenous NaHS not only promoted tobacco root development but also potentially reduced pesticide usage, contributing to a more sustainable ecological environment. Overall, this study sheds light on the primary metabolic pathways involved in tobacco root response to NaHS, offering new genetic insights for future investigations into plant root development.

Morphological, anatomical, and transcriptomics analysis reveals the regulatory mechanisms of cassava plant height development.

BACKGROUND: Cassava is one of three major potato crops and the sixth most important food crop globally. Improving yield remains a primary aim in cassava breeding. Notably, plant height significantly impacts the yield and quality of crops; however, the mechanisms underlying cassava plant height development are yet to be elucidated. RESULTS: In this study, we investigated the mechanisms responsible for cassava plant height development using phenotypic, anatomical, and transcriptomic analyses. Phenotypic and anatomical analysis revealed that compared to the high-stem cassava cultivar, the dwarf-stem cassava cultivar exhibited a significant reduction in plant height and a notable increase in internode tissue xylem area. Meanwhile, physiological analysis demonstrated that the lignin content of dwarf cassava was significantly higher than that of high cassava. Notably, transcriptome analysis of internode tissues identified several differentially expressed genes involved in cell wall synthesis and expansion, plant hormone signal transduction, phenylpropanoid biosynthesis, and flavonoid biosynthesis between the two cassava cultivars. CONCLUSIONS: Our findings suggest that internode tissue cell division, secondary wall lignification, and hormone-related gene expression play important roles in cassava plant height development. Ultimately, this study provides new insights into the mechanisms of plant height morphogenesis in cassava and identifies candidate regulatory genes associated with plant height that can serve as valuable genetic resources for future crop dwarfing breeding.

Pia-FLOW: Deciphering hemodynamic maps of the pial vascular connectome and its response to arterial occlusion.

The pial vasculature is the sole source of blood supply to the neocortex. The brain is contained within the skull, a vascularized bone marrow with a unique anatomical connection to the brain meninges. Recent developments in tissue clearing have enabled detailed mapping of the entire pial and calvarial vasculature. However, what are the absolute flow rate values of those vascular networks? This information cannot accurately be retrieved with the commonly used bioimaging methods. Here, we introduce Pia-FLOW, a unique approach based on large-scale transcranial fluorescence localization microscopy, to attain hemodynamic imaging of the whole murine pial and calvarial vasculature at frame rates up to 1,000 Hz and spatial resolution reaching 5.4 µm. Using Pia-FLOW, we provide detailed maps of flow velocity, direction, and vascular diameters which can serve as ground-truth data for further studies, advancing our understanding of brain fluid dynamics. Furthermore, Pia-FLOW revealed that the pial vascular network functions as one unit for robust allocation of blood after stroke.

Prognostic value of angiographic microvascular resistance in patients with ST-segment elevation myocardial infarction.

BACKGROUND: The Angiographic Microvascular Resistance (AMR), derived from a solitary angiographic view, has emerged as a viable substitute for the Index of Microcirculatory Resistance (IMR). However, the prognostic significance in ST-Segment Elevation Myocardial Infarction (STEMI) patients is yet to be established. This research endeavors to explore the prognostic capabilities of AMR in patients diagnosed with STEMI. METHODS: In this single-center, retrospective study, 232 patients diagnosed with STEMI who received primary Percutaneous Coronary Intervention (PCI) were recruited from January 1, 2018, to June 30, 2022. Utilizing the maximally selected log-rank statistics analysis, participants were divided into two cohorts according to an AMR threshold of 2.55 mmHg*s/cm. The endpoint evaluated was a composite of all-cause mortality or hospital readmission due to heart failure. RESULTS: At a median follow-up of 1.74 (1.07, 3.65) years, the composite endpoint event was observed in 28 patients within the higher AMR group and 8 patients within the lower AMR group. The higher AMR group showed a significantly higher risk for composite outcome compared to those within the low-AMR group (HRadj: 3.33; 95% CI 1.30‒8.52; p = 0.03). AMR ≥ 2.55 mmHg*s/cm was an independent predictor of the composite endpoint (HR = 2.33; 95% CI 1.04‒5.21; p = 0.04). Furthermore, a nomogram containing age, sex, left ventricle ejection fraction, post-PCI Quantitative Flow Ratio (QFR), and AMR was developed and indicated a poorer prognosis in the high-risk group for STEMI patients at 3 years. (HR=4.60; 95% CI 1.91‒11.07; p < 0.01). CONCLUSIONS: AMR measured after PCI can predict the risk of all-cause death or readmission for heart failure in patients with STEMI. AMR-involved nomograms improved predictive performance over variables alone.

Blood, Sweat, and Tears: Implications for Hydration Testing in Combat Sports-Investigating Body Mass Loss and Biomarker Changes.

Combat sports athletes often undergo rapid body mass loss (BML), which presents health risks. Hydration testing has been proposed as a possible solution to reduce or eliminate rapid BML. However, combat sports athletes may exhibit distinct physiological characteristics due to repeated exposure to BML. Thus, traditional and emerging hydration biomarkers should be investigated to determine their potential suitability for field use in this cohort. This study examined whether BML can explain changes in serum and urine osmolality (SosmΔ, UosmΔ), tear osmolarity (TosmΔ), hematocrit (HctΔ), and urine-specific gravity (USGΔ) after mild-moderate passive dehydration. Biomarker reliability was also assessed across two trials. Fifteen male and female combat sports athletes (age: 26.3 ± 5.3 years, body mass: 67.7 ± 9.9 kg) underwent a sauna protocol twice (5-28 days apart) aiming for 4% BML. The average BML in Trials 1 and 2 was 3.0 ± 0.7%. Regression analysis revealed that BML explained HctΔ (R2 = 0.22, p = 0.009) but not SosmΔ (R2 = 0.11, p = 0.079) or other biomarkers. Intraclass correlation coefficients (ICCs) were significant for all biomarkers except TosmΔ (ICC = 0.06, p = 0.37) and post-Tosm (ICC = 0.04, p = 0.42); post-Hct performed best (ICC = 0.82, p < 0.001). Contingency tables with post-Sosm (295 mOsm/kg) and post-USG (1.020) cutoffs revealed an 80% true negative rate (TNR) and a 62% true positive rate (TPR). Increasing the Sosm cutoff to 301 mOsm/kg decreased the TNR to 52% but increased the TPR to 83%. Although blood parameters were most sensitive to BML, they could only explain 11%-22% of biomarker variation. The typical USG cutoff misclassified 42% of athletes postdehydration, and reliability was generally poor-moderate. Alternative strategies should be pursued to manage rapid BML in combat sports.

Mentha piperita leaf extract suppresses the release of ATP from epidermal keratinocytes and reduces dermal thinning as well as wrinkle formation.

OBJECTIVES: To achieve a more beautiful and younger appearance, reducing wrinkles is a key concern. The process of wrinkle formation is complex and the development of truly effective cosmetic ingredients to reduce wrinkles remains a challenge. Recent studies have revealed a close relationship between wrinkles and skin thinning, suggesting that preventing skin thinning could also prevent wrinkle formation. In this study, we examined the role of extracellular adenosine triphosphate (eATP) in the progression of thinning, as eATP reportedly increases skin ageing factors, such as senescence-associated secreted phenotype (SASP) factors in epidermal cells. We determined the effects of Mentha piperita leaf extract on suppressing eATP to reduce thinning and wrinkles. METHODS: Adenosine triphosphate (ATP) levels were measured in normal human epidermal keratinocytes (NHEK) in the presence of M. piperita leaf extract. Dryness, high pH, and UVB radiation were used as extrinsic ageing factors. Intrinsic skin ageing was evaluated by comparing cells from adults (AD-NHEK) and newborns (NB-NHEK). A placebo-controlled in vivo study was carried out with a formulation containing 1% M. piperita leaf extract. RESULTS: The eATP levels were significantly higher in AD-NHEK compared with that in NB-NHEK cells. M. piperita leaf extract significantly decreased eATP levels in adult cells. Extrinsic ageing factors increased eATP levels in NHEK, whereas M. piperita leaf extract significantly suppressed eATP under all conditions. The active components of M. piperita leaf extract, luteolin glucuronide and rosmarinic acid, also decreased eATP. Moreover, compared with placebo lotion, M. piperita leaf extract-formulated lotion markedly increased dermal thickness and reduced wrinkles associated with crow's feet and the neck area. CONCLUSION: We demonstrated for the first time that M. piperita leaf extract containing rosmarinic acid and luteolin-7-O-glucuronide has the potential to reduce eATP release from epidermal keratinocytes. An increase in eATP was observed not only during inflammation but also during natural ageing. Furthermore, the in vivo experiment revealing that 1% M. piperita leaf extract-containing lotion improved dermal thinning and wrinkles across multiple areas is attributed to the amelioration of dermal thinning. Thus, our data suggest the possibility of a novel cosmetic approach for reducing skin ageing by reducing eATP-mediated dermal thinning.

OBJECTIFS: Pour obtenir une apparence plus belle et plus jeune, réduire les rides est une préoccupation clé. Le processus de formation des rides est complexe et le développement d'ingrédients cosmétiques réellement efficaces pour réduire les rides reste un défi. Des études récentes ont révélé une relation étroite entre les rides et l'amincissement de la peau, suggérant que la prévention de l'amincissement de la peau pourrait également prévenir la formation de rides. Dans cette étude, nous avons examiné le rôle de l'adénosine triphosphate extracellulaire (eATP) dans la progression de l'amincissement, car l'eATP augmente apparemment les facteurs de vieillissement de la peau, tels que les facteurs du phénotype sécrétoire associé à la sénescence (SASP) dans les cellules épidermiques. Nous avons déterminé les effets de l'extrait de feuille de Mentha piperita sur la suppression de l'eATP pour réduire l'amincissement et les rides. MÉTHODES: Les niveaux d'adénosine triphosphate (ATP) ont été mesurés dans les kératinocytes épidermiques humains normaux (NHEK) en présence d'extrait de feuille de M. piperita. La sécheresse, le pH élevé et les radiations UVB ont été utilisés comme facteurs de vieillissement extrinsèque. Le vieillissement intrinsèque de la peau a été évalué en comparant les cellules des adultes (AD­NHEK) et des nouveau­nés (NB­NHEK). Une étude in vivo contrôlée par placebo a été réalisée avec une formulation contenant 1% d'extrait de feuille de M. piperita. RÉSULTATS: Les niveaux d'eATP étaient significativement plus élevés dans les AD­NHEK comparés à ceux des cellules NB­NHEK. L'extrait de feuille de M. piperita a significativement diminué les niveaux d'eATP dans les cellules adultes. Les facteurs de vieillissement extrinsèque ont augmenté les niveaux d'eATP dans les NHEK, tandis que l'extrait de feuille de M. piperita a significativement supprimé l'eATP dans toutes les conditions. Les composants actifs de l'extrait de feuille de M. piperita, la lutéoline glucuronide et l'acide rosmarinique, ont également diminué l'eATP. De plus, comparée à la lotion placebo, la lotion formulée avec de l'extrait de feuille de M. piperita a considérablement augmenté l'épaisseur dermique et réduit les rides associées aux pattes d'oie et à la région du cou. CONCLUSION: Nous avons démontré pour la première fois que l'extrait de feuille de M. piperita contenant de l'acide rosmarinique et de la lutéoline­7­O­glucuronide a le potentiel de réduire la libération d'eATP des kératinocytes épidermiques. Une augmentation de l'eATP a été observée non seulement pendant l'inflammation mais aussi pendant le vieillissement naturel. En outre, l'expérience in vivo révélant que la lotion contenant 1% d'extrait de feuille de M. piperita a amélioré l'amincissement dermique et les rides sur plusieurs zones est attribuée à l'amélioration de l'amincissement dermique. Ainsi, nos données suggèrent la possibilité d'une nouvelle approche cosmétique pour réduire le vieillissement de la peau en réduisant l'amincissement dermique médié par l'eATP.

Age-related changes in the bacterial composition of healthy female facial skin in Beijing area.

OBJECTIVE: Exploring the effects of age on microbial community structure and understanding the effects of chronological ageing as well as sun exposure on microbial community diversity. METHOD: The microbial characteristics of the facial skin of 98 adult women aged 18-70 years were studied using 16S rRNA gene sequencing, and differences based on age and reported sun exposure were assessed. RESULTS: The cheek skin's bacterial diversity and richness increased with age. The relative abundance of Cutibacterium decreased with age, while the relative abundance of Corynebacterium, Anaerococcus, Paracoccus, Micrococcus, Kocuria, Kytococcus, and Chryseobacterium increased. In addition, an increase in Micrococcus and a decrease in Cutibacterium were observed in volunteers with more than 2 h of daily sun exposure compared to volunteers with <2 h of daily sun exposure. Under low-sunlight conditions, Cutibacterium was more prevalent in the youth group, and Corynebacterium, Anaerococcus, and Kytococcus were more prevalent in the older group. CONCLUSION: The diversity and composition of the bacterial community on the cheeks are affected by age and extrinsic factors (sun exposure) may also play a role in this.

OBJECTIF: Étudier les effets de l'âge sur la structure de la communauté microbienne et comprendre les effets du vieillissement chronologique ainsi que de l'exposition au soleil sur la diversité de la communauté microbienne. MÉTHODE: Les caractéristiques microbiennes de la peau du visage de 98 femmes adultes âgées de 18 à 70 ans ont été étudiées à l'aide du séquençage génétique de l'ARNr 16S, et les différences basées sur l'âge et l'exposition au soleil rapportée ont été évaluées. RÉSULTAT: La diversité et la richesse bactériennes de la peau des joues ont augmenté avec l'âge. L'abondance relative de Cutibacterium a diminué avec l'âge, tandis que l'abondance relative de Corynebacterium, Anaerococcus, Paracoccus, Micrococcus, Kocuria, Kytococcus et Chryseobacterium a augmenté. De plus, une augmentation de Micrococcus et une diminution de Cutibacterium ont été observées chez des volontaires ayant été exposés au soleil pendant plus de 2 heures par jour par rapport à des volontaires ayant été exposés au soleil pendant moins de 2 heures par jour. Dans des conditions de faible luminosité, Cutibacterium était plus prévalent dans le bras des personnes jeunes, et Corynebacterium, Anaerococcus et Kytococcus étaient plus prévalents dans le bras des personnes plus âgées. CONCLUSION: La diversité et la composition de la communauté bactérienne sur les joues sont affectées par l'âge et des facteurs extrinsèques (exposition au soleil) peuvent également y jouer un rôle.

Daily energy expenditure and water turnover in female netball players from the Netball Super League: A doubly labeled water observation study.

To establish the criterion-assessed energy and fluid requirements of female netball players, 13 adult players from a senior Netball Super League squad were assessed over 14 days in a cross-sectional design, representing a two- and one-match microcycle, respectively. Total energy expenditure (TEE) and water turnover (WT) were measured by doubly labeled water. Resting and activity energy expenditure were measured by indirect calorimetry and Actiheart, respectively. Mean 14-day TEE was 13.46 ± 1.20 MJ day-1 (95% CI, 12.63-14.39 MJ day-1). Resting energy expenditure was 6.53 ± 0.60 MJ day-1 (95% CI, 6.17-6.89 MJ day-1). Physical activity level was 2.07 ± 0.19 arbitrary units (AU) (95% CI, 1.95-2.18 AU). Mean WT was 4.1 ± 0.9 L day-1 (95% CI, 3.6-4.7 L day-1). Match days led to significantly greater TEE than training (+2.85 ± 0.70 MJ day-1; 95% CI, +1.00- +4.70 MJ day-1; p = 0.002) and rest (+4.85 ± 0.70 MJ day-1; 95% CI, +3.13-+6.56 MJ day-1; p < 0.001) days. Matches led to significantly greater energy expenditure (+1.85 ± 1.27 MJ; 95% CI, +0.95-+2.76 MJ day-1; p = 0.001) than court-based training sessions. There was no significant difference in TEE (+0.03 ± 0.35 MJ day-1; 95% CI, -0.74-+0.80 MJ day-1; p = 0.936) across weeks. Calibrated Actiheart 5 monitors underestimated TEE (-1.92 ± 1.21 MJ day-1). Energy and fluid turnover were greatest on match days, followed by training and rest days, with no difference across weeks. This study provides criterion-assessed energy and fluid requirements to inform dietary guidance for female netball players.

Exploring the Wilderness within: An Integrative Metabolomics and Transcriptomics Study on Near-Wild and Colonized Aedes aegypti.

This study examines the phenotypic differences between wild-derived F2 Central Valley mosquitoes and the insecticide-susceptible Rockefeller (Rock) lab strain of Ae. aegypti. Given the rarity of wild pyrethroid-susceptible populations, the focus of this work is to develop an understanding of the resistance physiology in this invasive mosquito population and explore the potential of metabolites as diagnostic biomarkers for metabolic resistance. This study utilizes metabolomic, gene expression, and lifespan data for a comparison between strains. The findings indicate that wild-derived mosquitoes with greater metabolic resistance have a lifespan sensitivity to restricted larval nutrition. In terms of metabolism and gene expression, Central Valley mosquitoes show increased activity in oxidoreductase, glutathione metabolism, and the pentose phosphate pathway. Conversely, Rock mosquitoes display signs of metabolic inefficiency and mitochondrial dysregulation, likely tolerated due to the consistency and nutritional abundance of a controlled lab environment. The study also examines Ae. aegypti P450 and GSTE profiles in relation to other insecticide-resistant groups. While metabolomic data can differentiate our study groups, the challenges in biomarker development arise from few detected markers meeting high fold change thresholds.

Treatment effects in epilepsy: a mathematical framework for understanding response over time.

Epilepsy is a neurological disorder characterized by recurrent seizures, affecting over 65 million people worldwide. Treatment typically commences with the use of anti-seizure medications, including both mono- and poly-therapy. Should these fail, more invasive therapies such as surgery, electrical stimulation and focal drug delivery are often considered in an attempt to render the person seizure free. Although a significant portion ultimately benefit from these treatment options, treatment responses often fluctuate over time. The physiological mechanisms underlying these temporal variations are poorly understood, making prognosis a significant challenge when treating epilepsy. Here we use a dynamic network model of seizure transition to understand how seizure propensity may vary over time as a consequence of changes in excitability. Through computer simulations, we explore the relationship between the impact of treatment on dynamic network properties and their vulnerability over time that permit a return to states of high seizure propensity. For small networks we show vulnerability can be fully characterised by the size of the first transitive component (FTC). For larger networks, we find measures of network efficiency, incoherence and heterogeneity (degree variance) correlate with robustness of networks to increasing excitability. These results provide a set of potential prognostic markers for therapeutic interventions in epilepsy. Such markers could be used to support the development of personalized treatment strategies, ultimately contributing to understanding of long-term seizure freedom.

Orexin receptor antagonist increases fat oxidation and suppresses protein catabolism during sleep in humans.

Suvorexant is an orexin receptor antagonist that targets the wake-promoting system. Orexin is also known to regulate energy metabolism in rodents, but its role in humans remains largely unknown. Here, we assessed the effect of suvorexant (20 mg) on energy metabolism during sleep and shortly after awakening in a randomized, double-blind, placebo-controlled, crossover study in 14 healthy men. Suvorexant increased rapid eye movement (REM) but decreased nonrapid eye movement (NREM) stage 1. Energy expenditure during wake after sleep onset (WASO) was higher than that during NREM and REM sleep in the placebo but not in the suvorexant trial, suggesting that the increase in energy expenditure during WASO was due to an activation of the orexin system. Fat oxidation during sleep increased, and its effect remained after waking the next morning. Suvorexant decreased protein catabolism but did not affect overall energy expenditure. The orexin system may affect fat oxidation independent of its roles in sleep regulation in humans.

A specialized population of monocyte-derived tracheal macrophages promote airway epithelial regeneration through a CCR2-dependent mechanism.

Macrophages are critical for maintenance and repair of mucosal tissues. While functionally distinct subtypes of macrophage are known to have important roles in injury response and repair in the lungs, little is known about macrophages in the proximal conducting airways. Single-cell RNA sequencing and flow cytometry demonstrated murine tracheal macrophages are largely monocyte-derived and are phenotypically distinct from lung macrophages at homeostasis. Following sterile airway injury, monocyte-derived macrophages are recruited to the trachea and activate a pro-regenerative phenotype associated with wound healing. Animals lacking the chemokine receptor CCR2 have reduced numbers of circulating monocytes and tracheal macrophages, deficient pro-regenerative macrophage activation and defective epithelial repair. Together, these studies indicate that recruitment and activation of monocyte-derived tracheal macrophages is CCR2-dependent and is required for normal airway epithelial regeneration.