Exploring antiviral effect and mechanism of Jinye Baidu granules（JYBD）against influenza A virus through network pharmacology and in vitro and invivo experiments.

ETHNOPHARMACOLOGICAL RELEVANCE: Jinye Baidu granules (JYBD) have been used to treat acute respiratory tract infections and demonstrated clinical efficacy for the treatment of emerging or epidemic respiratory viruses such as SARS-CoV-2 and influenza virus. AIM OF THE STUDY: This study is to investigate the antiviral effect of JYBD against influenza A viruses (IAV) in vitro and in vivo and elucidate its underlying mechanism. MATERIALS AND METHODS: Ultra-high-performance liquid chromatography connected with Orbitrap mass spectrometer (UHPLC-Orbitrap MS) was employed to describe the chemical profile of JYBD. The potential pathways and targets involved in JYBD against IAV infection were predicted by network pharmacology. The efficacy and mechanism of JYBD were validated through both in vivo and in vitro experiments. Moreover, combination therapy with JYBD and the classic anti-influenza drugs was also investigated. RESULTS: A total of 126 compounds were identified by UHPLC-Orbitrap MS, of which 9 compounds were unambiguously confirmed with reference standards. JYBD could significantly inhibit the replication of multiple strains of IAV, especially oseltamivir-resistant strains. The results of qRT-PCR and WB demonstrated that JYBD could inhibit the excessive induction of pro-inflammatory cytokines induced by IAV infection and regulate inflammatory response through inhibiting JAK/STAT, NF-κB and MAPK pathways. Moreover, both JYBD monotherapy or in combination with oseltamivir could alleviate IAV-induced severe lung injury in mice. CONCLUSIONS: JYBD could inhibit IAV replication and mitigate virus-induced excessive inflammatory response. Combinations of JYBD and neuraminidase inhibitors conferred synergistic suppression of IAV both in vitro and in vivo. It might provide a scientific basis for clinical applications of JYBD against influenza virus infected diseases.

Estimation of gaseous polycyclic aromatic hydrocarbons (PAHs) and characteristics of atmospheric PAHs at a traffic site in Kanazawa, Japan.

Size-fractionated particulate matter (PM2.5 and PM>2.5) was collected at a traffic site in Kanazawa, Japan in a seasonal sampling work in 2020. Nine polycyclic aromatic hydrocarbons (4- to 6-ring PAHs) were determined in fine and coarse particles. The gas/particle partitioning coefficients (Kp) of the PAHs were calculated from the supercooled liquid vapour pressure and octanol-air partitioning coefficient based on the relationships obtained in previous traffic pollution-related studies. Gaseous PAHs were estimated by Kp and the concentrations of PM and particulate PAHs. The concentrations of total PAHs were 32.5, 320.1 and 5646.2 pg/m3 in the PM>2.5, PM2.5 and gas phases, respectively. Significant seasonal trends in PAHs were observed (particle phase: lowest in summer, gas phase: lowest in spring, particle and gas phase: lowest in spring). Compared to 2019, the total PAH concentrations (in particles) decreased in 2020, especially in spring and summer, which might be due to reduced traffic trips during the COVID-19 outbreak. The incremental lifetime cancer risk (ILCR) calculated from the toxic equivalent concentrations relative to benzo[a]pyrene (BaPeq) was lower than the acceptable limit issued by the US Environmental Protection Agency, indicating a low cancer risk in long-term exposure to current PAH levels. It is notable that gaseous PAHs considerably contributed to BaPeq and ILCR (over 50%), which highlighted the significance of gaseous PAH monitoring for public health protection. This low-cost estimation method for gaseous PAHs can be expected to reliably and conveniently obtain PAH concentrations as a surrogate for traditional sampling in the future work.

Airborne fungal communities are more susceptible to anthropogenic activities than bacteria.

Airborne microorganisms (AM) have significant environmental and health implications. Extensive studies have been conducted to investigate the factors influencing the composition and diversity of AM. However, the knowledge of AM with anthropogenic activities has not reach a consensus. In this study, we took advantage of the dramatic decline of outdoor anthropogenic activities resulting from COVID-19 lockdown to reveal their associations. We collected airborne particulate matter before and during the lockdown period in two cities. The results showed that it was fungal diversity and communities but not bacteria obviously different between pre-lockdown and lockdown samples, suggesting that airborne fungi were more susceptible to anthropogenic activities than bacteria. However, after the implementation of lockdown, the co-occurrence networks of both bacterial and fungal community became more complex, which might be due to the variation of microbial sources. Furthermore, Mantel test and correlation analysis showed that air pollutants also partly contributed to microbial alterations. Airborne fungal community was more affected by air pollutants than bacterial community. Notably, some human pathogens like Nigrospora and Arthrinium were negatively correlated with air pollutants. Overall, our study highlighted the more impacts of anthropogenic activities on airborne fungal community than bacterial community and advanced the understanding of associations between anthropogenic activities and AM.

Polyphenol Treatment of Peripheral Blood Mononuclear Cells from Individuals of Different Ages.

Human peripheral blood mononuclear cells (PBMCs) have been largely utilized to assess the cytotoxic, immunomodulatory, and anti-inflammatory properties of both synthetic and natural compounds. Within the latter category, polyphenols from dietary sources have been extensively analyzed. PBMCs represent a feasible in vitro model to study polyphenol hallmarks and activity according to quantitative and qualitative differences in immune responses in individuals of different age. In this chapter, we propose a method for PBMC treatment with polyphenols and analysis designed on age-dependent qualitative and quantitative variability in immune cell performance.

Escala de alerta precoce na identificação de pacientes com risco de deterioração clínica / Early warning scale for identifying patients at risk of clinical deterioration / Escala de alerta temprana en la identificación de pacientes con riesgo de deterioro clínico

Objetivo: avaliar pontuação da National Early Warning Score (NEWS) em relação ao tipo de desfecho e perfil dos pacientes da enfermaria clínica médica de um hospital em Teresina, Piauí, Brasil. Método: estudo quantitativo realizado num hospital público, em Teresina, com 150 prontuários de pacientes internados no setor clínica médica de fevereiro de 2022 a dezembro de 2022, a partir de registros demográficos, clínicos e valores da escala na admissão e desfecho. Resultados: houve associação dos valores da escala com a faixa etária (p=0,029), tempo de internação (p=0,023) e tipo de desfecho (p < 0,001). Alto risco clínico prevaleceu entre pacientes do sexo masculino (13%), na faixa etária de 60 a 94 anos (13%), com permanência de 21 a 57 dias (19,2%) e óbito como desfecho (100%). Conclusão: implementação da referida escala evidenciou ser fundamental para prever agravos clínicos e melhorar qualidade da assistência.

Objective: to evaluate the National Early Warning Score (NEWS) in relation to the type of outcome and profile of patients in the medical clinical ward of a hospital in Teresina, Piauí, Brazil. Method: a quantitative study conducted in a public hospital in Teresina, with 150 medical records of patients admitted to the medical clinic sector from February 2022 to December 2022, based on demographic and clinical records and scale values at admission and outcome. Results: there was an association between the scale values and the age group (p=0.029), length of stay (p=0.023) and type of outcome (p < 0.001). High clinical risk prevailed among male patients (13%), aged between 60 and 94 years (13%), with a stay of 21 to 57 days (19.2%), and death as an outcome (100%). Conclusion: implementation of the aforementioned scale proved to be fundamental for predicting clinical problems and improving care quality.

Objetivo: evaluar el puntaje de la National Early Warning Score (NEWS) con respecto al tipo de desenlace y el perfil de los pacientes de la enfermería clínica médica de un hospital en Teresina, Piauí, Brasil. Método: estudio cuantitativo realizado en un hospital público en Teresina, con 150 historiales médicos de pacientes internados en el sector de clínica médica desde febrero de 2022 hasta diciembre de 2022, a partir de registros demográficos, clínicos y valores de la escala en la admisión y desenlace. Resultados: hubo asociación de los valores de la escala con la edad (p=0,029), tiempo de internación (p=0,023) y tipo de desenlace (p < 0,001). El alto riesgo clínico prevaleció entre los pacientes del sexo masculino (13%), en la franja de edad entre 60 y 94 años (13%), con una estancia de 21 a 57 días (19,2%) y fallecimiento como desenlace (100%). Conclusión: la implementación de dicha escala demostró ser fundamental para prever agravios clínicos y mejorar la calidad de la asistencia.

The assessment of attentional bias to cleanliness stimuli in different versions of the dot-probe task: Evidence for a motivational account.

Vogt et al. (2011) investigated the role of goal-relevance in attention. Specifically, they induced the emotional state of disgust and showed an attentional bias (AB) to goal-related stimuli (i.e., cleanliness pictures) using the dot-probe task. In two experiments, we tested (a) an alternative interpretation and (b) the role of an important methodological feature of the dot-probe task. As the effect can be interpreted alternatively as affective counter-regulation (i.e., cleanliness-related pictures attracted attention because they are positive in the negative disgust state), we added positive stimuli to test whether the AB in the disgust state extends to these stimuli. In Experiment 1, we used the location dot-probe task. That is, participants had to categorise the location of the target. It can be argued that this task confounds attentional processes with response priming processes. In Experiment 2, we used a discrimination dot-probe task, that is, participants had to categorise a target feature that varied orthogonally to location, thus eliminating the confound. In Experiment 1, we did not replicate the effect of emotional state on AB for cleanliness stimuli, whereas in Experiment 2, we did. Mean AB scores for positive stimuli were not affected by emotional state. Two conclusions were drawn: First, the result of Experiment 2 supports the motivational account of Vogt and colleagues. Second, the results support the use of the discrimination task for both theoretical reasons (i.e., effects can be more clearly interpreted as based on attentional processes) and empirical reasons (i.e., the location task did not replicate the expected pattern).

CXCL9/CXCL10 as biomarkers the monitoring of treatment responses in Pulmonary TB patients: a systematic review and meta-analysis.

BACKGROUND: Tuberculosis (TB) remains a persistent threat to global public health and traditional treatment monitoring approaches are limited by their potential for contamination and need for timely evaluation. Therefore, new biomarkers are urgently required for monitoring the treatment efficacy of TB. METHODS: This study aimed to elucidate the levels of CXCL10 and CXCL9 in pulmonary TB patients who underwent anti-TB treatment. The data was acquired from five databases, including PubMed, Ovid, Web of Science, Embase, and the Cochrane Library. A meta-analysis of CXCL10 data from all time points was conducted. Furthermore, a trend meta-analysis of temporal data of CXCL10 and CXCL9 from multiple time points was also performed. RESULTS: It was revealed that patients who responded poorly to anti-TB treatment had higher serum levels relative to those who responded well (SMD: 1.23, 95% CI: -0.37-2.84) at the end of intensive treatment (2 months). Furthermore, heterogeneity was observed in these results, which might be because patients with a prior history of TB and different treatment monitoring methods than those selected in this study were also included. The analysis of alterations in CXCL10 and CXCL9 levels since the last collection time points indicated that their levels reduced with time. CONCLUSION: In summary, the study revealed that reductions in CXCL10 levels during the first two months of anti-TB treatment are correlated with treatment responses. Furthermore, decreasing levels of CXCL9 during the treatment suggest that it may also serve as a biomarker with a similar value to CXCL10. Future in-depth studies are thus warranted to further probe the relevance of CXCL10 and CXCL9 in monitoring the treatment efficacy of TB.

Vanishing white matter.

"Vanishing white matter" (VWM) is a leukodystrophy caused by autosomal recessive pathogenic variants in the genes encoding the subunits of eukaryotic initiation factor 2B (eIF2B). Disease onset and disease course are extremely variable. Onset varies from the antenatal period until senescence. The age of onset is predictive of disease severity. VWM is characterized by chronic neurologic deterioration and, additionally, episodes of rapid and major neurologic decline, provoked by stresses such as febrile infections and minor head trauma. The disease is dominated by degeneration of the white matter of the central nervous system due to dysfunction of oligodendrocytes and in particular astrocytes. Organs other than the brain are rarely affected, with the exception of the ovaries. The reason for the selective vulnerability of the white matter of the central nervous system and, less consistently, the ovaries is poorly understood. eIF2B is a central regulatory factor in the integrated stress response (ISR). Genetic variants decrease eIF2B activity and thereby cause constitutive activation of the ISR downstream of eIF2B. Strikingly, the ISR is specifically activated in astrocytes. Modulation of eIF2B activity and ISR activation in VWM mouse models impacts disease severity, revealing eIF2B-regulated pathways as potential druggable targets.

Deep Molecular Response Rate in Chronic Phase Chronic Myeloid Leukemia: Eligibility to Discontinuation Related to Time to Response and Different Frontline TKI in the Experience of the Gimema Labnet CML National Network.

BACKGROUND: In the last decade, TKIs improved the overall survival (OS) of chronic myeloid leukemia (CML) patients who achieved a deep and sustained molecular response (DMR, defined as stable MR4 and MR4.5). Those patients may attempt therapy discontinuation. In our analysis, we report the differences in eligibility criteria due to time of response and different TKI used as frontline treatment analyzed in a large cohort of CP-CML patients. METHODS: Data were exported by LabNet CML, a network founded by GIMEMA in 2014. The network standardized and harmonized the molecular methodology among 51 laboratories distributed all over Italy for the diagnosis and molecular residual disease (MRD) monitoring. RESULTS: Out of 1777 patients analyzed, 774 had all evaluable timepoints (3, 6, and 12 months). At 3 months, 40 patients obtained ≥MR4: of them 14 (3.6%) with imatinib, 8 (5.8%) with dasatinib, and 18 (7.4%) with nilotinib (P = .093); at 6 months, 146 patients were in MR4: 42 (11%) with imatinib, 38 (28%) with dasatinib, and 66 (27%) with nilotinib (P < .001). At 12 months, 231 patients achieved a DMR: 85 (22%) with imatinib, 55 (40%) with dasatinib and 91 (38%) with nilotinib (P < .001). Achieving at least ≥MR2 at 3 months, was predictive of a DMR at any timepoint of observation: with imatinib 67% versus 30% of patients with 2 years was significant for patients who at 3 months had ≥MR2 (18% vs. 9.9% of pts with

Rapid response system and mortality in intensive care unit: a nationwide cohort study in South Korea.

The beneficial effects of a rapid response system (RRS) on clinical outcomes in patients admitted to a ward have been established. However, the relationship between RRS implementation and clinical outcomes in patients in the intensive care unit (ICU) has not yet been established. Therefore, we aimed to investigate whether the RRS affects clinical outcomes in critically ill patients admitted to the ICU. As a nationwide, population-based cohort study, all adult patients who were admitted to the ICU from 1 January 2019 to 31 December 2021 in South Korea were included. Patients in hospitals with an RRS formed the RRS group; those in hospitals lacking an RRS constituted the non-RRS group. In total, 900,606 patients admitted to the ICU were included in the final analysis. Among them, 365,305 (40.6%) were assigned to the RRS group, and 535,301 (59.4%) were assigned to the non-RRS group. After propensity score (PS) matching, a total of 454,748 patients (227,374 in each group) were included in the final analysis. In the PS-matched cohort, the RRS group showed 8% (odds ratio [OR]: 0.92, 95% confidence interval [CI]: 0.91, 0.94; P < 0.001) and 11% (hazard ratio: 0.89, 95% CI: 0.88, 0.90; P < 0.001) lower in-hospital mortality rates and 1-year all-cause mortality rates than the non-RRS group, respectively. In addition, ICU readmission rates and the occurrence rate for adverse events during hospitalization in the RRS group were 3% (OR: 0.97, 95% CI: 0.95, 0.98; P < 0.001) and 21% (OR: 0.79, 95% CI: 0.78, 0.80; P < 0.001) lower than those in the non-RRS group, respectively. RRS deployment was linked to lower in-hospital and 1-year all-cause mortality rates, ICU readmission rates, and the occurrence of adverse events during hospitalization among ICU patients. The findings indicate that using the RRS could assist not only patients in the ward but also critically ill patients in the ICU.

Extraction of mucilage polysaccharides from chia seed by hydrophobic deep eutectic solvents-based three-phase partitioning system: A phase behavior-driven approach.

By incorporating the hydrophobic deep eutectic solvents (DESs) into the three-phase partitioning (TPP) technique, a TPP-based method was developed to extract the chia seed polysaccharide (CSP) from chia seed. Through a single-factor experiment and response-surface model, the optimal condition for the TPP extraction was determined as DES composed of dodecanoic acid and octanoic acid in a 1:1 M ratio, (NH4)2SO4 concentration of 32.86 %, crude extract-DES ratio of 0.93 (v/v), aqueous phase pH of 4.38, extraction temperature of 35 °C, and extraction time of 10 min. The polysaccharide yield of the constructed TPP method is 8.65 %, which is higher than the conventional water extraction method (yield is 6.96 %). Molecular dynamics simulations reveal the phase behavior of proteins and polysaccharides in the TPP system, showing that noncovalent interactions play a crucial role in the TPP system. The CSP obtained by the TPP method exhibits distinctive composition, structural, physicochemical, and functional properties, leading to improved thermal stability, rheological behavior, and antioxidant performance. Compared with the traditional extraction method, efficient extraction of CSP can be achieved flexibly using the proposed TPP approach, resulting in high yield and quality of CSP, which provides a new path for the large-scale utilization of chia seed.

The inhibitory control deficit of internet gaming disorder: An Event-Related Potentials(ERPs) study.

INTRODUCTION: The primary difficulty and challenge encountered by individuals with Internet Gaming Disorder (IGD) is inhibitory control deficit. Given that different types of inhibitory control have different effects on IGD patients, it is critical to investigate the neurological cognitive processes underlying various inhibitory control problems. METHODS: The IGD-20 questionnaire was used to identify Internet game disorder and healthy control group, and finally Internet game disorder in (n=25) and healthy control group (n=28) in Flanker task, Internet game disorder (n=29) and health control group (n=24) in GO/NOGO task. The Flanker task was employed to investigate distractor interference inhibition control in those with IGD, while the Go/NoGo task was used to measure their prepotent response inhibitory control. Event-related potentials (ERPs) were used to evaluate the brain mechanisms difference of both IGD and healthy participants during these different inhibitory control tasks. RESULTS: Findings indicate that compared to healthy control subjects, individuals with Internet Gaming Disorder (IGD) have deficits in inhibitory control tasks during both distraction inhibition and prepotent response inhibition tasks, and distraction inhibition occurs earlier than prepotent response inhibition. In distraction inhibition tasks, the IGD group's N2 amplitude is significantly lower than the healthy control groups. In prepotent response inhibition, the N2 amplitude provoked in the IGD group is not only significantly lower than in the healthy control group, but the P3 amplitude is also significantly larger in the IGD group. The main brain activity areas of interference inhibitory control are the frontal lobe and prefrontal lobe, while the main brain activity areas of prepotent response inhibitory control are the frontal lobe and occipital lobe. CONCLUSION: The present study concentrates on the differential neurophysiological characteristics observed in individuals with Internet gaming problems, notably the ability to avoid distractions and prepotent reactions. The current research provides foundations for the assessment and development of tailored therapy and treatment methods to address the wide variety of cognitive problems reported in individuals with Internet Gaming Disorder (IGD).

Remifentanil-induced inflammation in microglial cells: Activation of the PAK4-mediated NF-κB/NLRP3 pathway and onset of hyperalgesia.

BACKGROUND: The perioperative use of remifentanil is associated with postoperative hyperalgesia, which can impair recovery and extend hospitalization. Recent studies have revealed that microglia-mediated activation of the NLRP3 inflammasome plays a critical role in opioid-induced hyperalgesia, with NF-κB acting as a pivotal activation point for NLRP3. Despite these findings, the specific molecular mechanisms underlying remifentanil-induced postoperative hyperalgesia remain unclear. This study aims to develop a model of remifentanil-induced hyperalgesia and investigate the molecular mechanisms, focusing on the NF-κB/NLRP3 pathway, using both in vitro and in vivo approaches. METHOD: We established a remifentanil-induced hyperalgesia model and performed proteomic analysis to identify differential protein expression in the spinal cord tissue of rats. NLRP3 or PAK4 antagonists were administered intrathecally in vivo, and mechanical pain thresholds in the hind paws were measured using Von Frey testing. In vitro, we applied NLRP3 or PAK4 inhibitors or used lentivirus infection to silence PAK4, NF-κB, and NLRP3 genes. Protein expression was assessed through immunohistochemistry, immunofluorescence, and Western blotting. Additionally, ELISA was performed to measure IL-1ß and IL-18 levels, and RT-qPCR was conducted to evaluate the transcription of target genes. RESULTS: Proteomic analysis revealed that remifentanil upregulates PAK4 protein in spinal cord tissue two hours after the surgery. In addition, remifentanil induces morphological changes in the spinal cord dorsal horn, characterized by increased expression of PAK4, p-p65, NLRP3 and Iba-1 proteins, which in turn leads to elevated IL-1ß and IL-18 levels and an inflammatory response. Intrathecal injection of NLRP3 or PAK4 inhibitors mitigates remifentanil-induced hyperalgesia and associated changes. In vitro, downregulation of PAK4 inhibits the increase in PAK4, p-p65, NLRP3 and Caspase-1 induced by LPS. Conversely, the downregulation of NLRP3 does not impact the levels of PAK4 and p-p65 proteins, aligning with the in vivo results and suggesting that PAK4 acts as an upstream signaling molecule of NLRP3. CONCLUSION: Remifentanil can increase PAK4 expression in spinal cord dorsal horn cells by activating the NF-κB/NLRP3 pathway and mediating microglial activation, thereby contributing to postoperative hyperalgesia.

Acptp2,3 participates in the regulation of spore production, stress response, and pigments synthesis in Aspergillus cirstatus.

Background: Aspergillus cristatus was a filamentous fungus that produced sexual spores under hypotonic stress and asexual spores under hypertonic stress. It could be useful for understanding filamentous fungi's sporulation mechanism. Previously, we conducted functional studies on Achog1, which regulated the hyperosmotic glycerol signaling (HOG) pathway and found that SI65_02513 was significantly downregulated in the transcriptomics data of ΔAchog1 knockout strain. This gene was located at multiple locations in the HOG pathway, indicating that it might play an important role in the HOG pathway of A. cristatus. Furthermore, the function of this gene had not been identified in Aspergillus fungi, necessitating further investigation. This gene's conserved domain study revealed that it has the same protein tyrosine phosphatases (PTPs) functional domain as Saccharomyces cerevisiae, hence SI65_02513 was named Acptp2,3. Methods: The function of this gene was mostly validated using gene knockout and gene complementation approaches. Knockout strains exhibited sexual and asexual development, as well as pigments synthesis. Morphological observations of the knockout strain were carried out under several stress conditions (osmotic stress, oxidative stress, Congo Red, and sodium dodecyl sulfate (SDS). Real-time fluorescence polymerase chain reaction (PCR) identified the expression of genes involved in sporulation, stress response, and pigments synthesis. Results: The deletion of Acptp2,3 reduced sexual and asexual spore production by 4.4 and 4.6 times, demonstrating that Acptp2,3 positively regulated the sporulation of A. cristatus. The sensitivity tests to osmotic stress revealed that ΔAcptp2,3 strains did not respond to sorbitol-induced osmotic stress. However, ΔAcptp2.3 strains grew considerably slower than the wild type in high concentration sucrose medium. The ΔAcptp2,3 strains grew slower than the wild type on media containing hydrogen peroxide, Congo red, and SDS. These findings showed that Acptp2,3 favorably controlled osmotic stress, oxidative stress, and cell wall-damaging chemical stress in A. cristatus. Deleting Acptp2,3 resulted in a deeper colony color, demonstrating that Apctp2,3 regulated pigment synthesis in A. cistatus. The expression levels of numerous stress-and pigments-related genes matched the phenotypic data. Conclusion: According to our findings, Acptp2,3 played an important role in the regulation of sporulation, stress response, and pigments synthesis in A. cristatus. This was the first study on the function of PTPs in Aspergillus fungi.

Surgery paradigm for locally advanced breast cancer following neoadjuvant systemic therapy.

Locally advanced breast cancer (LABC) remains a significant clinical challenge, particularly in developing countries. While neoadjuvant systemic therapy (NST) has improved the pathological complete response (pCR) rates, particularly in HER2-positive and triple-negative breast cancer patients, surgical management post-NST continues to evolve. The feasibility of omitting surgery and the increasing consideration of breast-conserving surgery, immediate reconstruction in LABC patients are important areas of exploration. Accurate assessment of tumor response to NST through advanced imaging and minimally invasive biopsies remains pivotal, though challenges persist in reliably predicting pCR. Additionally, axillary lymph node management continues to evolve, with emerging strategies aiming to minimize the extent of surgery in patients who achieve nodal downstaging post-NST. Minimizing axillary lymph node dissection in favor of less invasive approaches is gaining attention, though further evidence is needed to establish its oncological safety. The potential for personalized treatment approaches, reducing surgical morbidity, and improving quality of life are key goals in managing LABC, while maintaining the priority of achieving favorable long-term outcomes.

Reconceptualizing the Interaction of Behavior and Environment.

The concept of response strength and the process of strengthening by reinforcement are controversial in terms of their explanatory power. We clarify potential theoretical misconceptions following from a strength-based account such as essentialist thinking and circular reasoning. These problems also arise in the practice of latent variable modeling in psychometrics. To solve these conceptual problems, we discuss the Multilevel Model of Behavioral Selection (MLBS; Borgstede & Eggert, 2021) as an alternative theoretical framework. We use blocking from Pavlovian conditioning as an example to demonstrate how the MLBS framework prevents misconceptions arising from strength-based accounts and how it provides a more parsimonious and coherent explanation of the phenomenon. We illustrate the need for precisely defined and theoretically meaningful concepts and offer a reinterpretation of "strengthening by reinforcement." The reconceptualization in terms of the MLBS renders the concept of response strength superfluous. We conclude by highlighting the importance of theoretical reconsideration, putting aside difficulties that arise when attempting to validate strength by empirical means.

Cortisol in fish scales remains stable during extended periods of storage.

Measurement of cortisol in fish scales is attracting considerable attention as a non-invasive indicator of chronic stress in wild populations. For many fish species of management and conservation interest, extensive scale collections exist that could provide extended records of individual stress responses, by combining cortisol measurements with life history information. However, it is not yet known how well cortisol is preserved in the scale during storage. To investigate the stability of scale cortisol, we accelerated potential degradation by storing scales from an individual farmed Atlantic salmon (Salmo salar) in an oven at 50°C for between 2 and 12 weeks. We found no significant relationship between scale cortisol concentration and either storage time or storage temperature. Cortisol concentrations in scales from the same fish were consistent (18.54-21.82 ng. g-1; coefficient of variation (CV) = 3.6%), indicating that scale cortisol can be reliably quantified, even in scales stored for varying periods of time or under different conditions. We also examined the effects of storage in real time using Atlantic salmon scales that were stored in paper envelopes at room temperature for between 3 and 32 years and found no significant relationship between scale cortisol concentration and storage time. Scale cortisol concentrations ranged from 4.05 to 135.37 ng.g-1 and levels of between-individual variability were high (CV = 61%). Given that scale cortisol does not degrade during long-term storage, historical scale collections and associated data describing fish life histories could potentially be used to develop bioindicators of physiological responses in fish populations. Further research is needed to understand scale cortisol variability and its biological relevance.

Heme oxygenase 1-mediated ferroptosis in Kupffer cells initiates liver injury during heat stroke.

With the escalating prevalence of global heat waves, heat stroke has become a prominent health concern, leading to substantial liver damage. Unlike other forms of liver injury, heat stroke-induced damage is characterized by heat cytotoxicity and heightened inflammation, directly contributing to elevated mortality rates. While clinical assessments have identified elevated bilirubin levels as indicative of Kupffer cell dysfunction, their specific correlation with heat stroke liver injury remains unclear. Our hypothesis proposes the involvement of Kupffer cell ferroptosis during heat stroke, initiating IL-1ß-mediated inflammation. Using single-cell RNA sequencing of murine macrophages, a distinct and highly susceptible Kupffer cell subtype, Clec4F+/CD206+, emerged, with heme oxygenase 1 (HMOX-1) playing a pivotal role. Mechanistically, heat-induced HMOX-1, regulated by early growth response factor 1, mediated ferroptosis in Kupffer cells, specifically in the Clec4F+/CD206+ subtype (KC2), activating phosphatidylinositol 4-kinase beta and promoting PI4P production. This cascade triggered NLRP3 inflammasome activation and maturation of IL-1ß. These findings underscore the critical role of targeted therapy against HMOX-1 in ferroptosis within Kupffer cells, particularly in Clec4F+/CD206+ KCs. Such an approach has the potential to mitigate inflammation and alleviate acute liver injury in the context of heat stroke, offering a promising avenue for future therapeutic interventions.

Increases in the incremental exercise mean response time across the steady state domain: Implications for exercise testing & prescription.

We hypothesized that slowed oxygen uptake ( V ˙ O 2 ) kinetics for exercise transitions to higher power outputs (PO) within the steady state (SS) domain would increase the mean response time (MRT) with increasing exercise intensity during incremental exercise. Fourteen highly trained cyclists (mean ±â€¯standard deviation [SD]; age (39 ±â€¯6) years [yr]; and V ˙ O 2 peak = (61 ±â€¯9) mL/kg/min performed a maximal, ramp incremental cycling test and on separate days, four 6-min bouts of cycling at 30%, 45%, 65% & 75% of their incremental peak PO (Wpeak). SS trial data were used to calculate the MRT and verified by mono-exponential and linear curve fitting. When the ramp protocol attained the value from SS, the PO, in Watts (W), was converted to time (min) based on the ramp function W to quantify the incremental MRT (iMRT). Slope analyses for the V ˙ O 2 responses of the SS versus incremental exercise data below the gas exchange threshold (GET) revealed a significant difference (p = 0.003; [0.437 ±â€¯0.08] vs. [0.382 ±â€¯0.05] L⋅min-1). There was a significant difference between the 45% Wpeak steady state V ˙ O 2 (ss V ˙ O 2 ) ([3.08 ±â€¯0.30] L⋅min-1, respectively), and 30% Wpeak ss V ˙ O 2 (2.26 ±â€¯0.24) (p < 0.0001; [3.61 ±â€¯0.80] vs. [2.20 ±â€¯0.39] L⋅min-1) and between the iMRT for 45% and 30% Wpeak ss V ˙ O 2 values ([50.58 ±â€¯36.85] s vs. [32.20 ±â€¯43.28] s). These data indicate there is no single iMRT, which is consistent with slowed V ˙ O 2 kinetics and an increasing V ˙ O 2 deficit for higher exercise intensities within the SS domain.

Cadmium toxicity on endoplasmic reticulum functioning.

Cadmium (Cd) is a heavy metal pollutant widely distributed in the environment due to industrial activities, mining, and agricultural practices. Cadmium-induced Toxicity exerts profound effects on ER functioning through multiple mechanisms, leading to cellular dysfunction and pathological consequences. Cadmium disrupts protein folding and activates the unfolded protein response (UPR). Cd exposure leads to the accumulation of misfolded proteins, triggering UPR pathways mediated by critical ER transmembrane sensors: IRE1, PERK, and ATF6. The subsequent UPR aims to restore ER homeostasis but can also induce apoptosis under severe stress conditions. Cd disrupts ER calcium homeostasis by inhibiting the SERCA pump, further exacerbating ER stress. The generation of reactive oxygen species (ROS also plays a critical role in Cd toxicity, damaging ER-resident proteins and amplifying UPR activation). Cadmium also affects the lipid metabolism. This review examines the mechanisms by which Cd toxicity impairs ER functioning, disruption of protein folding and quality control mechanisms, and dysregulation of calcium signaling and lipid metabolism. The subsequent cellular consequences, including oxidative stress, apoptosis, and inflammation, are discussed in the context of Cd-induced pathogenesis of diseases such as Cancer and neurodegenerative and cardiovascular disorders. Finally, potential therapeutic strategies must be explored to mitigate the adverse effects of Cd on ER functioning and human health.