Differential Response Research Articles

Animal personality in multiple stressor environments: the evolutionary ecology of among-individual differences in responses to stressor suites.

Animal personality differences may have evolved as alternative strategies for negotiating multiple stressor landscapes. Indeed, ecologists are increasingly recognizing that interactions among multiple stressors can transform selective landscapes and behavioural and physiological responses to stress regimes. Yet, evaluating this hypothesis poses challenges, as most studies involving relationships between personality variation and the environment consider single stressors. Here, we review the literature to explore the theory and evidence that multiple stressor environments may mediate personality variation. We consider effects on evolution of personality variation, as influenced by life-history, energetic and behavioural trade-offs, and effects on phenotypic expression of personality traits. We then explore how personality variation may modulate behavioural and physiological responses to multiple stressors, and how differential responses may be affected by personality-dependent movement ecology and cognitive strategies. Among-individual differences in responses to multiple stressors are critical to elucidate, as multi-stress interactions may transform animal behavioural and physiological responses relative to those predicted under single stressor scenarios, and because among-individual variation comprises the basis for evolutionary shifts in stress responsiveness and population resiliency to global environmental change.

Responses of Growth, Enzyme Activity, and Flower Bud Differentiation of Pepper Seedlings to Nitrogen Concentration at Different Growth Stages

The concentration of nitrogen fertilizer is matched with the nutrient requirements in different growth stages of plants, which coordinates their vegetative and reproductive growth. In this study, the influences of nitrogen concentration before and after initiation of flower bud differentiation (first and second stage, respectively) on pepper seedling quality were studied. The chlorophyll a content, sucrose synthase activity, and sucrose phosphate synthase activity of pepper seedlings grown under moderate nitrogen (15 mmol L−1) in the first stage combined with high nitrogen (25.61 mmol L−1) in the second stage were 15.7%, 39.3%, and 34.6% higher than those of the same nitrogen concentration (15 mmol L−1) in the first and second stages treatment, respectively. The regression model also showed that the values of flower bud diameter, shoot fresh weight, root fresh weight, and glutamine synthetase activity of pepper were high under the condition of moderate nitrogen in the first stage and higher nitrogen in the second stage. In addition, the results of comprehensive evaluation showed that moderate nitrogen (15 mmol L−1) in the first stage and high nitrogen (25.61 mmol L−1) in the second stage treatment ranked first, which improved carbon and nitrogen metabolism, increased biomass accumulation, and promoted the flower bud differentiation and flowering of pepper seedlings.

EP.11B.04 Differential Durable Responses in Intrathoracic Versus Overall Lesions of Non-Small Cell Lung Cancer Treated with Immunotherapy

EP.11B.04 Differential Durable Responses in Intrathoracic Versus Overall Lesions of Non-Small Cell Lung Cancer Treated with Immunotherapy

Differential Cardiac Responses after Passive Leg Raising.

This study retrospectively examined the hemodynamic effects of passive leg raising (PLR) in mechanically ventilated patients during fluid removal before spontaneous breathing trials. In previous studies, we noticed varying cardiac responses after PLR completion, particularly in positive tests. Using a bioreactance monitor, we recorded and analyzed hemodynamic parameters, including stroke volume and cardiac index (CI), before and after PLR in post-acute ICU patients. We included 27 patients who underwent 60 PLR procedures. In preload-unresponsive patients, no significant CI changes were observed (CI_t-6 = 3.7 [2.6; 4.7] mL/min/m2 vs. CI_t9 = 3.3 [2.5; 3.4] mL/min/m2; p = 0.306), while in preload-responsive patients, two distinct CI response types to PLR were identified: a transient peak with immediate return to baseline (CI_t-6 = 2.7 [2.5; 3.1] mL/min/m2 vs. 3.3 [2.6; 3.8] L/min/m2; p = 0.119) and a sustained CI elevation lasting beyond the PLR maneuver (CI_t-6 = 2.8 [2.3; 2.9] L/min/m2 vs. 3.3 [2.8; 3.9] ml/min/m2; p = 0.034). The latter was particularly noted when ΔCI during PLR exceeded 25%. Our findings suggest that in certain preload-responsive patients, PLR can induce a more sustained increase in CI, indicating a possible persistent hemodynamic effect. This effect could be due to a combination of autotransfusion and sympathetic activation affecting venous return and vascular tone. Further research in larger cohorts and more comprehensive hemodynamic assessments are warranted to validate these observations and elucidate the possible underlying mechanisms.The Fluid unLoading On Weaning (FLOW) study was prospectively registered under the ID NCT04496583 on 2020-07-29 at ClinicalTrials.gov.

Characterizing metabolome signature of colostrum, transition and mature milk of indigenous cows (Bos indicus) adapted to high altitude environment of Leh-Ladakh

This study has identified 46 metabolites in colostrum, transition milk and mature milk of unique indigenous high altitude adapted Ladakhi cows using 1D 1H 800 MHz NMR spectroscopy. The multivariate analysis revealed that UDP-galactose, UDP-glucose, citrate, creatine phosphate, myo-inositol, lactose, 2-oxoglutarate, valine, maltose, leucine, dimethylamine, and choline with high VIP scores could differentiate the colostrum, transition and mature milk in separate clusters. . Highly enriched metabolites in colostrum such as UDP-galactose, UDP-glucose play crucial roles in cell growth, differentiation, and defense responses. Similarly, the presence of branched chain amino acids in colostrum could be linked to mammary gland development, N-acetylglucosamine, N-acetyl carnitine, choline etc. in high concentration in colostrum l might be helping in growth and development of neonatal calves of Ladakhi cows under hypoxia environment. Overall, this study has helped to characterize the metabolomic signatures of milk/colostrum of Ladakhi cows adapted to high altitude and cold desert of Leh-Ladakh.

Novel Therapeutic Target for ALI/ARDS: Forkhead Box Transcription Factors.

ALI/ARDS can be a pulmonary manifestation of a systemic inflammatory response or a result of overexpression of the body's normal inflammatory response involving various effector cells, cytokines, and inflammatory mediators, which regulate the body's immune response through different signalling pathways. Forkhead box transcription factors are evolutionarily conserved transcription factors that play a crucial role in various cellular processes, such as cell cycle progression, proliferation, differentiation, migration, metabolism, and DNA damage response. Transcription factors control protein synthesis by regulating gene transcription levels, resulting in diverse biological outcomes. The Fox family plays a role in activating or inhibiting the expression of various molecules related to ALI/ARDS through phosphorylation, acetylation/deacetylation, and control of multiple signalling pathways. An in-depth analysis of the integrated Fox family's role in ALI/ARDS can aid in the development of potential diagnostic and therapeutic targets for the condition.

NDRG1 regulates iron metabolism and inhibits pathological cardiac hypertrophy

BackgroundCardiac pathological hypertrophy, a pathological physiological alteration in many cardiovascular diseases, can progress to heart failure. The cellular biology underlying myocardial hypertrophy remains to be fully elucidated. While NDRG1 has been reported to participate in cellular proliferation, differentiation, and cellular stress responses, its role in cardiac diseases remains unexplored. Here, we investigated the role of NDRG1 in pathological hypertrophy. MethodCardiomyocyte-specific-NDRG1 knockout (KO) transgenic mice and NDRG1-AAV9 were used in mice. Angiotensin II (AngII) stimulation were applied to induce hypertrophy. Histological, molecular, and RNA-sequencing analyses were performed, and ferroptosis markers and iron levels were studied. We used co-IP and application of iron chelator to further studied the mechanisms of NDRG1 in cardiac hypertrophy. ResultsWe found that NDRG1 expression is decreased in pathological hypertrophy induced by AngII stimulation. Conditional knockout of NDRG1 in mouse cardiomyocytes led to progressive cardiac hypertrophy and heart failure. Cardiomyocyte-specific overexpression of NDRG1 via AAV9 significantly reversed AngII-induced ventricular hypertrophy and fibrosis. Mechanistically, NDRG1-deficient cardiomyocytes exhibited iron overload and increased ferroptosis, accompanied by elevated levels of reactive oxygen species (ROS) and lipid peroxidation. Subsequently, we confirmed the involvement of NDRG1 in regulating ferroptosis and iron metabolism in myocardial cells. Finally, we identified an interaction between NDRG1 and transferrin in cells. The iron chelator Dp44mT effectively reduced myocardial iron overload and ventricular remodeling induced by NDRG1 deficiency. ConclusionThese findings highlight NDRG1's critical role in iron metabolism and ferroptosis in cardiomyocytes, suggesting that NDRG1 or iron metabolism may serve as therapeutic targets for cardiac hypertrophy.

Retinoic Acid (RA): A Critical Immunoregulatory Molecule in Asthma and Allergies.

Asthma and allergies are chronic inflammatory disorders that are triggered owing to aberrant responses of the immune system against typically innocent environmental substances. Retinoic acid (RA) represents a biologically active metabolite of vitamin A (VA) and high-affinity ligand for RA receptor (RAR) that is implicated in a wide variety of biological processes, including cell proliferation, differentiation, apoptosis, organogenesis, reproduction, and immune responses. In the immune system, RA contributes to the induction of regulatory T (Treg) cells, adhesion molecules required for homing of B and T cells in the gut, and tolerance. Noteworthy, RA has a pivotal role in maintaining the balance of Th17-Treg cells and is also indispensable for appropriate responses of T helper (Th) cells. This mini-review article intends to expose the immune functions of RA, with an emphasis on the enzymatic pathways converting VA into RA and its receptor-dependent actions in asthma and allergies. Recent findings have depicted that RA levels are reduced in asthma and allergies and that treatment with RA alleviates allergy symptoms and airway inflammation. RA also modulates allergic airway disorders by inhibiting Th2/Th17 response and increasing Treg cells. Therefore, RA could be considered a novel and promising therapeutic agent to be studied and used for treating these diseases.

Differential Responses To Heat Stress On The Regeneration Of Injured Rat Soleus And Plantaris Muscles

Differential Responses To Heat Stress On The Regeneration Of Injured Rat Soleus And Plantaris Muscles

Seeds of language-like generativity in bird call combinations.

Language is unbounded in its generativity, enabling the flexible combination of words into novel sentences. Critically, these constructions are intelligible to others due to our ability to derive a sentence's compositional meaning from the semantic relationships among its components. Some animals also concatenate meaningful calls into compositional-like combinations to communicate more complex information. However, these combinations are structurally highly stereotyped, suggesting a bounded system of holistically perceived signals that impedes the processing of novel variants. Using long-term data and playback experiments on pied babblers, we demonstrate that, despite production stereotypy, they can nevertheless process structurally modified and novel combinations of their calls, demonstrating a capacity for deriving meaning compositionally. Furthermore, differential responses to artificial combinations by fledglings suggest that this compositional sensitivity is acquired ontogenetically. Our findings demonstrate animal combinatorial systems can be flexible at the perceptual level and that such perceptual flexibility may represent a precursor of language-like generativity.

Integrated transcriptomics, metabolomics and physiological analyses reveal differential response mechanisms of wheat to cadmium and/or salinity stress.

Many soils face dual challenges of cadmium (Cd) contamination and salinization. However, the response of crops, especially wheat, to combined Cd and salinity stress is not understood. Here, wheat was grown in a hydroponic model for 14 days under single and combined Cd and NaCl stresses. Growth parameters, tissue Cd2+ and Na+ contents, and leaf chlorophyll (Chl), O2•-, and MDA levels were determined. Comparative transcriptomic and metabolomic analyses of the leaves were performed. The results showed that combined stress had a greater inhibitory effect on Chl contents and generated more O2•- and MDA, resulting in more severe wheat growth retardation than those under Cd or NaCl stress. Stress-induced decrease in Chl levels may be attributed to the inhibition of Chl biosynthesis, activation of Chl degradation, or a decline in glutamate content. Cd addition weakened the promotional effect of NaCl on SOS1 gene expression, thereby increasing the Na+ content. Contrastingly, NaCl supplementation downregulated the Nramp and ZIP gene expressions related to Cd uptake and transport, thereby impeding Cd2+ accumulation. All stresses enhanced tryptophan content via promoting tryptophan biosynthesis. Meanwhile, Cd and NaCl stresses activated phenylpropanoid biosynthesis and purine metabolism, respectively, thereby increasing the levels of caffeic acid, fumaric acid, and uric acid. Activating the TCA cycle was important in the wheat's response to combined stress. Additionally, NaCl and combined stresses affected starch and sucrose metabolism, resulting in sucrose and trehalose accumulation. Our findings provide a comprehensive understanding of the response of wheat to the combined Cd and salinity stress.

Molecular Phenotyping of Patients with Sepsis and Kidney Injury and Differential Response to Fluid Therapy: Secondary Analysis of a Clinical Trial

Molecular Phenotyping of Patients with Sepsis and Kidney Injury and Differential Response to Fluid Therapy: Secondary Analysis of a Clinical Trial

Post-exercise Differential Response Of Central And Brachial Blood Pressure In Patients With Coronary Artery Disease

Post-exercise Differential Response Of Central And Brachial Blood Pressure In Patients With Coronary Artery Disease

Differential Responses of Total Ozone Content to Solar Activity Parameters at Two Saudi Arabian Locations

This study examines the correlations between Total Ozone Content (TOC) at two locations in Saudi Arabia—Abha and Jeddah—and various solar activity indicators (sunspot numbers, solar radio flux) and cosmic rays, using data spanning from 1979 to 2023. The research employs correlation analyses and spectral techniques, such as Fast Fourier Transform and wavelet analysis, to explore these relationships.The results reveal significant non-zero correlations between changes in TOC at both Saudi sites and the studied solar activity indicators and cosmic rays, with these correlations varying in strength and significance across different solar cycles and seasons.Spectral analysis suggests the presence of several periodicities in the TOC data from both sites, including cycles of 3.9 years, 2.63 years, 1.65 years, 1.1-1.2 years, 325 days (∼0.88 years), 285-293 days (∼0.78-0.80 years), 273 days (∼0.75 years), 249-232 days (∼0.68 years), and 202-188 days (∼0.52 years). Notable shared periodicities between TOC and solar activity and cosmic rays data include ∼ 2.6 years, 3.8-3.9 years, 1.56 years, 325 days, 273 days, and 166 days.The findings from both correlation and spectral analyses suggest a potential connection between variations in TOC and solar activity at the specific locations studied. This aligns with previous research indicating that increased UV radiation during periods of high solar activity enhances ozone production, particularly at lower latitudes, and that increased magnetic activity reduces the influx of cosmic rays into the heliosphere, impacting atmospheric ionization.

Insulin Regulation of Lysine and α-Aminoadipic Acid Dynamics and Amino Metabolites in Women With and Without Insulin Resistance.

Insulin is a key regulator of amino acids (AAs) metabolism. Many plasma AAs, including lysine and its metabolite, α-aminoadipic acid (α-AA), a predictor for developing diabetes, are elevated in insulin resistance. In 18 insulin-resistant (IR) over-weight women with polycystic ovary syndrome compared to 12 lean controls, high physiological insulin during a euglycemic clamp failed to normalize many elevated AA metabolites, including branched-chain and aromatic AA, alphaamino- butyric acid, and lysine, but normalized α-AA. To understand the underpinning of differential responses of lysine and its metabolic product α-AA to high physiological insulin in IR compared to controls, we developed a kinetic model utilizing [α-15N1] lysine and [13C1] α-AA as tracers and measured the two tracers simultaneously in α-AA by innovative mass spectrometry. High insulin increased lysine conversion to α-AA in IR and controls but failed to normalize plasma lysine concentrations in IR due to a decrease in lysine metabolic clearance rate (MCR). In contrast, despite higher conversion rates of lysine to α-AA by high insulin, α-AA concentration decreased in IR because of the sustained greater MCR of α-AA. The abnormal AAs and metabolites, even while on high physiological insulin, could potentially explain many functional derangements in IR.

A patient-derived HCC spheroid system to model the tumor microenvironment and treatment response

Background & AimsHepatocellular carcinoma (HCC) is the third leading and fastest rising cause of cancer-related death worldwide. The discovery and preclinical development of compounds targeting HCC is hampered by the absence of authentic tractable systems recapitulating the heterogeneity of patient HCC tumors and the tumor microenvironment (TME). MethodsWe established a novel and simple patient-derived multicellular tumorspheroid model based on clinical HCC tumor tissues, processed using enzymatic and mechanical dissociation. After quality controls, 22 HCC tissues and 17 HCC serum were selected for tumorspheroid generation and perturbation studies. Cells were grown in 3D in optimized medium in presence of patient serum. Characterization of the tumorspheroid cell populations was performed by flow cytometry, immunohistochemistry and functional assays. As a proof of concept, we treated patient-derived spheroids with FDA approved anti-HCC compounds. ResultsThe model was successfully established independently from cancer etiology and grade from 22 HCC tissues. We show that the use of HCC patient serum was essential for tumorspheroid generation, the TME function and to maintain cell viability. The tumorspheroids comprised the main cell compartments including epithelial cancer cells as well as all major cell populations of the TME (cancer-associated fibroblasts, macrophages and T cells, endothelial cells). Tumorspheroids reflect HCC heterogeneity, including variability in cell type proportions and TME, and mimic the original tumor features. Moreover, we observed differential responses to FDA HCC approved drugs between donors as observed in patients. ConclusionThis patient HCC serum-tumorspheroid model provides novel opportunities for drug discovery and development as well as mechanism of action studies including compounds targeting the TME. This model will likely contribute to improve the dismal outcome of patients with HCC. Impact and implicationsHepatocellular carcinoma (HCC) is a leading and fast rising cause of cancer-related death worldwide. Despite approval of novel therapies, the outcome of advanced HCC remains unsatisfactory. By developing a novel patient-derived tumorspheroid model recapitulating tumor heterogeneity and microenvironment, we provide new opportunities for HCC drug development and analysis of mechanism of action in authentic patient tissues. The application of the patient-derived tumorspheroids combined with other HCC models will likely contribute to drug development and to improve the dismal outcome of patients with HCC.

Shaking table test on shaft-tunnel junction in liquefiable sand site

The impact of a seismic shaking is likely to cause differential responses of shaft-tunnel junction due to its structural irregularities. Meanwhile, in a liquefiable ground, the distinctions of the two structures would heavily influence the local behavior of the surrounding soil, which, in return, exacerbates the differential responses thereof. In this paper, the complicated soil-structure interactions (SSI) involved in the process have been investigated through 1 g shaking table test, where a shaft-tunnel junction is buried in liquefiable Fujian sand. For the design of the physical models, a four-principle theory is proposed for the similitude relations taking into account both the vibration-induced deformations and the liquefaction-induced uplift of the underground structures. The test data of two shaking cases are presented and analyzed. The soil-structure model firstly undergoes a minor shaking of 0.05 g, whose purpose is to improve the homogeneity of the sand as well as obtain the soil-structure responses in a non-liquefied scenario. Then, a second case of 0.30 g is fired, where the soil fully liquefies. It is clearly observed that the presences of the structures have significant influences on the liquefaction of the surrounding soil. The spatially non-uniform behavior of the sand site then contributes to the differential responses between the shaft and the tunnel. The pertinent SSI mechanisms are thus analyzed at length.

Novel Intraprostatic MR-Guided Implantation of Multidrug-Eluting Microdevice for Testing of Systemic Therapy Agents In Situ: Proof of Concept in Intermediate-Risk and High-Risk Prostate Cancer.

The purpose of this study was to assess safety and feasibility of percutaneous MR-guided placement of an implantable microdevice (IMD) to evaluate in situ intratumor response to multiple pharmacologic agents in men with intermediate-risk and high-risk localized prostate cancer. Biocompatible IMDs measuring 750 µm in diameter and 5 mm in length were prepared with 20 reservoirs containing candidate drug and drug combinations including second-generation androgen inhibitors, PARP inhibitors, PD-1 inhibitors, and conventional chemotherapy. Men with intermediate-risk or high-risk localized prostate cancer and MRI-visible lesions were enrolled. Up to 4 IMDs were placed using a transperineal approach into MRI-visible tumors 2 days before planned radical prostatectomy. After radical prostatectomy, the IMDs and a small segment of surrounding tumor tissue were removed and sectioned, stained, and analyzed for tissue drug response by a variety of pharmacodynamic markers. Fourteen patients were enrolled: 7 (50%) with intermediate-risk and 7 (50%) with high-risk localized prostate cancer. A total of 53 IMDs were implanted (mean 3.8 per patient), and 49 IMDs (92%) were successfully retrieved. All men underwent uncomplicated robotic-assisted radical prostatectomy and bilateral pelvic lymph node dissection 2 days after IMD placement. There were no severe adverse events. Pathological examination of the tissues adjacent to the IMDs demonstrated differential drug response within patients and between patients. Limitations include small sample size. A multidrug IMD can be safely placed percutaneously into MRI-visible lesions before radical prostatectomy, enabling assessment of tumor-specific local response to multiple agents simultaneously within the tumor's normal stromal environment to guide targeted systemic therapy.

Identification, Cloning, and Characterization of Two Acupuncture-Injury-Inducing Promoters in Rice

As an important global food crop, rice is damaged by a variety of piercing–sucking pests. Identifying a broad-spectrum promoter induced by the physical signal of sucking pests and applying it to transgenic breeding to mitigate the damage caused by different sucking pests will significantly improve the efficiency of our breeding. This study compared the transcriptome changes in two rice varieties under needle-wounding stress to investigate their differential responses to mechanical damage. The results showed that the insect-susceptible variety TN1 exhibited more differentially expressed genes (DEGs) and greater changes in expression levels after needle treatment, indicating a more active internal gene regulatory network. GO and KEGG enrichment analysis further revealed that TN1 not only exhibited changes in genes related to the extracellular environment, but also mobilized more genes associated with stress response and defense. By screening the differentially expressed genes, we identified two promoters (P1 and P2) with inducible expression characteristics in both the resistant and susceptible rice varieties. These promoters were able to effectively drive the expression of the insect resistance gene OsLecRK1* and enhance the resistance of transgenic plants against the brown planthopper. This study provides promoter resources for the development of insect-resistant transgenic crops.

Integrated stress response plasticity governs normal cell adaptation to chronic stress via the PP2A-TFE3-ATF4 pathway.

The integrated stress response (ISR) regulates cell fate during conditions of stress by leveraging the cell's capacity to endure sustainable and efficient adaptive stress responses. Protein phosphatase 2A (PP2A) activity modulation has been shown to be successful in achieving both therapeutic efficacy and safety across various cancer models. However, the molecular mechanisms driving its selective antitumor effects remain unclear. Here, we show for the first time that ISR plasticity relies on PP2A activation to regulate drug response and dictate cellular survival under conditions of chronic stress. We demonstrate that genetic and chemical modulation of the PP2A leads to chronic proteolytic stress and triggers an ISR to dictate whether the cell lives or dies. More specifically, we uncovered that the PP2A-TFE3-ATF4 pathway governs ISR cell plasticity during endoplasmic reticular and cellular stress independent of the unfolded protein response. We further show that normal cells reprogram their genetic signatures to undergo ISR-mediated adaptation and homeostatic recovery thereby avoiding toxicity following PP2A-mediated stress. Conversely, oncogenic specific cytotoxicity induced by chemical modulation of PP2A is achieved by activating chronic and irreversible ISR in cancer cells. Our findings propose that a differential response to chemical modulation of PP2A is determined by intrinsic ISR plasticity, providing a novel biological vulnerability to selectively induce cancer cell death and improve targeted therapeutic efficacy.