Component Of Response Research Articles

A Holistic Approach to the Selection of Soybean (Glycine max) Cultivars for Shade Environments Based on Morphological, Yield and Genetic Traits

ABSTRACTThe reduction of photosynthetically active radiation impacts the growth and productivity of soybean in agroforestry and intercropping systems. Thus, this report explored the responses of 16 soybean cultivars submitted to shade levels in field conditions. Multi‐faceted and relative importance analyses revealed that the steam diameter and plant height are fundamental morphological markers for selecting shade‐resilient cultivars, both were high and positively correlated to yield components. Moreover, the responses to shade varied among soybean cultivars, with certain genotypes demonstrating distinct tolerance levels, which allowed also the estimative of genetic variance that revealed strong participation of genetic components in responses to shade. Multivariate and clustering analysis using steam diameter and plant height in combination with two yield components resulted in the identification of four soybean cultivars more tolerant to shade environments and two sensible. Therefore, this report provides insights into soybean cultivation under varying light conditions, provides a robust foundation for the integration of morphological and yield markers in breeding programmes focused on shade tolerance and guides future endeavours in crop improvement for optimal and sustainable yield and resilience in the climate change context.

Disentangling signal and noise in neural responses through generative modeling.

Measurements of neural responses to identically repeated experimental events often exhibit large amounts of variability. This noise is distinct from signal , operationally defined as the average expected response across repeated trials for each given event. Accurately distinguishing signal from noise is important, as each is a target that is worthy of study (many believe noise reflects important aspects of brain function) and it is important not to confuse one for the other. Here, we describe a principled modeling approach in which response measurements are explicitly modeled as the sum of samples from multivariate signal and noise distributions. In our proposed method-termed Generative Modeling of Signal and Noise (GSN)-the signal distribution is estimated by subtracting the estimated noise distribution from the estimated data distribution. Importantly, GSN improves estimates of the signal distribution, but does not provide improved estimates of responses to individual events. We validate GSN using ground-truth simulations and show that it compares favorably with related methods. We also demonstrate the application of GSN to empirical fMRI data to illustrate a simple consequence of GSN: by disentangling signal and noise components in neural responses, GSN denoises principal components analysis and improves estimates of dimensionality. We end by discussing other situations that may benefit from GSN's characterization of signal and noise, such as estimation of noise ceilings for computational models of neural activity. A code toolbox for GSN is provided with both MATLAB and Python implementations.

TRIM Proteins and Antiviral Microtubule Reorganization: A Novel Component in Innate Immune Responses?

TRIM proteins are a family of innate immune factors that play diverse roles in innate immunity and protect the cell against viral and bacterial aggression. As part of this special issue on TRIM proteins, we will take advantage of our findings on TRIM69, which acts by reorganizing the microtubules (MTs) in a manner that is fundamentally antiviral, to more generally discuss how host-pathogen interactions that take place for the control of the MT network represent a crucial facet of the struggle that opposes viruses to their cell environment. In this context, we will present several other TRIM proteins that are known to interact with microtubules in situations other than viral infection, and we will discuss evidence that may suggest a possible contribution to viral control. Overall, the present review will highlight the importance that the control of the microtubule network bears in host-pathogen interactions.

Comprehensive Sexuality Education (CSE) and HIV/AIDS Prevention among Youth in East Africa

Comprehensive Sexuality Education (CSE) is a pivotal strategy for reducing HIV/AIDS prevalence among youth in East Africa, where the growing young population presents significant challenges for effective prevention. This review examines the role of CSE in equipping young people with essential knowledge, skills, and attitudes to make informed decisions about their sexual health. We explore the importance of culturally relevant and evidence-based curricula, the impact of teacher training programmes, and the integration of CSE into both school and community settings. We highlight the crucial role of youth-friendly health services in providing accessible and confidential care and identify peer education and youth-led initiatives as key strategies for engaging and empowering young people in HIV prevention. We examine the role of economic empowerment strategies, such as microfinance and vocational training, in reducing HIV vulnerability. We discuss gender-sensitive approaches to address the unique needs of different genders, including LGBTQ+ youth. The review also explores the potential of innovative technologies and digital solutions, such as mobile health applications and social media campaigns, to enhance HIV prevention efforts. The review emphasises community engagement and support systems, policy advocacy, and research as essential components for a comprehensive response. By integrating these diverse strategies, the review underscores the need for a multi-faceted approach to effectively address HIV/AIDS among youth in East Africa, ultimately aiming to improve health outcomes and achieve sustainable prevention goals. Keywords: Comprehensive Sexuality Education (CSE), HIV/AIDS, Youth, East Africa

Mechanical analysis of a stitched sandwich structure and its SiO2f/SiO2 panels: Experimental and numerical investigation on compression and shear performances

The compression and shear performances of the stitched sandwich thermal protection structure (SSTPS) was systematically investigated through experimental and simulation methods in this study. Compression and shear testing methods were designed, and macroscopic performance data for SiO2f/SiO2 thin panels and SSTPS were successfully obtained, thereby validating the rationality of the experimental approach. By establishing mechanical experimental methods, the correlation between microscopic structural features and macroscopic mechanical performance was revealed, and mechanical modeling and analysis work was conducted. The experimental and numerical results indicate that compression and shear failure of thin panels mainly occur at the intersections of fiber bundles, exhibiting non-brittle failure. The delamination of sandwich materials or the buckling deformation of panels is identified as the primary cause of the nonlinear response in SSTPS. Elevated temperatures induce an increase in the modulus and strength of SSTPS and a decrease in toughness, correlated with the high-temperature densification of the matrix structure. Finite element simulations reveal the critical role of component and interface damage in macroscopic nonlinear mechanical responses. The research demonstrates that, the compressive and shear failure mechanisms of SiO2f/SiO2 thin panels and SSTPS were successfully elucidated through the implementation of an innovative experimental methodology.

Developing a community-responsive research model in the healthcare system: a mixed-method study

BackgroundResponsiveness to the population’s non-clinical needs encompasses various dimensions, including responsive research and an educational outreach plan at the community level. This study aims to develop a community-responsive research model in the healthcare system to ensure the connection between community-identified health priorities and research funds, as well as capacity-building efforts.MethodsA mixed-methods research study was conducted in three main phases, including a comprehensive literature review, a qualitative analysis of an expert panel’s points of view, and the developing of a model using the Equation Modeling (SEM) technique. R software version 3.2.4 was used to conduct statistical analysis, considering a significance level of 0.05.ResultsBased on the literature review, 41 responsiveness components were identified from sixteen relevant studies conducted between 2000 and 2022. Ten sub-themes in four major themes, including planning, implementation, monitoring and evaluation, and action, were identified through qualitative content analysis. Standardized coefficients revealed that components such as dissemination of results to all stakeholders, research prioritization aligned with community needs, commitment to implement research findings, and collaborative learning had statistically significant effects on the community-responsive research model.ConclusionIt is essential to identify community health priorities by following a community-focused, priority-setting process based on the principles of community engagement to develop a community-responsive research model. Afterward, dissemination of research findings to all stakeholders, commitment to apply the obtained results in the real world, and promotion of shared learning among research partners have been proven to facilitate collaborative investigation and mutual understanding between the community and academic partners.

Compilation of Evidence Supporting the Role of a T Helper 2 Reaction in the Pathogenesis of Acute Appendicitis.

Despite being the most common abdominal surgical emergency, the cause of acute appendicitis (AA) remains unclear, since in recent decades little progress has been made regarding its etiology. Obstruction of the appendicular lumen has been traditionally presented as the initial event of AA; however, this is often the exception rather than the rule, as experimental data suggest that obstruction is not an important causal factor in AA, despite possibly occurring as a consequence of the inflammatory process. Type I hypersensitivity reaction has been extensively studied, involving Th2 lymphocytes, and cytokines such as IL-4, IL-5, IL-9 and IL-13, which have well-defined functions, such as a positive-feedback effect on Th0 for differentiating into Th2 cells, recruitment of eosinophils and the release of eosinophilic proteins and the production of IgE with the activation of mast cells, with the release of proteins from their granules. Cytotoxic activity and tissue damage will be responsible for the clinical manifestation of the allergy. AA histological features are similar to those found in allergic reactions like asthma. The intestine has all the components for an allergic immune response. It has contact with hundreds of antigens daily, most of them harmless, but some can potentially induce an allergic response. In recent years, researchers have been trying to assess if allergy is a component of AA, with their latest advances in the understanding of AA as a Th2 reaction shown by the authors of this article.

Looking back, looking forward: lessons from COVID-19 communication measurement, evaluation and learning (MEL).

Communication is an integral component of an emergency response, including to the coronavirus disease (COVID-19) pandemic. Designing effective communication requires systematic measurement, evaluation and learning. In the Western Pacific Region, the World Health Organization (WHO) responded to the COVID-19 pandemic by using the Communication for Health (C4H) approach. This included the development and application of a robust measurement, evaluation and learning (MEL) framework to assess the effectiveness of COVID-19 communication, and to share and apply lessons in real time to continuously strengthen the pandemic response. MEL was applied during the planning, implementation and summative evaluation phases of COVID-19 communication, with evidence-based insights and recommendations continuously integrated in succeeding phases of the COVID-19 response. This article captures good practices that helped WHO to implement MEL during the COVID-19 pandemic. It focuses on lessons from the evaluation process, including the importance of planning, data integration, collaboration, partnerships, piggybacking, using existing data and leveraging digital media. Despite some limitations, the systematic application of MEL to COVID-19 communication shows its value in the planning and implementation of effective, evidence-based communication to address public health challenges. It enables the evaluation of outcomes and reflection on lessons identified to strengthen the response to the current pandemic and future emergencies.

International legal regulation of reforming the Armed Forces of Ukraine to NATO standards. studying the experience of command groups' activities in the armies of NATO member states and partner countries

The paper investigates the concept of mission command within the framework of military management, focusing on its application in modern military operations. Mission command, characterized by centralized intent and decentralized execution, is examined in terms of its origins, principles, and effectiveness in enhancing speed and initiative in military actions. The author conducts a comprehensive analysis of how mission command has been utilized by various military forces worldwide, assessing its alignment with contemporary strategic concepts and its contribution to achieving strategic objectives. Special attention is paid to its relevance and applicability in the context of the Ukrainian Armed Forces reform, particularly in enhancing command and control structures. The research highlights mission command as a vital component of effective military leadership, facilitating adaptability and responsiveness in complex operational environments. The findings underscore the importance of integrating mission command principles into modern military management systems to optimize decision-making processes and achieve mission success. Overall, the study provides valuable insights into the practical implementation and impact of mission command on military operations, offering recommendations for its further development and refinement within the Ukrainian Armed Forces and beyond.

Abstract 6090: Integration of innate and adaptive immune signatures for early detection of cancer

Abstract Up to 50% of cancer patients are diagnosed at a late stage with tumors that are often unresectable, leading to intensive treatments and a preventable loss of life. Whilst multiple assays have been developed to tackle the issue of disease mortality, these approaches have serious limitations. For example, circulating tumor DNA (ctDNA) preferentially detects hard-to-treat tumors and micrometastatic disease, with limited sensitivity and specificity for early-stage malignancy, underscoring an urgent need for novel early detection strategies. Substantial evidence exists to demonstrate that signals related to innate (e.g. pro-inflammatory cytokines) and adaptive (e.g. antibodies and T cell receptors [TCRs]) immune engagement arise early in the development of cancer. The immune system therefore offers potential as an exquisitely sensitive and highly specific intrinsic early detection system for cancer. Here we propose the development of a pan-cancer novel early detection assay, using peripheral blood to measure three key cancer-specific components of the anti-tumor immune response: i) T cell receptor (TCR) sequences, ii) antibody signatures, iii) cytokine markers. Our preliminary data demonstrates that an age and smoking-matched cohort of lung cancer patients can be distinguished from healthy donors using TCR sequencing data processed through a published machine learning approach (p<0.01). In support of this, a pilot study on a custom peptide microarray comprised of lung cancer associated antigens and recurrent neoantigens demonstrated that lung cancer patient samples show significantly higher antibody intensities than healthy donors. Thirdly, using data from a prospective cohort study, we have demonstrated that inflammatory markers can be leveraged to predict future cancer diagnosis, and identified key protein markers for future work. These data provide proof-of-principle for the use of these analytes as a tool for early detection. We are actively curating a unique cohort of samples for this work from a prospective study, Nodule Immunophenotyping Biomarker for Lung Cancer Early Diagnosis (NIMBLE) (NCT05432739), which recruits patients with indeterminate lung nodules that may represent early cancers (>280 patients to date). This malignancy has high mortality rates and a significant need for early detection strategies. Through this, we aim to understand the early immunobiological response to cancer and leverage this information to design a novel multi-parametric immunopredictor assay for early detection of cancer. Citation Format: Evelyn Fitzsimons, Alexander Coulton, Hongchang Fu, Marcellus Augustine, Richard Lee, James Reading, Kevin Litchfield. Integration of innate and adaptive immune signatures for early detection of cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6090.

The nonlinear instability of transverse vibration behavior of functionally graded materials sandwich rectangular plates of under a harmonic loading and subsonic flow

This work is devoted to studying the combined action of periodic in-plane load and tangential subsonic flow on the nonlinear mechanism of the out-plane deformation of the functionally graded composite plate. Three distribution functions are proposed to investigate the distribution of the transverse shear strains and stresses across the thickness of the plates. By using Hamilton’s variational principle, the equations governing the plate instability boundaries are formulated. A nonlinear differential equation describing the first mode of the plate dynamic instability behavior by employing Galerkin’s method. The method of multiple time scales is used to obtain a periodic one-mode solution, which directly leads to the solvability condition. The different resonance cases for the interaction between the frequency of out- plane deformation and the external forces are discussed to discover the extent of the sandwich functionally graded material (FGM) rectangular plate resistance in the presence of external influences. Various bifurcation diagrams for different cases of resonance are obtained versus the basic parameters. In view of this study, we could get a deeper look at the complexity of frequency components in resonance responses of the sandwich FGM rectangular plate. The results could provide some suggestions for the sandwich plate’s vibration reduction design or fault diagnosis field or design fault diagnosis.

LRRK2 regulates ferroptosis through the system Xc-GSH-GPX4 pathway in the neuroinflammatory mechanism of Parkinson's disease.

Parkinson's disease (PD) is the most prevalent neurodegenerative disorder. Neuroinflammation mediated by activated microglia and apoptosis of dopaminergic (DA) neurons in the midbrain are its primary pathological manifestations. Leucine-rich repeat protein kinase 2 (LRRK2) kinase has been observed to increase expression during neuroinflammation,however, the effect of LRRK2 on microglia activation remains poorly understood. In this study, we have established lipopolysaccharide (LPS) treated BV2 cells and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) models for both in vivo and in vitro investigation. Our data in vivo reveal that LRRK2 can promote microglia activation by regulating ferroptosis and activatingnuclear factor-κB. Inhibition of LRRK2 expression effectively suppressed the LPS-induced pro-inflammatory cytokines and facilitated the secretion of neuroprotective factors. Importantly, by co-overexpressing LRRK2 and glutathione peroxidase 4 (GPX4), we identified the system Xc-GSH-GPX4 pathway as a crucial component in LRRK2-mediated microglial ferroptosis and inflammatory responses. Using a microglial culture supernatant (MCS) transfer model, we found that inhibiting LRRK2 or downregulating ferroptosis in BV2 cells prevented SH-SY5Y cell apoptosis. Additionally, we observed abundant expression of LRRK2 and P-P65 in the midbrain, which was elevated in the MPTP-induced PD model, along with microglia activation. LRRK2 and P-P65 expression inhibition with PF-06447475 attenuated microglia activation in the nigrostriatal dense part of MPTP-treated mice. Based on our findings, it is evident that LRRK2 plays a critical role in promoting the neuroinflammatory response during the pathogenesis of PD by regulating the system Xc-GSH-GPX4 pathway. Taken together, our data highlights the potential research and therapeutic value of targeting LRRK2 to regulate neuroinflammatory response in PD through ferroptosis.

Neglected impacts of plant protection products on invertebrate aquatic biodiversity: a focus on eco-evolutionary processes.

The application of plant protection products (PPPs) may have delayed and long-term non-intentional impacts on aquatic invertebrates inhabiting agricultural landscapes. Such effects may induce population responses based on developmental and transgenerational plasticity, selection of genetic resistance, as well as increased extirpation risks associated with random genetic drift. While the current knowledge on such effects of PPPs is still scarce in non-target aquatic invertebrate species, evidences are accumulating that support the need for consideration of evolutionary components of the population response to PPPs in standard procedures of risk assessment. This mini-review, as part of a contribution to the collective scientific assessment on PPP impacts on biodiversity and ecosystem services performed in the period 2020-2022, presents a brief survey of the current results published on the subject, mainly in freshwater crustaceans, and proposes some research avenues and strategies that we feel relevant to fill this gap.

Novel peptide-based oncolytic vaccine for enhancement of adaptive antitumor immune response via co-engagement of innate Fcγ and Fcα receptors

BackgroundCancer immunotherapy relies on using the immune system to recognize and eradicate cancer cells. Adaptive immunity, which consists of mainly antigen-specific cytotoxic T cells, plays a pivotal role in controlling...

The effect of combining an inhaled corticosteroid and a long-acting muscarinic antagonist on human airway epithelial cells in vitro

BackgroundAirway epithelial cells (AECs) are a major component of local airway immune responses. Direct effects of type 2 cytokines on AECs are implicated in type 2 asthma, which is driven by epithelial-derived cytokines and leads to airway obstruction. However, evidence suggests that restoring epithelial health may attenuate asthmatic features.MethodsWe investigated the effects of passive sensitisation on IL-5, NF-κB, HDAC-2, ACh, and ChAT in human bronchial epithelial cells (HBEpCs) and the effects of fluticasone furoate (FF) and umeclidinium (UME) alone and in combination on these responses.ResultsIL-5 and NF-κB levels were increased, and that of HDAC-2 reduced in sensitised HEBpCs. Pretreatment with FF reversed the effects of passive sensitisation by concentration-dependent reduction of IL-5, resulting in decreased NF-κB levels and restored HDAC-2 activity. Addition of UME enhanced these effects. Sensitized HEBpCs also exhibited higher ACh and ChAT levels. Pretreatment with UME significantly reduced ACh levels, and addition of FF caused a further small reduction.ConclusionThis study confirmed that passive sensitisation of AECs results in an inflammatory response with increased levels of IL-5 and NF-κB, reduced levels of HDAC-2, and higher levels of ACh and ChAT compared to normal cells. Combining FF and UME was found to be more effective in reducing IL-5, NF-κB, and ACh and restoring HDAC-2 compared to the individual components. This finding supports adding a LAMA to established ICS/LABA treatment in asthma and suggests the possibility of using an ICS/LAMA combination when needed.

Rhizosheath drought responsiveness is variety-specific and a key component of belowground plant adaptation.

Biophysicochemical rhizosheath properties play a vital role in plant drought adaptation. However, their integration into the framework of plant drought response is hampered by incomplete mechanistic understanding of their drought responsiveness and unknown linkage to intraspecific plant-soil drought reactions. Thirty-eight Zea mays varieties were grown under well-watered and drought conditions to assess the drought responsiveness of rhizosheath properties, such as soil aggregation, rhizosheath mass, net-rhizodeposition, and soil organic carbon distribution. Additionally, explanatory traits, including functional plant trait adaptations and changes in soil enzyme activities, were measured. Drought restricted soil structure formation in the rhizosheath and shifted plant-carbonfrom litter-derived organic matter in macroaggregates to microbially processed compounds in microaggregates. Variety-specific functional trait modifications determined variations in rhizosheath drought responsiveness. Drought responses of the plant-soil system ranged among varieties from maintaining plant-microbial interactions in the rhizosheath through accumulation of rhizodeposits, to preserving rhizosheath soil structure while increasing soil exploration through enhanced root elongation. Drought-induced alterations at the root-soil interface may hold crucial implications for ecosystem resilience in a changing climate. Our findings highlight that rhizosheath soil properties are an intrinsic component of plant drought response, emphasizing the need for a holistic concept of plant-soil systems in future research on plant drought adaptation.

A comparative study of apoptosis, pyroptosis, necroptosis, and PANoptosis components in mouse and human cells.

Regulated cell death is a key component of the innate immune response, which provides the first line of defense against infection and homeostatic perturbations. However, cell death can also drive pathogenesis. The most well-defined cell death pathways can be categorized as nonlytic (apoptosis) and lytic (pyroptosis, necroptosis, and PANoptosis). While specific triggers are known to induce each of these cell death pathways, it is unclear whether all cell types express the cell death proteins required to activate these pathways. Here, we assessed the protein expression and compared the responses of immune and non-immune cells of human and mouse origin to canonical pyroptotic (LPS plus ATP), apoptotic (staurosporine), necroptotic (TNF-α plus z-VAD), and PANoptotic (influenza A virus infection) stimuli. When compared to fibroblasts, both mouse and human innate immune cells, macrophages, expressed higher levels of cell death proteins and activated cell death effectors more robustly, including caspase-1, gasdermins, caspase-8, and RIPKs, in response to specific stimuli. Our findings highlight the importance of considering the cell type when examining the mechanisms regulating inflammation and cell death. Improved understanding of the cell types that contain the machinery to execute different forms of cell death and their link to innate immune responses is critical to identify new strategies to target these pathways in specific cellular populations for the treatment of infectious diseases, inflammatory disorders, and cancer.

Data-driven, cross-disciplinary collaboration: lessons learned at the largest academic health center in Latin America during the COVID-19 pandemic.

The COVID-19 pandemic has prompted global research efforts to reduce infection impact, highlighting the potential of cross-disciplinary collaboration to enhance research quality and efficiency. At the FMUSP-HC academic health system, we implemented innovative flow management routines for collecting, organizing and analyzing demographic data, COVID-related data and biological materials from over 4,500 patients with confirmed SARS-CoV-2 infection hospitalized from 2020 to 2022. This strategy was mainly planned in three areas: organizing a database with data from the hospitalizations; setting-up a multidisciplinary taskforce to conduct follow-up assessments after discharge; and organizing a biobank. Additionally, a COVID-19 curated collection was created within the institutional digital library of academic papers to map the research output. Over the course of the experience, the possible benefits and challenges of this type of research support approach were identified and discussed, leading to a set of recommended strategies to enhance collaboration within the research institution. Demographic and clinical data from COVID-19 hospitalizations were compiled in a database including adults and a minority of children and adolescents with laboratory confirmed COVID-19, covering 2020-2022, with approximately 350 fields per patient. To date, this database has been used in 16 published studies. Additionally, we assessed 700 adults 6 to 11 months after hospitalization through comprehensive, multidisciplinary in-person evaluations; this database, comprising around 2000 fields per subject, was used in 15 publications. Furthermore, thousands of blood samples collected during the acute phase and follow-up assessments remain stored for future investigations. To date, more than 3,700 aliquots have been used in ongoing research investigating various aspects of COVID-19. Lastly, the mapping of the overall research output revealed that between 2020 and 2022 our academic system produced 1,394 scientific articles on COVID-19. Research is a crucial component of an effective epidemic response, and the preparation process should include a well-defined plan for organizing and sharing resources. The initiatives described in the present paper were successful in our aim to foster large-scale research in our institution. Although a single model may not be appropriate for all contexts, cross-disciplinary collaboration and open data sharing should make health research systems more efficient to generate the best evidence.

PIKFYVE inhibitors trigger interleukin-24-dependent cell death of autophagy-dependent melanoma.

Inhibitors specifically targeting the 1-phosphatidylinositol 3-phosphate 5-kinase (PIKFYVE) disrupt lysosome homeostasis, thereby selectively terminating autophagy-dependent human cancer cells in vivo as well as in vitro without harming the viability of nonmalignant cells. To elucidate the mechanism by which PIKFYVE inhibition induces cell death, autophagy-dependent melanoma cells were compared with normal foreskin fibroblasts. RNA sequence profiling suggested that PIKFYVE inhibitors upregulated an endoplasmic reticulum (ER) stress response involving interleukin-24 (IL24; also known as MDA7) selectively in melanoma cells. Subsequent biochemical and genetic analyses confirmed these results and extended them to tumor xenografts in which tumor formation and expansion were inhibited. IL24 expression was upregulated by the DDIT3/CHOP/CEBPz transcription factor, a component of the PERK-dependent ER-stress response. Ectopic expression of IL24-induced cell death in melanoma cells, but not in foreskin fibroblasts, whereas ablation of the IL24 gene in melanoma cells prevented death. IL24 upregulation was triggered specifically by PIKFYVE inhibition. Thus, unlike thapsigargin and tunicamycin, which induce ER-stress indiscriminately, PIKFYVE inhibitors selectively terminated PIKFYVE-sensitive melanoma by inducing IL24-dependent ER-stress. Moreover, induction of cell death by a PIKFYVE inhibitor together with ectopic expression of IL24 protein was cumulative, thereby confirming the therapeutic potential of PIKFYVE inhibitors in the treatment of melanoma.

Temperature-dependent dispersal and ectotherm species' distributions in a warming world.

Dispersal is a crucial component of species' responses to climate warming. Warming-induced changes in species' distributions are the outcome of how temperature affects dispersal at the individual level. Yet, there is little or no theory that considers the temperature dependence of dispersal when investigating the impacts of warming on species' distributions. Here I take a first step towards filling this key gap in our knowledge. I focus on ectotherms, species whose body temperature depends on the environmental temperature, not least because they constitute the majority of biodiversity on the planet. I develop a mathematical model of spatial population dynamics that explicitly incorporates mechanistic descriptions of ectotherm life history trait responses to temperature. A novel feature of this framework is the explicit temperature dependence of all phases of dispersal: emigration, transfer and settlement. I report three key findings. First, dispersal, regardless of whether it is random or temperature-dependent, allows both tropical and temperate ectotherms to track warming-induced changes in their thermal environments and to expand their distributions beyond the lower and upper thermal limits of their respective climate envelopes. In the absence of dispersal mortality, warming does not alter these new distributional limits. Second, an analysis based solely on trait response data predicts that tropical ectotherms should be able to expand their distributions polewards to a greater degree than temperate ectotherms. Analysis of the dynamical model confirms this prediction. Tropical ectotherms have an advantage when moving to cooler climates because they experience lower within-patch and dispersal mortality, and their higher thermal optima and maximal birth rates allow them to take advantage of the warmer parts of the year. Previous theory has shown that tropical ectotherms are more successful in invading and adapting the temperate climates than vice versa. This study provides the key missing piece, by showing how temperature-dependent dispersal could facilitate both invasion and adaptation. Third, dispersal mortality does not affect the poleward expansion of ectotherm distributions. But, it prevents both tropical and temperate ectotherms from maintaining sink populations in localities that are too warm to be viable in the absence of dispersal. Dispersal mortality also affects species' abundance patterns, causing a larger decline in abundance throughout the range when species disperse randomly rather than in response to thermal habitat suitability. In this way, dispersal mortality can facilitate the evolution of dispersal modes that maximize fitness in warmer thermal environments.