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Introduction: Program signaling (PS), which enables residency applicants to signal their preference for a specific program, was introduced in emergency medicine (EM) in the 2022–2023 residency application cycle. In this study we evaluated EM program directors’ (PD) utilization of PS in application review and ranking. This study also explores the relationship between program characteristics and number of signals received as well as the relative importance and utilization of signals related to the number of signals received.Methods: This is an institutional review board-approved, cross-sectional study of PDs at Accreditation Council for Graduate Medical Education-accredited EM residency programs. We used descriptive statistics to describe the characteristics of residency programs and practices around PS. Measures of central tendency and dispersion summarized continuous variables. We used chi-square analysis or the Fisher exact test for comparisons between groups for categorical variables. Comparisons for continuous variables were made using the t-test for independent samples or analysis of variance.Results: The response rate was 41% (n = 113/277 EM programs). Most programs participated in PS(n = 261/277 EM programs, 94.2%). Mean number of signals received was 60 (range 2–203). Signals received varied based on program characteristics including geographic location and program type, duration, environment, and longevity. Most used PS in holistic review (52.2%), but other uses varied by proportion of applications that were signaled. The importance of PS in application review (mean 2.9; 1–5scale,1= not important, 5 = extremely important) and rank list preparation (2.1) was relatively low compared to other application elements such as standardized letters of evaluation (4.97 for review, 4.90 for ranking).Conclusion: The study provides insights into PS utilization in EM’s inaugural year. We have identified patterns of signal use based on program characteristics and number of signals received that can inform signal allocation and utilization on an individual applicant and program level. A more nuanced understanding of signal use can provide valuable insight as the specialty of EM grapples with fluctuations in its applicant numbers and shifting demographics of its applicant pool.

Detailed binding experiments reveal new insights into the Norrin/Wnt signaling pathway that helps to control vascularization in the retina.

Plants shed organs such as leaves, petals, or fruits through the process of abscission. Monitoring cues such as age, resource availability, and biotic and abiotic stresses allow plants to abscise organs in a timely manner. How these signals are integrated into the molecular pathways that drive abscission is largely unknown. The INFLORESCENCE DEFICIENT IN ABSCISSION (IDA) gene is one of the main drivers of floral organ abscission in Arabidopsis and is known to transcriptionally respond to most abscission-regulating cues. By interrogating the IDA promoter in silico and in vitro, we identified transcription factors that could potentially modulate IDA expression. We probed the importance of ERF- and WRKY-binding sites for IDA expression during floral organ abscission, with WRKYs being of special relevance to mediate IDA up-regulation in response to biotic stress in tissues destined for separation. We further characterized WRKY57 as a positive regulator of IDA and IDA-like gene expression in abscission zones. Our findings highlight the promise of promoter element-targeted approaches to modulate the responsiveness of the IDA signaling pathway to harness controlled abscission timing for improved crop productivity.

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PIP3-dependent Rac exchanger 1 (P-Rex1) is abundantly expressed in neutrophils and plays central roles in chemotaxis and cancer metastasis by serving as a guanine-nucleotide exchange factor (GEF) for Rac. The enzyme is synergistically activated by PIP3 and heterotrimeric Gβγ subunits, but mechanistic details remain poorly understood. While investigating the regulation of P-Rex1 by PIP3, we discovered that Ins(1,3,4,5)P4 (IP4) inhibits P-Rex1 activity and induces large decreases in backbone dynamics in diverse regions of the protein. Cryo-electron microscopy analysis of the P-Rex1·IP4 complex revealed a conformation wherein the pleckstrin homology (PH) domain occludes the active site of the Dbl homology (DH) domain. This configuration is stabilized by interactions between the first DEP domain (DEP1) and the DH domain and between the PH domain and a 4-helix bundle (4HB) subdomain that extends from the C-terminal domain of P-Rex1. Disruption of the DH-DEP1 interface in a DH/PH-DEP1 fragment enhanced activity and led to a more extended conformation in solution, whereas mutations that constrain the occluded conformation led to decreased GEF activity. Variants of full-length P-Rex1 in which the DH-DEP1 and PH-4HB interfaces were disturbed exhibited enhanced activity during chemokine-induced cell migration, confirming that the observed structure represents the autoinhibited state in living cells. Interactions with PIP3-containing liposomes led to disruption of these interfaces and increased dynamics protein-wide. Our results further suggest that inositol phosphates such as IP4 help to inhibit basal P-Rex1 activity in neutrophils, similar to their inhibitory effects on phosphatidylinositol-3-kinase.

Here, we introduce the EMPH special issue on Evolutionary and Biopsychosocial Perspectives on Sickness Communication. This Commentary provides an overview of each article and places them in the wider context of sickness as a social phenomenon with verbal and nonverbal signals. This Commentary, and the special issue, in general, calls for greater attention to these signals that can affect pathogen transmission and may be at the evolutionary root of our caregiving systems and behaviours.

FGF9 is a potent mitogen and survival factor, but FGF9 protein levels are generally low and restricted to a few adult organs. Aberrant expression of FGF9 usually results in cancer. However, the mechanism of FGF9 action has not been fully established. Previous studies showed that FGF1 and FGF2 directly bind to integrin αvβ3, and this interaction is critical for signaling functions (FGF-integrin crosstalk). FGF1 and FGF2 mutants defective in integrin binding were defective in signaling, whereas the mutants still bound to FGFR suppressed angiogenesis and tumor growth, indicating that they act as antagonists. We hypothesize that FGF9 requires direct integrin binding for signaling. Here, we show that docking simulation of the interaction between FGF9 and αvβ3 predicted that FGF9 binds to the classical ligand-binding site of αvβ3. We show that FGF9 bound to integrin αvβ3 and generated FGF9 mutants in the predicted integrin-binding interface. An FGF9 mutant (R108E) was defective in integrin binding, activating FRS2α and ERK1/2, inducing DNA synthesis, cancer cell migration, and invasion in vitro. R108E suppressed DNA synthesis and activation of FRS2α and ERK1/2 induced by WT FGF9 (dominant-negative effect). These findings indicate that FGF9 requires direct integrin binding for signaling and that R108E has potential as an antagonist to FGF9 signaling.

The third Asia Pacific Drosophila Neurobiology Conference (APDNC3) was held in the Wako Campus of RIKEN in Tokyo, Japan, from February 27th to March 1st, 2024. While APDNC2 was held in Taiwan in 2019, the global coronavirus pandemic enforced a long hiatus. Hence, APDNC3 was a much‐anticipated meeting that attracted ~218 scientists from 18 different countries and regions, 154 from outside Japan. The meeting was divided into 13 scientific, 2 poster, and 3 career development sessions. Two plenary talks were delivered by Professor Daisuke Yamamoto, from NICT and Professor Claude Desplan from NYU. Thirty‐seven other speakers were invited to give lectures. Eighty‐six poster presenters were selected from submitted abstracts. Talks and posters described how neuronal circuits underlying specific behaviors were identified and how they developed. The presented work also demonstrated circuit‐specific cellular and molecular mechanisms in health and disease. It was clear that technological advances, like molecular genetic tools for identifying, manipulating, and imaging individual neurons and the great granularity of the fly brain connectome, were significantly augmenting research. Overall, the meeting highlighted the remarkable biological insights that fly neurobiologists continue to provide. [ABSTRACT FROM AUTHOR]

Background: Normal cells express functional tumor suppressor WW domain-containing oxidoreductase (WWOX), designated WWOXf. UV irradiation induces WWOXf cells to undergo bubbling cell death (BCD) — an event due to the accumulation of nuclear nitric oxide (NO) gas that forcefully pushes the nuclear and cell membranes to form one or two bubbles at room temperature (22 °C) and below. In contrast, when WWOX-deficient or -dysfunctional (WWOXd) cells are exposed to UV and/or cold shock, the cells undergo nuclear pop-out explosion death (POD). We aimed to determine the morphological and biochemical changes in WWOXf cells during BCD versus apoptosis. Methods: WWOXf and WWOXd cells were exposed to UV followed by measuring BCD or POD by time-lapse microscopy and/or time-lapse holographic microscopy at 4, 22, or 37 °C to visualize morphological changes. Live cell stains were used to measure the kinetics of nitric oxide (NO) production and Ca2+ influx. Extent of cell death was measured by uptake of propidium iodide and by internucleosomal DNA fragmentation using agarose gel electrophoresis. Results: WWOXf cells were exposed to UV and then cold shock, or cold shock and then UV, and cultured at 4, 10, and 22 °C, respectively. Initially, UV induced calcium influx and NO production, which led to nuclear bubbling and final death. Cold shock pretreatment completely suppressed UV-mediated bubbling at 37 °C, so the UV/cold shock-treated cells underwent apoptosis. Without cold shock, UV only induced bubbling at all temperatures, whereas the efficiency of bubbling at 37 °C was reduced by greater than 50%. Morphologically, the WWOXf cell height or thickness was significantly increased during cell division or apoptosis, but the event did not occur in BCD. In comparison, when WWOXd cancer cells received UV or UV/cold shock, these cells underwent NO-independent POD. UV/cold shock effectively downregulated the expression of many proteins such as the housekeeping α-tubulin (> 70%) and β-actin (< 50%), and cortactin (> 70%) in WWOXf COS7 cells. UV/cold shock induced relocation of α-tubulin to the nucleus and nuclear bubbles in damaged cells. UV induced co-translocation of the WWOX/TRAF2 complex to the nuclei, in which the prosurvival TRAF2 blocked the proapoptotic WWOX via its zinc finger domain. Without WWOX, TRAF2 did not relocate to the nuclei. Cold shock caused the dissociation of the WWOX/TRAF2 complex in the nucleus needed for BCD. In contrast, the formation of the WWOX/TRAF2 complex, plus p53, was strengthened at 37 °C required for apoptosis. Conclusions: The temperature-sensitive nuclear WWOX/TRAF2 complex acts as a molecular switch, whose dissociation favors BCD at low temperatures, and the association supports apoptosis at 37 °C in UV-treated WWOXf cells. [ABSTRACT FROM AUTHOR]

Reelin, a secreted glycoprotein, plays a crucial role in guiding neocortical neuronal migration, dendritic outgrowth and arborization, and synaptic plasticity in the adult brain. Reelin primarily operates through the canonical lipoprotein receptors apolipoprotein E receptor 2 (Apoer2) and very low-density lipoprotein receptor (Vldlr). Reelin also engages with noncanonical receptors and unidentified coreceptors; however, the effects of which are less understood. Using high-throughput tandem mass tag (TMT) liquid chromatography tandem mass spectrometry (LC-MS/MS)-based proteomics and gene set enrichment analysis (GSEA), we identified both shared and unique intracellular pathways activated by Reelin through its canonical and noncanonical signaling in primary murine neurons of either sex during dendritic growth and arborization. We observed pathway cross talk related to regulation of cytoskeleton, neuron projection development, protein transport, and actin filament-based process. We also found enriched gene sets exclusively by the noncanonical Reelin pathway including protein translation, mRNA metabolic process, and ribonucleoprotein complex biogenesis suggesting Reelin fine-tunes neuronal structure through distinct signaling pathways. A key discovery is the identification of aldolase A, a glycolytic enzyme and actin-binding protein, as a novel effector of Reelin signaling. Reelin induced de novo translation and mobilization of aldolase A from the actin cytoskeleton. We demonstrated that aldolase A is necessary for Reelin-mediated dendrite growth and arborization in primary murine neurons and mouse brain cortical neurons. Interestingly, the function of aldolase A in dendrite development is independent of its known role in glycolysis. Altogether, our findings provide new insights into the Reelin-dependent signaling pathways and effector proteins that are crucial for dendritic development. [ABSTRACT FROM AUTHOR]

Over the last several decades, there has been an arms race to acquire credentials as higher education has shifted from an elitist system to mass education. From an individual perspective, given the higher education system and labor market conditions, it is rational to pursue advanced qualifications. However, whether the education system delivers improvements in human capital or is principally a signaling mechanism is questionable. Estimates of the proportion of labor market rewards due to signaling range as high as 80%, suggesting that education is not only expensive but inefficient. In an increasingly transactional environment in which education providers are highly motivated by financial considerations, this situation is only likely to be exacerbated by the rapid developments in artificial intelligence (AI). The use of AI has the potential to make learning more effective, but given that many students see credential acquisition as transactional, it may reduce both human capital and the value of the signaling effect. If the credibility of the credentials offered is further damaged, the higher education sector in its present form and scale may well be unsustainable. We examine the evidence on credential inflation, returns to education, and mismatch of graduates to jobs before analyzing how AI is likely to affect these trends. We then suggest possible responses of prospective students, education providers, and employers to the growing adoption of AI in both education and the workplace. We conclude that the current offerings of generalist degrees, as opposed to vocational qualifications, are not sustainable and that to survive, even in a downsized form, the sector must respond to this disruptive technology by changing both the nature of its offerings and its methods of ensuring that the credentials they offer reflect genuine student learning. [ABSTRACT FROM AUTHOR]

Protease-activated receptor 2 (PAR2) is a cell-surface receptor expressed in various cell types, including keratinocytes, neurons, immune and inflammatory cells. Activation of PAR2, whether via its canonical or biased pathways, triggers a series of signaling cascades that mediate numerous functions. This review aims to highlight the emerging roles and interactions of PAR2 in different skin cells. It specifically summarizes the latest insights into the roles of PAR2 in skin conditions such as atopic dermatitis (AD), psoriasis, vitiligo and melasma. It also considers these roles from the perspective of the cutaneous microenvironment in relation to other inflammatory and autoimmune dermatological disorders. Additionally, the review explores PAR2's involvement in associated comorbidities from both cutaneous and extracutaneous diseases. Therefore, PAR2 may serve as a key target for interactions among various cells within the local skin environment. [ABSTRACT FROM AUTHOR]

The chemokine receptors CCR1 and CCR5 display overlapping expression patterns and ligand dependency. Here we find that ligand activation of CCR5, not CCR1, is dependent on N-terminal receptor O-glycosylation. Release from O-glycosylation dependency is obtained by increasing CCR5 N-terminus acidity to the level of CCR1. Ligand activation of CCR5, not CCR1, drastically improves in the absence of glycosaminoglycans (GAGs). Ligand activity at both CCR1 and CCR5 is boosted by positively charged/basic peptides shown to interact with acidic chemokine receptor N-termini. We propose that receptors with an inherent low N-terminus acidity rely on post-translational modifications (PTMs) to efficiently compete with acidic entities in the local environment for ligand capture. Although crucial for initial ligand binding, strong electrostatic interactions between the ligand and the receptor N-terminus may counteract following insertion of the ligand into the receptor binding pocket and activation, a process that seems to be aided in the presence of basic peptides. Basic peptides bind to the naked CCR1 N-terminus, not the CCR5 N-terminus, explaining the loss of boosting of ligand-induced signaling via CCR5 in cells incapable of glycosylation. [ABSTRACT FROM AUTHOR]

Senescent cells produce a Senescence‐Associated Secretory Phenotype (SASP) that involves factors with diverse and sometimes contradictory activities. One key SASP factor, interleukin‐6 (IL‐6), has the potential to amplify cellular senescence in the SASP‐producing cells in an autocrine action, while simultaneously inducing proliferation in the neighboring cells. The underlying mechanisms for the contrasting actions remain unclear. We found that the senescence action does not involve IL‐6 secretion nor the interaction with the receptor expressed in the membrane but is amplified through an intracrine mechanism. IL‐6 sustains intracrine senescence interacting with the intracellular IL‐6 receptor located in anterograde traffic specialized structures, with cytosolic DNA, cGAS‐STING, and NFκB activation. This pathway triggered by intracellular IL‐6 significantly contributes to cell‐autonomous induction of senescence and impacts in tumor growth control. Inactivation of IL‐6 in somatotrophic senescent cells transforms them into strongly tumorigenic in NOD/SCID mice, while re‐expression of IL‐6 restores senescence control of tumor growth. The intracrine senescent IL‐6 pathway is further evidenced in three human cellular models of therapy‐induced senescence. The compartmentalization of the intracellular signaling, in contrast to the paracrine tumorigenic action, provides a pathway for IL‐6 to sustain cell‐autonomous senescent cells, driving the SASP, and opens new avenues for clinical consideration to senescence‐based therapies. [ABSTRACT FROM AUTHOR]

Irritable bowel syndrome (IBS) is a condition that significantly impacts the lifestyle, health, and habits of numerous individuals worldwide. Its diagnosis and classification are based on the Rome criteria, updated periodically to reflect new research findings in this field. IBS can be classified into different types based on symptoms, each with distinct treatment approaches and some differences in their pathophysiology. The exact pathological background of IBS remains unclear, with many aspects still unknown. Recent research developments suggest that disorders in the brain-gut–microbiota axis are key contributors to the symptoms and severity of IBS. The central nervous system (CNS) interacts bidirectionally with intestinal processes within the lumen and the intestinal wall, with the autonomic nervous system, particularly the vagus nerve, playing an important role. However, the enteric nervous system (ENS) is also crucial in the pathophysiological pathway of IBS. The apeline–corticotropin-releasing factor (CRF)–toll-like receptor 4 (TLR4) signaling route via enteric glia and serotonin production in enteroendocrine cells at the enteric barrier are among the most well-understood new findings that affect IBS through the ENS. Additionally, the microbiota regulates neuronal signals, modifying enteric function by altering the number of enteric bacteria and other mechanisms. Given the limited therapeutic options currently available, it is essential to identify new treatment targets, with the brain-gut axis, particularly the enteric nervous system, being a promising focus. This study aims to delineate the molecular mechanisms that induce IBS and to suggest potential targets for future research and treatment of this potentially debilitating disease. [ABSTRACT FROM AUTHOR]

Phytohormones are signaling substances that control essential elements of growth, development, and reactions to environmental stress. Drought, salt, heat, cold, and floods are a few examples of abiotic factors that have a significant impact on plant development and survival. Complex sensing, signaling, and stress response systems are needed for adaptation and tolerance to such pressures. Abscisic acid (ABA) is a key phytohormone that regulates stress responses. It interacts with the jasmonic acid (JA) and salicylic acid (SA) signaling pathways to direct resources toward reducing the impacts of abiotic stressors rather than fighting against pathogens. Under exposure to nanoparticles, the plant growth hormones also function as molecules that regulate stress and are known to be involved in a variety of signaling cascades. Reactive oxygen species (ROS) are detected in excess while under stress, and nanoparticles can control their formation. Understanding the way these many signaling pathways interact in plants will tremendously help breeders create food crops that can survive in deteriorating environmental circumstances brought on by climate change and that can sustain or even improve crop production. Recent studies have demonstrated that phytohormones, such as the traditional auxins, cytokinins, ethylene, and gibberellins, as well as more recent members like brassinosteroids, jasmonates, and strigolactones, may prove to be significant metabolic engineering targets for creating crop plants that are resistant to abiotic stress. In this review, we address recent developments in current understanding regarding the way various plant hormones regulate plant responses to abiotic stress and highlight instances of hormonal communication between plants during abiotic stress signaling. We also discuss new insights into plant gene and growth regulation mechanisms during stress, phytohormone engineering, nanotechnological crosstalk of phytohormones, and Plant Growth-Promoting Rhizobacteria's Regulatory Powers (PGPR) via the involvement of phytohormones. [ABSTRACT FROM AUTHOR]

Humans display a remarkable tendency to cooperate with strangers; however, identifying prospective cooperation partners accurately before entering any new relationship is essential to mitigate the risk of being exploited. Visual appearance, as inferrable, for example, from facial images on job portals and dating sites, may serve as a potential signal of cooperativeness. This experimental study examines whether static images enable the correct detection of an individual's propensity to cooperate. Participants first played the Prisoner's Dilemma (PD) game, a standard cooperation task. Subsequently, they were asked to predict the cooperativeness of participants from a prior PD study relying solely on their static facial photographs. While our main results indicate only marginal accuracy improvements over random guessing, a more detailed analysis reveals that participants were more successful at identifying cooperative tendencies similar to their own. Despite no detectable main effect in our primary treatment variations (time pressure versus time delay), participants exhibited increased accuracy in identifying male cooperators under time pressure. These findings point towards a limited yet nuanced role of static facial images in predicting cooperativeness, advancing our understanding of non-behavioral cues in cooperative interactions. [ABSTRACT FROM AUTHOR]

Ferroptosis is a new form of regulated necrosis characterized by iron-dependent lipid peroxidation, leading to irreparable lipid damage, membrane permeabilization, and necrotic cell death. Ferroptosis has recently been implicated in the pathogenesis of multiple forms of heart disease such as myocardial infarction, cardiac hypertrophy, heart failure, and various cardiomyopathies. Important progress has also been made regarding how ferroptosis is regulated in vitro and in vivo as well as its role in cardiac homeostasis and disease pathogenesis. In this review, we discuss molecular mechanisms that regulates ferroptosis in the heart, including pathways leading to iron overload and lipid peroxidation as well as the roles of key organelles in this process. We also discuss recent findings pertaining to the new pathogenic role of ferroptosis in various forms of heart disease as well as genetic and pharmacologic strategies targeting ferroptosis in the heart. [ABSTRACT FROM AUTHOR]

Lipopolysaccharide (LPS) in blood circulation causes endotoxemia and is linked to various disease conditions. Current treatments focus on preventing LPS from interacting with its receptor Toll-like receptor 4 (TLR4) and reducing inflammation. However, our body has a natural defense mechanism: reticuloendothelial cells in the liver rapidly degrade and inactivate much of the circulating LPS within minutes. But this LPS clearance mechanism is not perfect. Excessive LPS that escape this clearance mechanism cause systemic inflammatory damage through TLR4. Despite its importance, the role of reticuloendothelial cells in LPS elimination is not well-studied, especially regarding the specific cells, receptors, and mechanisms involved. This gap hampers the development of effective therapies for endotoxemia and related diseases. This review consolidates the current understanding of LPS clearance, narrates known and explores potential mechanisms, and discusses the relationship between LPS clearance and LPS signaling. It also aims to highlight key insights that can guide the development of strategies to reduce circulating LPS by way of bolstering host defense mechanisms. Ultimately, we seek to provide a foundation for future research that could lead to innovative approaches for enhancing the body's natural ability to clear LPS and thereby lower the risk of endotoxin-related inflammatory diseases, including sepsis. [ABSTRACT FROM AUTHOR]

Platelets are small cell fragments that play a crucial role in hemostasis, requiring fast response times and fine signaling pathway regulation. For this regulation, platelets require a balance between two pathway types: the activatory and negative signaling pathways. Activatory signaling mediators are positive responses that enhance stimuli initiated by a receptor in the platelet membrane. Negative signaling regulates and controls the responses downstream of the same receptors to roll back or even avoid spontaneous thrombotic events. Several blood-related pathologies can be observed when these processes are unregulated, such as massive bleeding in activatory signaling inhibition or thrombotic events for negative signaling inhibition. The study of each protein and metabolite in isolation does not help to understand the role of the protein or how it can be contrasted; however, understanding the balance between active and negative signaling could help develop effective therapies to prevent thrombotic events and bleeding disorders. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) associated with viral or metabolic liver diseases is a growing cancer without effective therapy. AMPK is downregulated in HCC and its activation diminishes tumor growth. Alpha lipoic acid (ALA), an indirect AMPK activator that inhibits hepatic steatosis, shows antitumor effects in different cancers. We aimed to study its putative action in liver-cancer derived cell lines through AMPK signaling. We performed cytometric studies for apoptosis and cell cycle, and 2D and 3D migration analysis in HepG2/C3A and Hep3B cells. ALA led to significant inhibition of cell migration/invasion only in HepG2/C3A cells. We showed that these effects depended on AMPK, and ALA also increased the levels and nuclear compartmentalization of the AMPK target p53. The anti-invasive effect of ALA was abrogated in stable-silenced (shTP53) versus isogenic-TP53 HepG2/C3A cells. Furthermore, ALA inhibited epithelial-mesenchymal transition (EMT) in control HepG2/C3A but not in shTP53 nor in Hep3B cells. Besides, we spotted that in patients from the HCC-TCGA dataset some EMT genes showed different expression patterns or survival depending on TP53. ALA emerges as a potent activator of AMPK-p53 axis in HCC cells, and it decreases migration/invasion by reducing EMT which could mitigate the disease in wild-type TP53 patients. [ABSTRACT FROM AUTHOR]

Nitrogen (N) and phosphorus (Pi) are essential macronutrients that affect plant growth and development by influencing the molecular, metabolic, biochemical, and physiological responses at the local and whole levels in plants. N and Pi stresses suppress the physiological activities of plants, resulting in agricultural productivity losses and severely threatening food security. Accordingly, plants have elaborated diverse strategies to cope with N and Pi stresses through maintaining N and Pi homeostasis. MicroRNAs (miRNAs) as potent regulators fine-tune N and Pi signaling transduction that are distinct and indivisible from each other. Specific signals, such as noncoding RNAs (ncRNAs), interact with miRNAs and add to the complexity of regulation. Elucidation of the mechanisms by which miRNAs regulate N and Pi signaling transduction aids in the breeding of plants with strong tolerance to N and Pi stresses and high N and Pi use efficiency by fine-tuning MIR genes or miRNAs. However, to date, there has been no detailed and systematic introduction and comparison of the functions of miRNAs in N and Pi signaling transduction from the perspective of miRNAs and their applications. Here, we summarized and discussed current advances in the involvement of miRNAs in N and Pi signaling transduction and highlighted that fine-tuning the MIR genes or miRNAs involved in maintaining N and Pi homeostasis might provide valuable sights for sustainable agriculture. [ABSTRACT FROM AUTHOR]

GPR56, an adhesion G-protein coupled receptor (aGPCRs) with constitutive and ligand-promoted activity, is involved in many physiological and pathological processes. Whether the receptor's constitutive or ligand-promoted activation occur through the same molecular mechanism, and whether different activation modes lead to functional selectivity between G proteins is unknown. Here we show that GPR56 constitutively activates both G12 and G13. Unlike constitutive activation and activation with 3-α-acetoxydihydrodeoxygedunin (3αDOG), stimulation with an antibody, 10C7, directed against GPR56's extracellular domain (ECD) led to an activation that favors G13 over G12. An autoproteolytically deficient mutant, GPR56-T383A, was also activated by 10C7 indicating that the tethered agonist (TA) exposed through autocatalytic cleavage, is not required for this activation modality. In contrast, this proteolysis-resistant mutant could not be activated by 3αDOG indicating different modes of activation by the two ligands. We show that an N-terminal truncated GPR56 construct (GPR56-Δ1-385) is devoid of constitutive activity but was activated by 3αDOG. Similarly to 3αDOG, 10C7 promoted the recruitment of β-arrestin-2 but GPR56 internalization was β-arrestin independent. Despite the slow activation mode of 10C7 that favors G13 over G12, it efficiently activated the downstream Rho pathway in BT-20 breast cancer cells. These data show that different GPR56 ligands have different modes of activation yielding differential G protein selectivity but converging on the activation of the Rho pathway both in heterologous expressions system and in cancer cells endogenously expressing the receptor. 10C7 is therefore an interesting tool to study both the processes underlying GPR56 activity and its role in cancer cells. [ABSTRACT FROM AUTHOR]

During pregnancy, the adipokines leptin and adiponectin can affect placental nutrient transport and inflammatory pathways, potentially leading to altered fetal growth and pregnancy complications including gestational diabetes mellitus (GDM) and preeclampsia (PE). The aim of this systematic review is to gather and analyze research on maternal circulating leptin and adiponectin levels and their relationship to adverse pregnancy and birth outcomes. Additionally, it seeks to determine whether these hormones are linked to alterations in placental transporters and cell signaling pathways. PubMed and MEDLINE were systematically searched to include studies published between 2012 and 2022. All primary data studies reporting serum adiponectin and/or leptin, placental mRNA and protein levels of related transporters, and adverse birth outcomes were eligible. The current systematic review encompasses a total of 14 articles. Abnormal serum maternal leptin and adiponectin levels were associated with changes in fetal growth and placental cellular signaling and nutrient transporters. A majority of studies associated elevated maternal leptin and reduced adiponectin with fetal overgrowth, although this relationship was not consistent and may be complicated when other pathologies are present. The effects of maternal leptin and adiponectin on fetal growth may be driven by placental adaptation in nutrient transporters and mitochondria. Future studies should determine if the placental effects of leptin and adiponectin that have been found in models have mechanistic roles in human pregnancy. [ABSTRACT FROM AUTHOR]

Simple Summary: The current review article focused on the complex interaction between plant hormones and transcription factors in the response to salt stress, a pressing global issue that has a considerable effect on agricultural productivity. The study unveils the effect of salt stress on the ion equilibrium and triggers a cascade of molecular reactions that have a response to plant growth and development. Transcription factors are essential in regulating gene expression under salt stress. The transcription factors function in collaboration with hormones to regulate environmental stress responses. The study sheds light on the underlying regulatory networks, thus providing crucial knowledge for cultivating salt-tolerant crops through selective breeding and genetic engineering. This review significantly contributes to the establishment of sustainable agricultural techniques, which are essential in addressing the increasing problem of soil salinization and securing global food security. The negative impacts of soil salinization on ion homeostasis provide a significant global barrier to agricultural production and development. Plant physiology and biochemistry are severely affected by primary and secondary NaCl stress impacts, which damage cellular integrity, impair water uptake, and trigger physiological drought. Determining how transcriptional factors (TFs) and hormone networks are regulated in plants in response to salt stress is necessary for developing crops that tolerate salt. This study investigates the complex mechanisms of several significant TF families that influence plant responses to salt stress, involving AP2/ERF, bZIP, NAC, MYB, and WRKY. It demonstrates how these transcription factors (TFs) help plants respond to the detrimental effects of salinity by modulating gene expression through mechanisms including hormone signaling, osmotic stress pathway activation, and ion homeostasis. Additionally, it explores the hormonal imbalances triggered by salt stress, which entail complex interactions among phytohormones like jasmonic acid (JA), salicylic acid (SA), and abscisic acid (ABA) within the hormonal regulatory networks. This review highlights the regulatory role of key transcription factors in salt-stress response, and their interaction with plant hormones is crucial for developing genome-edited crops that can enhance agricultural sustainability and address global food security challenges. [ABSTRACT FROM AUTHOR]

The hormone renin is produced in the kidney by the juxtaglomerular cells. It is the rate-limiting factor in the circulating renin–angiotensin–aldosterone system (RAAS), which contributes to electrolyte, water, and blood pressure homeostasis. In the kidneys, the distal tubule and the collecting duct are the key target segments for RAAS. The collecting duct is important for urine production and also for salt, water, and acid–base homeostasis. The critical functional role of the collecting duct is mediated by the principal and the intercalated cells and is regulated by different hormones like aldosterone and vasopressin. The collecting duct is not only a target for hormones but also a place of hormone production. It is accepted that renin is produced in the collecting duct at a low level. Several studies have described that the cells in the collecting duct exhibit plasticity properties because the ratio of principal to intercalated cells can change under specific circumstances. This narrative review focuses on two aspects of the collecting duct that remain somehow aside from mainstream research, namely the cell plasticity and the renin expression. We discuss the link between these collecting duct features, which we see as a promising area for future research given recent findings. [ABSTRACT FROM AUTHOR]

Land plants grow throughout their life cycle via the continuous activity of stem cell reservoirs contained within their apical meristems. The shoot apical meristem (SAM) of Arabidopsis and other land plants responds to a variety of environmental cues, yet little is known about the response of meristems to seasonal changes in day length, or photoperiod. Here, the vegetative and reproductive growth of Arabidopsis wild-type and clavata3 (clv3) plants in different photoperiod conditions was analyzed. It was found that SAM size in wild-type Arabidopsis plants grown in long-day (LD) conditions gradually increased from embryonic to reproductive development. clv3 plants produced significantly more leaves as well as larger inflorescence meristems and more floral buds than wild-type plants in LD and short-day (SD) conditions, demonstrating that CLV3 signaling limits vegetative and inflorescence meristem activity in both photoperiods. The clv3 phenotypes were more severe in SDs, indicating a greater requirement for CLV3 restriction of SAM function when the days are short. In contrast, clv3 floral meristem size and carpel number were unchanged between LD and SD conditions, which shows that the photoperiod does not affect the regulation of floral meristem activity through the CLV3 pathway. This study reveals that CLV3 signaling specifically restricts vegetative and inflorescence meristem activity in both LD and SD photoperiods but plays a more prominent role during short days. [ABSTRACT FROM AUTHOR]

Mergers and acquisitions (M&As) are an important way for non-Big 4 accounting firms to grow their businesses. Non-Big 4 firms also account for the vast majority of PCAOB inspections. Consistent with negative inspection reports signaling low quality at inspected firms, we find that non-Big 4 accounting firms conduct fewer M&A deals after they receive negative inspection reports. Additional analyses support our hypothesized signaling mechanism: (1) the chilling effect of inspection reports on M&A activity is stronger when the inspected firm's business is focused on public company audits, (2) the effect is stronger when stakeholders at the target firm know less about the acquirer because the acquirer is located in a different city, and (3) clients at the target firm switch to new firms rather than move over to the acquirer if the acquirer received a negative inspection report prior to the M&A date. [ABSTRACT FROM AUTHOR]

Lung adenocarcinoma (LUAD) is the most prevalent subtype of lung cancer and presents clinically with a high degree of biological heterogeneity and distinct clinical outcomes. The current paradigm of LUAD etiology posits alveolar epithelial type II (AT2) cells as the primary cell of origin, while the role of AT1 cells in LUAD oncogenesis remains unknown. Here, we examine oncogenic transformation in mouse Gram-domain containing 2 (Gramd2)+ AT1 cells via oncogenic KRASG12D. Activation of KRASG12D in AT1 cells induces multifocal LUAD, primarily of papillary histology. Furthermore, KRT8+ intermediate cell states were observed in both AT2- and AT1-derived LUAD, but SCGB3A2+, another intermediate cell marker, was primarily associated with AT1 cells, suggesting different mechanisms of tumor evolution. Collectively, our study reveals that Gramd2+ AT1 cells can serve as a cell of origin for LUAD and suggests that distinct subtypes of LUAD based on cell of origin be considered in the development of therapeutics.

Abstract Background Normal cells express functional tumor suppressor WW domain-containing oxidoreductase (WWOX), designated WWOXf. UV irradiation induces WWOXf cells to undergo bubbling cell death (BCD) — an event due to the accumulation of nuclear nitric oxide (NO) gas that forcefully pushes the nuclear and cell membranes to form one or two bubbles at room temperature (22 °C) and below. In contrast, when WWOX-deficient or -dysfunctional (WWOXd) cells are exposed to UV and/or cold shock, the cells undergo nuclear pop-out explosion death (POD). We aimed to determine the morphological and biochemical changes in WWOXf cells during BCD versus apoptosis. Methods WWOXf and WWOXd cells were exposed to UV followed by measuring BCD or POD by time-lapse microscopy and/or time-lapse holographic microscopy at 4, 22, or 37 °C to visualize morphological changes. Live cell stains were used to measure the kinetics of nitric oxide (NO) production and Ca2+ influx. Extent of cell death was measured by uptake of propidium iodide and by internucleosomal DNA fragmentation using agarose gel electrophoresis. Results WWOXf cells were exposed to UV and then cold shock, or cold shock and then UV, and cultured at 4, 10, and 22 °C, respectively. Initially, UV induced calcium influx and NO production, which led to nuclear bubbling and final death. Cold shock pretreatment completely suppressed UV-mediated bubbling at 37 °C, so the UV/cold shock-treated cells underwent apoptosis. Without cold shock, UV only induced bubbling at all temperatures, whereas the efficiency of bubbling at 37 °C was reduced by greater than 50%. Morphologically, the WWOXf cell height or thickness was significantly increased during cell division or apoptosis, but the event did not occur in BCD. In comparison, when WWOXd cancer cells received UV or UV/cold shock, these cells underwent NO-independent POD. UV/cold shock effectively downregulated the expression of many proteins such as the housekeeping α-tubulin (> 70%) and β-actin ( 70%) in WWOXf COS7 cells. UV/cold shock induced relocation of α-tubulin to the nucleus and nuclear bubbles in damaged cells. UV induced co-translocation of the WWOX/TRAF2 complex to the nuclei, in which the prosurvival TRAF2 blocked the proapoptotic WWOX via its zinc finger domain. Without WWOX, TRAF2 did not relocate to the nuclei. Cold shock caused the dissociation of the WWOX/TRAF2 complex in the nucleus needed for BCD. In contrast, the formation of the WWOX/TRAF2 complex, plus p53, was strengthened at 37 °C required for apoptosis. Conclusions The temperature-sensitive nuclear WWOX/TRAF2 complex acts as a molecular switch, whose dissociation favors BCD at low temperatures, and the association supports apoptosis at 37 °C in UV-treated WWOXf cells.

Objective: This work characterized fluctuations in cell components involved in the regulation of cell redox homeostasis during Caco-2 cell differentiation into enterocytes. Methods: Caco-2 cells were differentiated for 10 days. Gene expression of NADPH oxidases; enzymes that metabolize superoxide anion and hydrogen peroxide, proteins involved in the production and/or regeneration of glutathione, thioredoxin, and in NADPH production, and NRF2-dependent genes were measured by qPCR at 0, 1, 4, 7, and 10 days post-confluence. Results: NADPH oxidase 1 mRNA levels decreased with Caco-2 cell differentiation, in agreement with its role in regulating cell proliferation. NADPH oxidase 4, DUOX2, superoxide dismutase 1, and catalase mRNA levels increased with differentiation. NRF2 mRNA levels increased with differentiation up to day 4 post-confluence, reaching a plateau until day 10. A similar pattern was observed for the NRF2-regulated genes: NAD(P)H quinone dehydrogenase 1, glutathione reductase 1, and thioredoxin reductase 1. On the contrary, glutamate-cysteine ligase catalytic subunit mRNA levels decreased after reaching a maximum 4 days post-confluence. This and the finding of a correlation between glutathione reductase 1 and thioredoxin reductase 1 mRNA levels suggest that recycling of glutathione and thioredoxin is more relevant than their synthesis during Caco-2 cell differentiation. Conclusion: Results support the relevance of redox homeostasis for cell fate decisions and in preparing enterocytes to interact with their environment. Significance statement Current findings resemble changes in redox components previously characterized in vivo. This stresses the concept that Caco-2 cells are an appropriate model to be used to evaluate redox-regulated mechanisms in human enterocytes.

Abstract Humans display a remarkable tendency to cooperate with strangers; however, identifying prospective cooperation partners accurately before entering any new relationship is essential to mitigate the risk of being exploited. Visual appearance, as inferrable, for example, from facial images on job portals and dating sites, may serve as a potential signal of cooperativeness. This experimental study examines whether static images enable the correct detection of an individual’s propensity to cooperate. Participants first played the Prisoner’s Dilemma (PD) game, a standard cooperation task. Subsequently, they were asked to predict the cooperativeness of participants from a prior PD study relying solely on their static facial photographs. While our main results indicate only marginal accuracy improvements over random guessing, a more detailed analysis reveals that participants were more successful at identifying cooperative tendencies similar to their own. Despite no detectable main effect in our primary treatment variations (time pressure versus time delay), participants exhibited increased accuracy in identifying male cooperators under time pressure. These findings point towards a limited yet nuanced role of static facial images in predicting cooperativeness, advancing our understanding of non-behavioral cues in cooperative interactions.

Abstract Nitrogen (N) and phosphorus (Pi) are essential macronutrients that affect plant growth and development by influencing the molecular, metabolic, biochemical, and physiological responses at the local and whole levels in plants. N and Pi stresses suppress the physiological activities of plants, resulting in agricultural productivity losses and severely threatening food security. Accordingly, plants have elaborated diverse strategies to cope with N and Pi stresses through maintaining N and Pi homeostasis. MicroRNAs (miRNAs) as potent regulators fine-tune N and Pi signaling transduction that are distinct and indivisible from each other. Specific signals, such as noncoding RNAs (ncRNAs), interact with miRNAs and add to the complexity of regulation. Elucidation of the mechanisms by which miRNAs regulate N and Pi signaling transduction aids in the breeding of plants with strong tolerance to N and Pi stresses and high N and Pi use efficiency by fine-tuning MIR genes or miRNAs. However, to date, there has been no detailed and systematic introduction and comparison of the functions of miRNAs in N and Pi signaling transduction from the perspective of miRNAs and their applications. Here, we summarized and discussed current advances in the involvement of miRNAs in N and Pi signaling transduction and highlighted that fine-tuning the MIR genes or miRNAs involved in maintaining N and Pi homeostasis might provide valuable sights for sustainable agriculture.

Abstract Hepatocellular carcinoma (HCC) associated with viral or metabolic liver diseases is a growing cancer without effective therapy. AMPK is downregulated in HCC and its activation diminishes tumor growth. Alpha lipoic acid (ALA), an indirect AMPK activator that inhibits hepatic steatosis, shows antitumor effects in different cancers. We aimed to study its putative action in liver-cancer derived cell lines through AMPK signaling. We performed cytometric studies for apoptosis and cell cycle, and 2D and 3D migration analysis in HepG2/C3A and Hep3B cells. ALA led to significant inhibition of cell migration/invasion only in HepG2/C3A cells. We showed that these effects depended on AMPK, and ALA also increased the levels and nuclear compartmentalization of the AMPK target p53. The anti-invasive effect of ALA was abrogated in stable-silenced (shTP53) versus isogenic-TP53 HepG2/C3A cells. Furthermore, ALA inhibited epithelial-mesenchymal transition (EMT) in control HepG2/C3A but not in shTP53 nor in Hep3B cells. Besides, we spotted that in patients from the HCC-TCGA dataset some EMT genes showed different expression patterns or survival depending on TP53. ALA emerges as a potent activator of AMPK-p53 axis in HCC cells, and it decreases migration/invasion by reducing EMT which could mitigate the disease in wild-type TP53 patients.

Context: Prostate cancer remains a significant global health concern, and understanding the molecular drivers of this disease is crucial for developing effective diagnostic and therapeutic strategies. Steroid receptor coactivator-3 (SRC-3), a member of the SRC family, has emerged as a key player in prostate cancer pathogenesis. Aims: To examine the role of SRC-3 in prostate cancer, encompassing molecular mechanisms, clinical implications, and therapeutic opportunities. Methods: A systematic literature search following PRISMA guidelines was conducted in PubMed, PMC, and other relevant databases to identify studies that investigate SRC-3 in prostate cancer. Results: 785 articles were retrieved from databases using specific keywords and MeSH terms related to SRC-3 and Prostate Cancer. After removing 461 duplicates, 260 articles were excluded based on title and abstract review. Subsequently, a comprehensive screening by three researchers resulted in 47 relevant articles for this systematic review. Evidence suggests that SRC-3 expression correlates with prostate cancer aggressiveness, disease recurrence, and poor patient outcomes. Its potential as a diagnostic biomarker and therapeutic target if explored, offers insights into personalized medicine approaches. Conclusions: SRC-3 plays a pivotal role in prostate cancer, influencing disease progression and clinical outcomes. Understanding the molecular intricacies of SRC-3 in prostate cancer offers new opportunities for precision medicine and innovative therapeutic approaches. This review provides a comprehensive overview of SRC-3's involvement in prostate cancer, emphasizing its clinical relevance and potential as a therapeutic target, ultimately contributing to improved patient care in the era of personalized oncology.

Cells produce short single-stranded non-coding RNAs (ncRNAs) called microRNAs (miRNAs), which actively regulate gene expression at the posttranscriptional level. Several miRNAs have been observed to exert significant impacts on bone health and bone-related disorders. One of these, miR-124, is observed in bone microenvironments and is conserved across species. It affects bone cell growth and differentiation by activating different transcription factors and signaling pathways. In-depth functional analyses of miR-124 have revealed several physiological and pathological roles exerted through interactions with other ncRNAs. Deciphering these RNA-mediated signaling networks and pathways is essential for understanding the potential impacts of dysregulated miRNA functions on bone biology. In this review, we aim to provide a comprehensive analysis of miR-124's involvement in bone physiology and pathology. We highlight the importance of miR-124 in controlling transcription factors and signaling pathways that promote bone growth. This review reveals therapeutic implications for the treatment of bone-related diseases.

β-arrestins play a key role in G protein-coupled receptor (GPCR) internalization, trafficking, and signaling. Whether β-arrestins act independently of G protein-mediated signaling has not been fully elucidated. Studies using genome-editing approaches revealed that whereas G proteins are essential for mitogen-activated protein kinase activation by GPCRs., β-arrestins play a more prominent role in signal compartmentalization. However, in the absence of G proteins, GPCRs may not activate β-arrestins, thereby limiting the ability to distinguish G protein from β-arrestin-mediated signaling events. We used β2-adrenergic receptor (β2AR) and its β2AR-C tail mutant expressed in human embryonic kidney 293 cells wildtype or CRISPR-Cas9 gene edited for Gαs, β-arrestin1/2, or GPCR kinases 2/3/5/6 in combination with arrestin conformational sensors to elucidate the interplay between Gαs and β-arrestins in controlling gene expression. We found that Gαs is not required for β2AR and β-arrestin conformational changes, β-arrestin recruitment, and receptor internalization, but that Gαs dictates the GPCR kinase isoforms involved in β-arrestin recruitment. By RNA-Seq analysis, we found that protein kinase A and mitogen-activated protein kinase gene signatures were activated by stimulation of β2AR in wildtype and β-arrestin1/2-KO cells but absent in Gαs-KO cells. These results were validated by re-expressing Gαs in the corresponding KO cells and silencing β-arrestins in wildtype cells. These findings were extended to cellular systems expressing endogenous levels of β2AR. Overall, our results support that Gs is essential for β2AR-promoted protein kinase A and mitogen-activated protein kinase gene expression signatures, whereas β-arrestins initiate signaling events modulating Gαs-driven nuclear transcriptional activity.

ABSTRACTCopines are a family of calcium-dependent membrane-binding proteins. To study these proteins, anull mutant for cpnC was created in Dictyostelium, which has six copines genes (cpnA-cpnF). During development, cpnC− cells were able to aggregate, but did not form streams. Once aggregated into mounds, they formed large ring structures. cpnC− cells were less adherent to plastic substrates, but more adherent to other cells. These phenotypes correlated with changes in adhesion protein expression with decreased expression of SibA and increased expression of CsaA in developing cpnC− cells. We also measured the expression of RegA, a cAMP phosphodiesterase, and found that cpnC− cells have reduced RegA expression. The reduced RegA expression in cpnC− cells is most likely responsible for the observed phenotypes.

MicroRNAs (miRNAs) have been demonstrated to control chicken skeletal muscle growth, however, the potential function of the miR-181-5p family in chicken myogenesis remains largely unknown. Here, our study identified the two chicken (Gallus gallus; Gga) miR-181-5p family members widely expressed in various tissues, specifically miR-181a-5p and miR-181b-5p. Besides, the breast muscles of fast-growing broilers expressed higher levels of miR-181a-5p and miR-181b-5p than those of slow-growing layers. Functionally, miR-181a-5p and miR-181b-5p both promote the expression level of myogenic factors including myogenin (MyoG), myogenic differentiation 1 (MyoD1), and myosin heavy chain (MyHC), meanwhile accelerating the myotube formation of skeletal muscle satellite cells (SMSCs). Mechanistically, miR-181a-5p and miR-181b-5p directly bind to the 3´ untranslated region (UTR) of the transforming growth factor beta receptor 1 (TGFBR1) mRNA, further reducing the expression of TGFBR1. TGFBR1 is a key Transforming growth factor beta (TGF-β) signaling transduction receptor and had a negative function in muscle cell differentiation. Furthermore, knockdown of TGFBR1 facilitated the expression of chicken myogenic factors, boosted myotube formation, and decreased the SMAD family member 2/3 (SMAD2/3) phosphorylation in chicken SMSCs. SMAD2/3 are downstream of TGF-β signaling, and miR-181a-5p and miR-181b-5p could reduce the expression of TGFBR1 to further diminish the SMAD2/3 phosphorylation. Our findings revealed that the miR-181-5p family targets TGFBR1 to break the TGF-β signaling transduction, which resulted in promoting chicken skeletal muscle development.

Abstract Mass spectrometry has revolutionized cell signaling research by vastly simplifying the analysis of many thousands of phosphorylation sites in the human proteome. Defining the cellular response to perturbations is crucial for further illuminating the functionality of the phosphoproteome. Here we describe µPhos (‘microPhos’), an accessible phosphoproteomics platform that permits phosphopeptide enrichment from 96-well cell culture and small tissue amounts in 90% selectivity, and excellent quantitative reproducibility. Employing highly sensitive trapped ion mobility mass spectrometry, we quantify ~17,000 Class I phosphosites in a human cancer cell line using 20 µg starting material, and confidently localize ~6200 phosphosites from 1 µg. This depth covers key signaling pathways, rendering sample-limited applications and perturbation experiments with hundreds of samples viable. We employ µPhos to study drug- and time-dependent response signatures in a leukemia cell line, and by quantifying 30,000 Class I phosphosites in the mouse brain we reveal distinct spatial kinase activities in subregions of the hippocampal formation.

Abstract Background Zinc finger SWIM-type containing 4 (ZSWIM4) is a zinc finger protein with its function largely uncharacterized. In this study, we aimed to investigate the role of ZSWIM4 in gastrointestinal stromal tumors (GISTs). Results We found that ZSWIM4 expression is inhibited by the predominantly mutated protein KIT in GISTs, while conversely, ZSWIM4 inhibits KIT expression and downstream signaling. Consistent with the observation, ZSWIM4 inhibited GIST cell survival and proliferation in vitro. RNA sequencing of GISTs from KITV558A/WT mice and KITV558A/WT/ZSWIM4−/− mice showed that loss of ZSWIM4 expression increases the expression of circadian clock pathway member BMAL1 which contributes to GIST cell survival and proliferation. In addition, we found that KIT signaling increases the distribution of ZSWIM4 in the nucleus of GIST cells, and which is important for its inhibition of KIT and BMAL1. In agreement with the results in vitro, the in vivo studies showed that ZSWIM4 deficiency increases the tumorigenesis of GISTs in KITV558A/WT mice. Conclusions Taken together, our results revealed that the entry of ZSWIM4 to the nucleus is important for its inhibition of KIT and BMAL1, ultimately attenuating GIST tumorigenesis. The results provide a novel insight in the understanding of signal transduction in GISTs and lay strong theoretical basis for the advancement of GIST treatment.

In micro-level data concerning the housing market, the apartment quality may be signaled via textual statements or the attached descriptions/photos. It may be done using hard information related to the easier-to-measure structural characteristics or soft information related to the apartment condition and design - soft quality. This paper checks whether the choice of the approach to handling the issue of soft quality of apartments influences the properties of hedonic models and the course of hedonic rent indices. The study shows that hedonic models that account for soft quality have better statistical properties than those without soft-quality-related variables. Among them, the models that include the information on quality extracted from descriptions of apartments prove to be the best. Still, considerable differences in the indicated course of hedonic rent indices have not been detected. However, the paper concludes that utilizing information on apartments’ soft quality may be crucial to understanding the market adjustment process to economic shocks. It has been proven that the price reaction of the Poznań (Poland) rental market to the COVID-19 pandemic and the Russian aggression on Ukraine has been diversified in the quality-related market segments.

Abstract Background Alzheimer’s disease is the most common cause of dementia and is characterized by amyloid-β plaques, tau neurofibrillary tangles, and neuronal loss. Although neuronal loss is a primary hallmark of Alzheimer’s disease, it is known that non-neuronal cell populations are ultimately responsible for maintaining brain homeostasis and neuronal health through neuron-glia and glial cell crosstalk. Many signaling pathways have been proposed to be dysregulated in Alzheimer’s disease, including WNT, TGFβ, p53, mTOR, NFkB, and Pi3k/Akt signaling. Here, we predict altered cell-cell communication between glia and neurons. Methods Using public snRNA-sequencing data generated from postmortem human prefrontal cortex, we predicted altered cell-cell communication between glia (astrocytes, microglia, oligodendrocytes, and oligodendrocyte progenitor cells) and neurons (excitatory and inhibitory). We confirmed interactions in a second and third independent orthogonal dataset. We determined cell-type-specificity using Jaccard Similarity Index and investigated the downstream effects of altered interactions in inhibitory neurons through gene expression and transcription factor activity analyses of signaling mediators. Finally, we determined changes in pathway activity in inhibitory neurons. Results Cell-cell communication between glia and neurons is altered in Alzheimer’s disease in a cell-type-specific manner. As expected, ligands are more cell-type-specific than receptors and targets. We identified ligand-receptor pairs in three independent datasets and found involvement of the Alzheimer’s disease risk genes APP and APOE across datasets. Most of the signaling mediators of these interactions were not significantly differentially expressed, however, the mediators that are also transcription factors had differential activity between AD and control. Namely, MYC and TP53, which are associated with WNT and p53 signaling, respectively, had decreased TF activity in Alzheimer’s disease, along with decreased WNT and p53 pathway activity in inhibitory neurons. Additionally, inhibitory neurons had both increased NFkB signaling pathway activity and increased TF activity of NFIL3, an NFkB signaling-associated transcription factor. Conclusions Cell-cell communication between glia and neurons in Alzheimer’s disease is altered in a cell-type-specific manner involving Alzheimer’s disease risk genes. Signaling mediators had altered transcription factor activity suggesting altered glia-neuron interactions may dysregulate signaling pathways including WNT, p53, and NFkB in inhibitory neurons.

Hydrogen selenide (H2Se) is an emerging biomolecule of interest with similar properties to that of other gaseous signaling molecules (i.e., gasotransmitters that include nitric oxide, carbon monoxide, and hydrogen sulfide). H2Se is enzymatically generated in humans where it serves as a key metabolic intermediate in the production of selenoproteins and other selenium-containing biomolecules. However, beyond its participation in biosynthetic pathways, its involvement in cellular signaling or other biological mechanisms remains unclear. To uncover its true biological significance, H2Se-specific chemical tools capable of functioning under physiological conditions are required but lacking in comparison to those that exist for other gasotransmitters. Recently, researchers have begun to fill this unmet need by developing new H2Se-releasing compounds, along with pioneering methods for selenide detection and quantification. In combination, the chemical tools highlighted in this review have the potential to spark groundbreaking explorations into the chemical biology of H2Se, which may lead to its branding as the fourth official gasotransmitter. [ABSTRACT FROM AUTHOR]

Conventional cancer therapy strategies, although centered around killing tumor cells, often lead to severe side effects on surrounding normal tissues, thus compromising the chronic quality of life in cancer survivors. Hydrogen peroxide (H2O2) is a secondary signaling molecule that has an array of functions in both tumor and normal cells, including the promotion of cell survival pathways and immune cell modulation in the tumor microenvironment. H2O2 is a reactive oxygen species (ROS) crucial in cellular homeostasis and signaling (at concentrations maintained under nM levels), with increased steady-state levels in tumors relative to their normal tissue counterparts. Increased steady-state levels of H2O2 in tumor cells, make them vulnerable to oxidative stress and ultimately, cell death. Recently, H2O2-producing therapies—namely, pharmacological ascorbate and superoxide dismutase mimetics—have emerged as compelling complementary treatment strategies in cancer. Both pharmacological ascorbate and superoxide dismutase mimetics can generate excess H2O2 to overwhelm the impaired H2O2 removal capacity of cancer cells. This review presents an overview of H2O2 metabolism in the physiological and malignant states, in addition to discussing the anti-tumor and normal tissue-sparing mechanism(s) of, and clinical evidence for, two H2O2-based therapies, pharmacological ascorbate and superoxide dismutase mimetics. [ABSTRACT FROM AUTHOR]

The spatial arrangement of variant phenotypes during stem cell division plays a crucial role in the self-organization of cell tissues. The patterns observed in these cellular assemblies, where multiple phenotypes vie for space and resources, are largely influenced by a mixture of different diffusible chemical signals. This complex process is carried out within a chronological framework of interplaying intracellular and intercellular events. This includes receiving external stimulants, whether secreted by other individuals or provided by the environment, interpreting these environmental signals, and incorporating the information to designate cell fate. Here, given two distinct signaling patterns generated by Turing systems, we investigated the spatial distribution of differentiating cells that use these signals as external cues for modifying the production rates. By proposing a computational map, we show that there is a correspondence between the multiple signaling and developmental cellular patterns. In other words, the model provides an appropriate prediction for the final structure of the differentiated cells in a multi-signal, multi-cell environment. Conversely, when a final snapshot of cellular patterns is given, our algorithm can partially identify the signaling patterns that influenced the formation of the cellular structure, provided that the governing dynamic of the signaling patterns is already known. [ABSTRACT FROM AUTHOR]

Competition over resources is often decided via aggressive interactions, which may or may not escalate to all-out fights. Weapons and body size play important roles in such interactions, as they often provide reliable cues of an individual's fighting ability. In contrast, traits like nonfunctional display "weapons" may dishonestly exaggerate fighting ability in order to intimidate opponents into retreating. Signals used in the context of aggressive interactions potentially evolve via very different mechanisms than courtship signals, but have received far less theoretical attention. Here, we contrast the evolution of honest and dishonest signals of fighting ability using a game-theoretic model. Contests are assumed to consist of three discrete stages: display from a distance, low-intensity physical contact, and fighting. At each stage, contestants evaluate the fighting ability of their opponents in comparison to their own based on body size and an aggressive signal. After making this evaluation, contestants decide whether to escalate the interaction or cede to their opponent. Our model predicts that both honest and dishonest aggressive signals can exaggerate far beyond their ecological optima, but that exaggeration is more pronounced for honest signals. Equilibrium levels of aggressiveness—as measured by individuals' propensity to escalate aggressive interactions to the next stage—are independent of the honesty of signals. We additionally develop a novel approach, based on causal inference theory, to understand how changes in underlying parameters shape the coevolution of multiple traits. We use this approach to study how aggression coevolves with body and signal size in response to changes in the cost of losing a fight. [ABSTRACT FROM AUTHOR]

The rationalist bargaining literature explains how public statements and military mobilizations can signal resolve. But recent political psychology scholarship shows how such actions can "provoke" targets, increasing their resolve by arousing emotions among their leaders and public. While rationalist models have largely omitted provocation, psychological approaches have neglected its strategic consequences. We model provocation in bargaining, assuming that a challenger's signals endogenously increase the target's resolve. Our model shows that introducing provocation can make signals of resolve more credible precisely because their provocative effects make them more costly to send. Moreover, against the prevailing intuition that provocation uniformly promotes conflict, the information from these signals can mitigate their provocative effects and elicit more generous offers than not signaling. Thus, in contrast to psychological accounts, we show that taking provocative actions can be rational and necessary for reaching peaceful bargains. We illustrate these findings with the 1911 Agadir Crisis. [ABSTRACT FROM AUTHOR]

Many viral, protozoal, and fungal pathogens represent major human and animal health problems due to their great potential of causing infectious diseases. Research on these pathogens has contributed substantially to our current understanding of both microbial virulence determinants and host key factors during infection. Countless studies have also shed light on the molecular mechanisms of host–pathogen interactions that are employed by these microbes. For example, actin cytoskeletal dynamics play critical roles in effective adhesion, host cell entry, and intracellular movements of intruding pathogens. Cortactin is an eminent host cell protein that stimulates actin polymerization and signal transduction, and recently emerged as fundamental player during host–pathogen crosstalk. Here we review the important role of cortactin as major target for various prominent viral, protozoal and fungal pathogens in humans, and its role in human disease development and cancer progression. Most if not all of these important classes of pathogens have been reported to hijack cortactin during infection through mediating up‐ or downregulation of cortactin mRNA and protein expression as well as signaling. In particular, pathogen‐induced changes in tyrosine and serine phosphorylation status of cortactin at its major phospho‐sites (Y‐421, Y‐470, Y‐486, S‐113, S‐298, S‐405, and S‐418) are addressed. As has been reported for various Gram‐negative and Gram‐positive bacteria, many pathogenic viruses, protozoa, and fungi also control these regulatory phospho‐sites, for example, by activating kinases such as Src, PAK, ERK1/2, and PKD, which are known to phosphorylate cortactin. In addition, the recruitment of cortactin and its interaction partners, like the Arp2/3 complex and F‐actin, to the contact sites between pathogens and host cells is highlighted, as this plays an important role in the infection process and internalization of several pathogens. However, there are also other ways in which the pathogens can exploit the function of cortactin for their needs, as the cortactin‐mediated regulation of cellular processes is complex and involves numerous different interaction partners. Here, the current state of knowledge is summarized. [ABSTRACT FROM AUTHOR]