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Purpose: To study the therapeutic effect of hemagglutinin-2 and fimbrial (HA2-FimA) vaccine on experimental periodontitis in rats. Materials and Methods: The first batch of rats was divided into two groups and immunised with pure water or pVAX1-HA2- FimA at the age of 6, 7, and 9 weeks. After sacrificing the animals, total RNA was extracted from the spleens for RNA high-throughput sequencing (RNA-Seq) analysis. The second batch of rats was divided into four groups (A, B, C, D), and an experimental periodontitis rat model was established by suturing silk thread around the maxillary second molars of rats in groups B, C, and D for 4 weeks. The rats were immunised with pure water, pVAX1-HA2-FimA vaccine, empty pVAX1 vector, and pure water at 10, 11, and 13 weeks of age, respectively. Secretory immunoglobulin A (SIgA) antibodies and cathelicidin antimicrobial peptide (CAMP) levels in saliva were measured by enzyme-linked immunosorbent assay (ELISA). All rats were euthanised at 17 weeks of age, and alveolar bone loss was examined using micro-computed tomography (Micro-CT). Results: Through sequencing analysis, six key genes, including Camp, were identified. Compared with the other three groups, the rats in the periodontitis+pVAX1-HA2-FimA vaccine group showed higher levels of SIgA and CAMP (p < 0.05). MicroCT results showed significantly less alveolar bone loss in the periodontitis+pVAX1-HA2-FimA vaccine group compared to the periodontitis+pVAX1 group and periodontitis+pure water group (p < 0.05). Conclusion: HA2-FimA DNA vaccine can increase the levels of SIgA and CAMP in the saliva of experimental periodontitis model rats and reduce alveolar bone loss. [ABSTRACT FROM AUTHOR]

Tendons, which transmit force from muscles to bones, are highly prone to injury. Understanding the mechanisms driving tendon fate would impact efforts to improve tendon healing, yet this knowledge is limited. To find direct regulators of tendon progenitor emergence, we performed a zebrafish high-throughput chemical screen. We established forskolin as a tenogenic inducer across vertebrates, functioning through Creb1a, which is required and sufficient for tendon fate. Putative enhancers containing cyclic AMP (cAMP) response elements (CREs) in humans, mice, and fish drove specific expression in zebrafish cranial and fin tendons. Analysis of these genomic regions identified motifs for early B cell factor (Ebf/EBF) transcription factors. Mutation of CRE or Ebf/EBF motifs significantly disrupted enhancer activity and specificity in tendons. Zebrafish ebf1a/ebf3a mutants displayed defects in tendon formation. Notably, Creb1a/CREB1 and Ebf1a/Ebf3a/EBF1 overexpression facilitated tenogenic induction in zebrafish and human pluripotent stem cells. Together, our work identifies the functional conservation of two transcription factors in promoting tendon fate. [Display omitted] • Chemical screen identifies the cAMP-PKA-Creb1/CREB1 pathway as promoting tendon fate • Creb1a induces tendon fate by directly activating the newly identified scxa enhancer SEN • Motif analysis of enhancer regions identifies Ebf/EBF as a novel tendon regulator • Creb1/CREB1 and Ebf/EBF are sufficient and necessary for tendon development From a zebrafish chemical screen to mammalian stem cell culture, Niu et al. demonstrate that forskolin promotes tendon fate across vertebrate species through the cyclic AMP-PKA-Creb1/CREB1 axis. The induction involves previously unidentified zebrafish and putative human enhancers, which led to the discovery of the tendon-inducing functions of Ebf/EBF transcription factors. [ABSTRACT FROM AUTHOR]

Queer subjectivity invites discussions around gender performativity, culture, narratives of "coming out," and identity politics. Postcolonial queer subjects—like those emerging from the Philippines—require additional layers of critique attending to language, practice, and resistance. This brief reflection will explore the place of camp, rampa, and posthuman worldviews in the constitution of Filipino queer bodies. It argues that as queer narratives become global—and normalized— camp and rampa offer a place where queerness can both expand critical theology and imaginations of the human. [ABSTRACT FROM AUTHOR]

We studied the level of immunocompetent blood cells, phagocytic activity of neutrophils, concentrations of cytokines, circulating immune complexes and levels of cyclic nucleotides (cAMP and cGMP) in blood serum with different levels of soluble adhesion molecules NCAM (CD56) and immunoglobulin Fc-receptor III (CD16) in nearly healthy people living in the Arctic territory. An increase in serum concentrations of sCD56 and sCD16 in nearly healthy adults of working age was found to be associated with an increase in the level of cells bearing the corresponding membrane receptors. An increase in sCD56 concentrations was accompanied by an increase in the level of NK (CD3-CD16+CD56+) and T-NK cells (CD3+CD16+CD56+), whereas an increase in sCD16 level, by a decrease in the counts of lymphocytes circulating in blood, mainly, T-helper cells (CD3+CD4+), cytotoxic T-lymphocytes (CD3+CD8+), and activated T-lymphocytes (CD3+HLADR+). Elevated sCD56 concentrations were associated with the increased levels of pro-inflammatory IL-1β, IL-6, TNF-α, and anti-inflammatory IL-10 cells. Concentrations of circulating immune complexes rose with increasing sCD16 and sCD56 levels. The signal conduction activity grew with increasing concentrations of CD16+ and CD56+ leukocytes of peripheral blood and sCD56+ leukocytes, and the shedding of these molecules occurred against the background of cAMP and cGMP decreasing concentrations. [ABSTRACT FROM AUTHOR]

Background and Purpose: The PDE4 family is considered a prime target for therapeutic intervention in several fibro‐inflammatory diseases. We have investigated the molecular mechanisms of nerandomilast (BI 1015550), a preferential PDE4B inhibitor. Experimental Approach: In addition to clinically relevant parameters of idiopathic pulmonary fibrosis (IPF; lung function measurement/high‐resolution computed tomography scan/AI‐Ashcroft score), whole‐lung homogenates from a therapeutic male Wistar rat model of pulmonary fibrosis were analysed by next‐generation sequencing (NGS). Data were matched with public domain data derived from human IPF samples to investigate how well the rat model reflected human IPF. We scored the top counter‐regulated genes following treatment with nerandomilast in human single cells and validated disease markers discovered in the rat model using a human disease‐relevant in vitro assay of IPF. Key Results: Nerandomilast improved the decline of lung function parameters in bleomycin‐treated animals. In the NGS study, most transcripts deregulated by bleomycin treatment were normalised by nerandomilast treatment. Most notably, a significant number of deregulated transcripts that were identified in human IPF disease were also found in the animal model and reversed by nerandomilast. Mapping to single‐cell data revealed the strongest effects on mesenchymal, epithelial and endothelial cell populations. In a primary human epithelial cell culture system, several disease‐related (bio)markers were inhibited by nerandomilast in a concentration‐dependent manner. Conclusions and Implications: This study further supports the available knowledge about the anti‐inflammatory/antifibrotic mechanisms of nerandomilast and provides novel insights into the mode of action and signalling pathways influenced by nerandomilast treatment of lung fibrosis. [ABSTRACT FROM AUTHOR]

In a crisis‐shaken globalised world, migration‐related sites of detention emerge as a harmful figure of attempts to contain human mobility. The new Closed Controlled Access Centre (CCAC) on Samos is a blueprint for the EU's future border practices. While openly dehumanising conditions contributed to the previous “old camp” amounting to a torturing environment, the new remote and securitised CCAC promised safety and humanitarian care. Psycho‐geographical counter‐mappings by people living in the camps and of human rights defenders allow the reading of the hotspot camps as a built environment and social space. They expose how the violent neglect of the old camp transforms into the surveilled and weaponised space of yet another torturing environment. This time, it operates a necropolitical space of uncare that distributes harm differentially. The findings emphasise the abolitionist argument that camps cannot be turned into “better” places. [ABSTRACT FROM AUTHOR]

Background and Purpose Experimental approach Key Results Conclusions and Implications Acetylcholine plays a key role in striatal function. Firing properties of striatal cholinergic interneurons depend on intracellular cAMP through the regulation of Ih currents. Yet, the dynamics of cyclic nucleotide signalling in these neurons have remained elusive.We used highly selective FRET biosensors and pharmacological compounds to analyse the functional contribution of phosphodiesterases in striatal cholinergic interneurons in mouse brain slices.PDE1A, PDE3A and PDE4 appear as the main controllers of cAMP levels in striatal cholinergic interneurons. The calcium signal elicited through NMDA or metabotropic glutamate receptors activates PDE1A, which degrades both cAMP and cGMP. Interestingly, the nitric oxide/cGMP pathway amplifies cAMP signalling via PDE3A inhibition—a mechanism hitherto unexplored in a neuronal context.The expression pattern of specific PDE enzymes in striatal cholinergic interneurons, by integrating diverse intracellular pathways, can adjust cAMP responses bidirectionally. These properties eventually allow striatal cholinergic interneurons to dynamically regulate their overall activity and modulate acetylcholine release. Remarkably, this effect is the opposite of the cGMP‐induced inhibition of cAMP signals involving PDE2A in striatal medium‐sized spiny neurons, which provides important insights for the understanding of signal integration in the striatum. [ABSTRACT FROM AUTHOR]

Brain astrocyte glycogenolysis is regulated in part by the second messenger adenosine 3′5′‐cyclic monophosphate (cAMP). Hypothalamic astrocyte glycogen metabolism shapes glucose counterregulation, under the control of glucose transporter‐2 (GLUT2), a plasma membrane glucose carrier and sensor. Hypothalamic astrocyte cAMP is subject to neurotransmitter control, but effects of nutrient cues on this messenger are unclear. Here, an established hypothalamic primary astrocyte culture model and gene knockdown tools were used to investigate the premise that GLUT2 exerts sex‐dimorphic regulation of cAMP‐protein kinase A (PKA) signalling in these glia. Data show that basal cAMP was elevated in female versus male; GLUT2 gene silencing up‐regulated or down‐regulated this profile in male versus female. Glucoprivation increased cAMP content in astrocytes of each sex, yet GLUT2 siRNA pretreatment exacerbated (male) or blunted (female) this stimulatory effect. PKA and phosphoPKA levels in glucose‐supplied astrocytes were increased (male) or decreased (female) by GLUT2 knockdown. PKA protein was amplified, yet phosphoPKA was refractory to glucose withdrawal in male, while females showed sustained PKA expression alongside diminished phosphoPKA. GLUT2 siRNA pretreatment exacerbated glucoprivic augmentation of PKA content in male but down‐regulated both PKA and phosphoPKA proteins in female. Evidence for parallel GLUT2 siRNA‐associated changes in cAMP and PKA, albeit in opposing directions in the two sexes, infers that GLUT2 control of hypothalamic astrocyte cAMP‐dependent PKA signalling is sex‐specific. Data also disclose that in the female, GLUT2 curbs the baseline phosphoPKA/PKA expression ratio but is not involved in glucoprivic suppression of this ratio. [ABSTRACT FROM AUTHOR]

Simple Summary: This pilot study examined the association of participating in a recreational oncology camp (ROC) with the psychosocial health (resilience, hope, social support, and mental well-being) of children aged 6 to 18 who have experienced cancer. Participating youth completed surveys at the start and end of an 11-day ROC, as well as three months later. While the results showed that children experienced strong psychosocial health during the ROC, their levels of hope decreased after three months, suggesting a need for ongoing support. This study highlights the importance of recreational programs like ROC in promoting psychosocial health among youth who have experienced cancer. Children with lived cancer experience encounter adversity, therefore experiences promoting psychosocial health are necessary. This pilot study determined the impact of recreational oncology camps (ROC) on resilience, hope, social support, and mental well-being in youth who have lived with cancer. Youth (6–18 years) with cancer experience enrolled in an 11-day session of ROC (Muskoka, Ontario, Canada) were invited to participate. Participants completed a survey [Children's Hope Scale (CHS), Child and Youth Resilience Measure (CYRM-R), Social Provisions Scale (SPS-5), and Short Warwick–Edinburgh Mental Wellbeing Scale (SWEMWBS)] on the first (T1) and last day (T2) of camp, and 3 months post-camp (T3). Repeated-measures ANOVAs evaluated differences in survey scores among time points. Ten participants (14.1 ± 2.5 years) were included in the analysis. CHS scores at T3 were lower than T1 and T2 (F = 9.388, p = 0.008). CYRM-R, SPS-5, and SWEMWBS scores were high but did not differ between time points. Hope decreased 3 months post-camp, suggesting a need for continued psychosocial support. Overall, the ROC environment is associated with positive psychosocial health. [ABSTRACT FROM AUTHOR]

Phosphodiesterase type 5 (PDE5) is an enzyme primarily found in the smooth muscle of the corpus cavernosum and also highly expressed in the substantia nigra, cerebellum, caudate, hippocampal regions and cerebellar purkinje cells, responsible for selectively breaking down cyclic guanosine monophosphate (cGMP) into 5′‐GMP and regulate intracellular cGMP levels. As a second messenger, cyclic GMP enhances signals at postsynaptic receptors and triggers downstream effector molecules, leading to changes in gene expression and neuronal responses. Additionally, cGMP signaling transduction cascade, present in the brain, is also essential for learning and memory processes. Mechanistically, PDE5 inhibitors share structural similarities with cGMP, competitively binding to PDE5 and inhibiting cGMP hydrolysis. This action enhances the effects of nitric oxide, resulting in anti‐inflammatory and neuroprotective effects. Neurodegenerative disorders entail the progressive loss of neuron structure, culminating in neuronal cell death, with currently available drugs providing only limited symptomatic relief, rendering neurodegeneration considered incurable. PDE5 inhibitors have recently emerged as a potential therapeutic approach for neurodegeneration, neuroinflammation, and diseases involving cognitive impairment. This review elucidates the principal roles of 3′,5′‐cyclic adenosine monophosphate (cAMP) and cGMP signaling pathways in neuronal functions, believed to play pivotal roles in the pathogenesis of various neurodegenerative disorders. It provides an updated assessment of PDE5 inhibitors as disease‐modifying agents for conditions such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, cerebral ischemia, Huntington's disease, and neuroinflammation. The paper aims to review the current understanding of PDE5 inhibitors, which concurrently regulate both cAMP and cGMP signaling pathways, positing that they may exert complementary and synergistic effects in modifying neurodegeneration, thus presenting a novel direction in therapeutic discovery. Moreover, the review provides critical about biological functions, therapeutic potentials, limitations, challenges, and emerging applications of selective PDE5 inhibitors. This comprehensive overview aims to guide future academic and industrial endeavors in this field. [ABSTRACT FROM AUTHOR]

Background: Parkinson's disease is characterized by a progressive loss of dopaminergic neurons in the nigrostriatal pathway, leading to dopamine deficiency and motor impairments. Current treatments, such as L-DOPA, provide symptomatic relief but result in off-target effects and diminished efficacy over time. This study explores an alternative approach by investigating the activation of tyrosine hydroxylase, the rate-limiting enzyme in dopamine synthesis. Specifically, we explore the effects of phosphodiesterase (PDE) inhibition and guanylate cyclase-C (GUCY2C) activation on tyrosine hydroxylase Ser40 phosphorylation and their impact on motor behavior in a 6-hydroxydopamine (6-OHDA) Parkinson's disease model. Results: Our findings demonstrate that increasing cyclic nucleotide levels through PDE inhibition and GUCY2C activation significantly enhances tyrosine hydroxylase Ser40 phosphorylation. In a Pitx3-deficient mouse model, which mimics the loss of dopaminergic neurons seen in Parkinson's disease, Ser40 phosphorylation remained manipulable despite reduced tyrosine hydroxylase protein levels. Moreover, we observed no evidence of tyrosine hydroxylase degradation due to Ser40 phosphorylation, challenging previous reports. Furthermore, both PDE inhibition and GUCY2C activation resulted in improved motor behavior in the 6-OHDA Parkinson's disease mouse model, highlighting the potential therapeutic benefits of these approaches. Conclusions: This study underscores the therapeutic potential of enhancing tyrosine hydroxylase Ser40 phosphorylation to improve motor function in Parkinson's disease. Both PDE inhibition and GUCY2C activation represent promising non-invasive strategies to modulate endogenous dopamine biosynthesis and address motor deficits. These findings suggest that targeting cyclic nucleotide pathways could lead to novel therapeutic approaches, either as standalone treatments or in combination with existing therapies like L-DOPA, aiming to provide more durable symptom relief and potentially mitigate neurodegeneration in Parkinson's disease. [ABSTRACT FROM AUTHOR]

Large-scale genome-wide association studies (GWASs) have associated intronic variants in PDE4B, encoding cAMP-specific phosphodiesterase-4B (PDE4B), with increased risk for post-traumatic stress disorder (PTSD), as well as schizophrenia and substance use disorders that are often comorbid with it. However, the pathophysiological mechanisms of genetic risk involving PDE4B are poorly understood. To examine the effects of PDE4B variation on phenotypes with translational relevance to psychiatric disorders, we focused on PDE4B missense variant M220T, which is present in the human genome as rare coding variant rs775201287. When expressed in HEK-293 cells, PDE4B1-M220T exhibited an attenuated response to a forskolin-elicited increase in the intracellular cAMP concentration. In behavioral tests, homozygous Pde4bM220T male mice with a C57BL/6JJcl background exhibited increased reactivity to novel environments, startle hyperreactivity, prepulse inhibition deficits, altered cued fear conditioning, and enhanced spatial memory, accompanied by an increase in cAMP signaling pathway-regulated expression of BDNF in the hippocampus. In response to a traumatic event (10 tone-shock pairings), neuronal activity was decreased in the cortex but enhanced in the amygdala and hippocampus of Pde4bM220T mice. At 24 h post-trauma, Pde4bM220T mice exhibited increased startle hyperreactivity and decreased plasma corticosterone levels, similar to phenotypes exhibited by PTSD patients. Trauma-exposed Pde4bM220T mice also exhibited a slower decay in freezing at 15 and 30 d post-trauma, demonstrating enhanced persistence of traumatic memories, similar to that exhibited by PTSD patients. These findings provide substantive mouse model evidence linking PDE4B variation to PTSD-relevant phenotypes and thus highlight how genetic variation of PDE4B may contribute to PTSD risk. [ABSTRACT FROM AUTHOR]

Dopamine transfers information to striatal neurons, and disrupted neurotransmission leads to motor deficits observed in movement disorders. Striatal dopamine converges downstream to Adenylyl Cyclase Type 5 (AC5)-mediated synthesis of cAMP, indicating the essential role of signal transduction in motor physiology. However, the relationship between dopamine decoding and AC5 regulation is unknown. Here, we utilized an unbiased global protein stability screen to identify Potassium Channel Tetramerization Domain 1 (KCTD1) as a key regulator of AC5 level that is mechanistically tied to N-linked glycosylation. We then implemented a CRISPR/SaCas9 approach to eliminate KCTD1 in striatal neurons expressing a Förster resonance energy transfer (FRET)-based cAMP biosensor. 2-photon imaging of striatal neurons in intact circuits uncovered that dopaminergic signaling was substantially compromised in the absence of KCTD1. Finally, knockdown of KCTD1 in genetically defined dorsal striatal neurons significantly altered motor behavior in mice. These results reveal that KCTD1 acts as an essential modifier of dopaminergic signaling by stabilizing striatal AC5. [ABSTRACT FROM AUTHOR]

This article argues that Souviens-toi de moi, a novel published in 2014 by French writer Martine Laffon, reclaims the memory of travailleurs chinois on the Western Front during the First World War, at the same time exposing the deliberate agenda of forgetting in both French and Chinese memory cultures. Referring to Mary Louise Pratt’s concept of contact zone and Leela Gandhi’s concept of affective cosmopolitanism, I show how the novel creates an inclusive ethics across race, gender and species, challenging the fixed hierarchies of Western modernity. Synchronously, by applying the multidirectional framework of noeuds de mémoire, the article demonstrates how Laffon constructs war remembrance at the conjunction of anti-militarism, anti-imperialism, feminism and the struggle for animal rights. The novel thus offers a vision of the First World War that radically departs from the French récit national and the Chinese instrumentalization of the laborers’ war memory. [ABSTRACT FROM AUTHOR]

1940 saw the mass internment of so‐called ‘enemy aliens’ within Britain as a response to the rapid advance of Nazi forces on the continent; this meant that innocent civilians—including many who were already refugees from Nazism—were incarcerated in camps across the country, particularly within the tourist spaces of the Isle of Man. We do not seek to argue that internees simply experienced internment as being akin to a holiday, or that the overarching internment process itself shared any similarity with leisure time per se. Nonetheless, the appropriation of tourist infrastructures for use within the internment process contributed towards the presence of a lingering tourist gaze in a situation to which it should not, ostensibly pertain. A state of ambivalence may not accurately capture internment's effects—exclusion and imprisonment—but it certainly captured the dissonances experienced, how it was remembered (particularly with the passage of time), and how the internment camp's exceptional level of control was rendered much more fragile and complex (Katz 2015, p. 49, 84). We interrogate how residual touristic ways of seeing, infrastructures, practices and sensibilities, are evident in a variety of archival source material, contemporaneous newspaper articles, and eyewitness accounts, and consider the rhythms and practices of camp life, deportations abroad on ships such as the SS Arandora Star and the HMT Dunera, and the gaze of locals and the press. The holiday—as a geography of ideas, spaces, practices, movements and sensibilities—became a frame of reference, both by those in charge of the process, and the internees who had to make sense of it. We proffer an exploration of internment and ‘the holiday’ to the burgeoning geographies of camp and detainment spaces, (im)mobilities and their politics. [ABSTRACT FROM AUTHOR]

Contrast-induced acute kidney injury (CIAKI) is a common complication with limited treatments. Intermedin (IMD), a peptide belonging to the calcitonin gene-related peptide family, promotes vasodilation and endothelial stability, but its role in mitigating CIAKI remains unexplored. This study investigates the protective effects of IMD in CIAKI, focusing on its mechanisms, particularly the cAMP/Rac1 signaling pathway. Human umbilical vein endothelial cells (HUVECs) were treated with iohexol to simulate kidney injury in vitro. The protective effects of IMD were assessed using CCK8 assay, flow cytometry, ELISA, and Western blotting. A CIAKI rat model was utilized to evaluate renal peritubular capillary endothelial cell injury and renal function through histopathology, immunohistochemistry, immunofluorescence, Western blotting, and transmission electron microscopy. In vitro, IMD significantly enhanced HUVEC viability and mitigated iohexol-induced toxicity by preserving intercellular adhesion junctions and activating the cAMP/Rac1 pathway, with Rac1 inhibition attenuating these protective effects. In vivo, CIAKI caused severe damage to peritubular capillary endothelial cell junctions, impairing renal function. IMD treatment markedly improved renal function, an effect negated by Rac1 inhibition. IMD protects against renal injury in CIAKI by activating the cAMP/Rac1 pathway, preserving peritubular capillary endothelial integrity and alleviating acute renal injury from contrast media. These findings suggest that IMD has therapeutic potential in CIAKI and highlight the cAMP/Rac1 pathway as a promising target for preventing contrast-induced acute kidney injury in at-risk patients, ultimately improving clinical outcomes. [ABSTRACT FROM AUTHOR]

Titanium dioxide fine particles (TiO2-FPs) and nanoparticles (TiO2-NPs) are the most widely used whitening pigments worldwide. Inhalation of TiO2-FPs and TiO2-NPs can be harmful as it triggers toxicity in the airway epithelial cells. The airway epithelium serves as the respiratory system's first line of defense in which airway epithelial cells are significant targets of inhaled pathogens and environmental particles. Our group previously found that TiO2-NPs lead to a disrupted barrier in the polarized airway epithelial cells. However, the effect of TiO2-FPs on the respiratory epithelial barrier has not been examined closely. In this study, we aimed to compare the effects of TiO2-FPs and TiO2-NPs on the structure and function of the airway epithelial barrier. Additionally, we hypothesized that 8-Bromo-cAMP, a cyclic adenosine monophosphate (cAMP) derivative, would alleviate the disruptive effects of both TiO2-FPs and TiO2-NPs. We observed increased epithelial membrane permeability in both TiO2-FPs and TiO2-NPs after exposure to 16HBE cells. Immunofluorescent labeling showed that both particle sizes disrupted the structural integrity of airway epithelial tight junctions and adherens junctions. TiO2-FPs had a slightly more, but insignificant impact on the epithelial barrier disruption than TiO2-NPs. Treatment with 8-Bromo-cAMP significantly attenuated the barrier-disrupting impact of both TiO2-FPs and TiO2-NPs on cell monolayers. Our study demonstrates that both TiO2-FPs and TiO2-NPs cause comparable barrier disruption and suggests a protective role for cAMP signaling. The observed effects of TiO2-FPs and TiO2-NPs provide a necessary understanding for characterizing the pathways involved in the defensive role of the cAMP pathway on TiO2-induced airway barrier disruption. [ABSTRACT FROM AUTHOR]

A central aspect of type 2 diabetes is decreased functional β-cell mass. The orphan nuclear receptor Nr4α1 is critical for fuel utilization, but little is known regarding its regulation and function in the β-cell. Nr4α1 expression is decreased in type 2 diabetes rodent β-cells and type 2 diabetes patient islets. We have shown that Nr4α1-deficient mice have reduced β-cell mass and that Nr4α1 knockdown impairs glucose-stimulated insulin secretion (GSIS) in INS-1 832/13 β-cells. Here, we demonstrate that glucose concentration directly regulates b-cell Nr4α1 expression. We show that 11 mM glucose increases Nr4a1 expression in INS-1 832/13 β-cells and primary mouse islets. We show that glucose functions through the cAMP/PKA/CREB pathway to regulate Nr4α1 mRNA and protein expression. Using Nr4α1-/- animals, we show that Nr4α1 is necessary for GSIS and systemic glucose handling. Using RNA-seq, we define Nr4α1-regulated pathways in response to glucose in the mouse islet, including Glut2 expression. Our data suggest that Nr4α1 plays a critical role in the β-cells response to the fed state. [ABSTRACT FROM AUTHOR]

The localization of humanitarian operations is commonly characterized as a return of ownership to local and national actors. Localization policies in Kenya have made refugee‐led community‐based organizations a viable alternative for humanitarian provisioning. Simultaneously, localization facilitated the ongoing enlargement of the Kenyan state into refugee management. Incidentally, the Kenyan state has introduced limitations on community‐based organizations’ international funding and registration through a verification process. Drawing on 12 months of ethnographic research in Kakuma Refugee Camp, Kenya, this article explores how community‐based organizations mediate Kenyan state control through verification. The article develops the concept of “stateness” to examine how refugee actors claim legitimacy as a state function. Stateness is generated by members of community‐based organizations through practices involving fellow refugees and Kenyan state actors. Using stateness, this article seeks to draw attention to how refugees can become a part of wider state apparatus and shape how the state is constituted within the camp. [ABSTRACT FROM AUTHOR]

The adaptive proliferation of bacteria, or cell division in the absence of an exogenous substrate, is controlled by density-dependent mechanisms with the participation of AHL- and AI-2-dependent quorum sensing systems. Along with the signaling molecules of these bacterial communication systems, bacterial metabolites that are permanently released during microbial metabolism, for example, CO2, can also participate in the regulation and can serve as biomarkers of cell density. It has been found that carbon dioxide is necessary to the adaptive proliferation initiation, and the elevated atmospheric CO2 content causes this process to terminate prematurely. Thus, CO2 is able to regulate bacterial adaptive reactions and is probably one of the signals involved in the initiation and termination of the process of adaptive proliferation. It was shown that CO2 in the form of the bicarbonate ion can activate the cAMP-dependent signaling cascade and is also included in the bacterial cell mass. [ABSTRACT FROM AUTHOR]

Aim: To identify the physiological role of the acid‐base sensing enzyme, soluble adenylyl cyclase (sAC), in red blood cells (RBC) of the model teleost fish, rainbow trout. Methods: We used: (i) super‐resolution microscopy to determine the subcellular location of sAC protein; (ii) live‐cell imaging of RBC intracellular pH (pHi) with specific sAC inhibition (KH7 or LRE1) to determine its role in cellular acid‐base regulation; (iii) spectrophotometric measurements of haemoglobin–oxygen (Hb‐O2) binding in steady‐state conditions; and (iv) during simulated arterial‐venous transit, to determine the role of sAC in systemic O2 transport. Results: Distinct pools of sAC protein were detected in the RBC cytoplasm, at the plasma membrane and within the nucleus. Inhibition of sAC decreased the setpoint for RBC pHi regulation by ~0.25 pH units compared to controls, and slowed the rates of RBC pHi recovery after an acid‐base disturbance. RBC pHi recovery was entirely through the anion exchanger (AE) that was in part regulated by HCO3−‐dependent sAC signaling. Inhibition of sAC decreased Hb‐O2 affinity during a respiratory acidosis compared to controls and reduced the cooperativity of O2 binding. During in vitro simulations of arterial‐venous transit, sAC inhibition decreased the amount of O2 that is unloaded by ~11%. Conclusion: sAC represents a novel acid‐base sensor in the RBCs of rainbow trout, where it participates in the modulation of RBC pHi and blood O2 transport though the regulation of AE activity. If substantiated in other species, these findings may have broad implications for our understanding of cardiovascular physiology in vertebrates. [ABSTRACT FROM AUTHOR]

This study aimed to investigate the effects and possible mechanisms of adenylate cyclase 1 (ADCY1) on pirarubicin‐induced cardiomyocyte injury. HL‐1 cells were treated with pirarubicin (THP) to induce intracellular toxicity, and the extent of damage to mouse cardiomyocytes was assessed using CCK‐8, Edu, flow cytometry, ROS, ELISA, RT‐qPCR and western blotting. THP treatment reduced the viability of HL‐1 cells, inhibited proliferation, induced apoptosis and triggered oxidative stress. In addition, the RT‐qPCR results revealed that ADCY1 expression was significantly elevated in HL‐1 cells, and molecular docking showed a direct interaction between ADCY1 and THP. Western blotting showed that ADCY1, phospho‐protein kinase A and GRIN2D expression were also significantly elevated. Knockdown of ADCY1 attenuated THP‐induced cardiotoxicity, possibly by regulating the ADCY1/PKA/GRIN2D pathway. [ABSTRACT FROM AUTHOR]

Abstract Aquaporin 2 (AQP2) contributes to water reabsorption and urine concentration by migrating to the luminal surface of the collecting ducts in an anti-diuretic hormone-stimulated manner, and the signaling pathway involved in AQP2 subcellular localization is a target for arginine vasopressin receptor antagonists (aquaretics). This study investigated the involvement of AQP2 in the diuretic effect and mechanisms of Goreisan (GRS), a traditional Japanese Kampo medicine used to treat conditions such as edema in patients with decreased urination. GRS exerted diuretic effects on desmopressin (DDAVP)-induced decreases in urine output and the level of AQP2 phosphorylated at Serine269 (pSer269-AQP2) in the renal tissues of mice. Furthermore, GRS inhibited the accumulation of pSer269-AQP2 to the luminal side following forskolin stimulation using a 3D culture model of the kidney collecting duct cell line mIMCD-3. GRS induced a transient increase in the intracellular Ca2+ concentration via the calcium-sensing receptor (CaSR) and suppressed the forskolin-stimulated increase in cAMP production. These results suggest that GRS regulates urine volume by modulating the subcellular localization of AQP2 via CaSR.

Children with lived cancer experience encounter adversity, therefore experiences promoting psychosocial health are necessary. This pilot study determined the impact of recreational oncology camps (ROC) on resilience, hope, social support, and mental well-being in youth who have lived with cancer. Youth (6–18 years) with cancer experience enrolled in an 11-day session of ROC (Muskoka, Ontario, Canada) were invited to participate. Participants completed a survey [Children’s Hope Scale (CHS), Child and Youth Resilience Measure (CYRM-R), Social Provisions Scale (SPS-5), and Short Warwick–Edinburgh Mental Wellbeing Scale (SWEMWBS)] on the first (T1) and last day (T2) of camp, and 3 months post-camp (T3). Repeated-measures ANOVAs evaluated differences in survey scores among time points. Ten participants (14.1 ± 2.5 years) were included in the analysis. CHS scores at T3 were lower than T1 and T2 (F = 9.388, p = 0.008). CYRM-R, SPS-5, and SWEMWBS scores were high but did not differ between time points. Hope decreased 3 months post-camp, suggesting a need for continued psychosocial support. Overall, the ROC environment is associated with positive psychosocial health.

Abstract Osteocrin (OSTN) is an endogenous protein sharing structural similarities with the natriuretic peptides [NPs; atrial (ANP), B‐type (BNP) and C‐type (CNP) NP], which are hormones known for their crucial role in maintaining pressure/volume homeostasis. Osteocrin competes with the NPs for binding to the receptor involved in their clearance (NPR‐C). In the present study, having identified, for the first time, the major circulating form of OSTN in human and ovine plasma, we examined the integrated haemodynamic, endocrine and renal effects of vehicle‐controlled incremental infusions of ovine proOSTN (83–133) and its metabolism in eight conscious normal sheep. Incremental i.v. doses of OSTN produced stepwise increases in circulating concentrations of the peptide, and its metabolic clearance rate was inversely proportional to the dose. Osteocrin increased plasma levels of ANP, BNP and CNP in a dose‐dependent manner, together with concentrations of their intracellular second messenger, cGMP. Increases in plasma cGMP were associated with progressive reductions in arterial pressure and central venous pressure. Plasma cAMP, renin and aldosterone were unchanged. Despite significant increases in urinary cGMP levels, OSTN administration was not associated with natriuresis or diuresis in normal sheep. These results support OSTN as an endogenous ligand for NPR‐C in regulating plasma concentrations of NPs and associated cGMP‐mediated bioactivity. Collectively, our findings support a role for OSTN in maintaining cardiovascular homeostasis.

Transgressing the boundaries of fiction and the real world, satire opens a dialogue between the aesthetic and political stakes of a work of art. A comparative analysis of “Springtime for Hitler” and “If You Could See Her”, comic songs from the 20th-century American musical films The Producers (1967) and Cabaret (1972) reveal multiple potentialities offered by intermediality in the construction of satirical meaning. Music critic Werner Wolf theorises narrativity and self-reflective irony as post-medial specific storytelling techniques that transgress media. An analysis of choreography and costume in the two case studies showcases how comic effect is produced through contrast, exposing the underpinnings of homogenising structures within both fascist and democratic contexts. Moreover, the works foreground their intermedialities through the aesthetic mode of Camp, defined in Susan Sontag’s seminal 1964 essay, “Notes on Camp” as a means of creating satirical meaning. Synthesising violent content with humorous form, intermedial interactions in the two case studies feature the employment of Camp–as an aesthetic and political tool–to engage their audience to expose the logical fallacies of the fascist symbolism and ideology that form the targets of musical satire.

Previous research identified the expression of EDN3 in granulosa cells of preovulatory follicles in chickens. Notably, the expression level of EDN3 in Silky Fowl with low egg-laying performance was significantly higher than that in high-yield laying breed White Leghorn. Given the crucial role of granulosa cells in follicular development and maturation, it is very important to study the effect of EDN3 on the biological function of granular cells. In this study, an EDN3 overexpression plasmid was constructed and transfected into granular cells. The viability of these cells was detected using quantiative (qPCR), Cell Counting Kit-8 (CCK8), and 5-Ethynyl-2′-deoxyuridine (EdU) assays. Gonadal hormone synthesis was detected using enzyme-linked immunosorbent assay (ELISA) techniques. Finally, transcriptome sequencing was employed to identify differentially expressed genes. Result showed thatoverexpression of EDN3 was observed to promote cell viability. In addition, it significantly inhibits the expressions of LHR and cAMP-PKA signaling pathways. Cell transcriptome sequencing data displayed that EDN3 can upregulate energy metabolism and immune-related signaling pathways, whereas follicle maturation and the GnRH signaling pathway were downregulated. In conclusion, this study demonstrates that EDN3 can enhance granulosa cell viability and inhibit the expression of LHCGR, a process likely mediated through the cAMP-PKA signaling pathway. However, further evidence is required to substantiate the regulatory relationship between EDN3 and the cAMP-PKA signaling pathway.

We recently characterized the competitive inhibition of cyclic AMP (cAMP) on three periplasmic acid phosphatases, AphAHi, NadNHi, and eP4 (HelHi), in Haemophilus influenzae Rd KW20. This inhibitory effect is vital for orchestrating the nutritional growth and competence development in KW20. Initially discovered in Escherichia coli, the function of AphA remains however obscure. This study investigates the regulation of E. coli aphA expression under nutrient starvation conditions. Using transcriptional reporters with truncated aphA promoter sequences, we found that starvations of carbon and phosphate, but not amino acid, stimulated aphA expression through distinct promoter regions. Deletions of crp or cyaA abolished aphA expression, confirming their crucial roles. Conversely, CytR deletion increased aphA expression, suggesting CytR's role as a repressor of aphA expression. Additionally, we extended the study of three other second messengers, i.e., cyclic GMP, cyclic UMP, and cyclic CMP, each sharing structural similarities with cAMP. Notably, cGMP competitively inhibits AphAHi's acid phosphatase activity akin to cAMP. In contrast, both cUMP and cCMP stimulate AphAHi's phosphatase activity in a concentration dependent manner. Collectively, these data imply a complicated connection between nucleotide metabolism, AphA, cyclic purine and pyrimidine nucleotides in bacterial nutrient uptake and natural competence.

Abstract Background Enhanced glycolysis is a crucial metabolic event that drives the development of liver fibrosis, but the molecular mechanisms have not been fully understood. Lactate is the endproduct of glycolysis, which has recently been identified as a bioactive metabolite binding to G-protein-coupled receptor 81 (GPR81). We then questioned whether GPR81 is implicated in the development of liver fibrosis. Methods The level of GPR81 was determined in mice with carbon tetrachloride (CCl4)-induced liver fibrosis and in transforming growth factor beta 1 (TGF-β1)-activated hepatic stellate cells (HSCs) LX-2. To investigate the significance of GPR81 in liver fibrosis, wild-type (WT) and GPR81 knockout (KO) mice were exposed to CCl4, and then the degree of liver fibrosis was determined. In addition, the GPR81 agonist 3,5-dihydroxybenzoic acid (DHBA) was supplemented in CCl4-challenged mice and TGF-β1-activated LX-2 cells to further investigate the pathological roles of GPR81 on HSCs activation. Results CCl4 exposure or TGF-β1 stimulation significantly upregulated the expression of GPR81, while deletion of GPR81 alleviated CCl4-induced elevation of aminotransferase, production of pro-inflammatory cytokines, and deposition of collagen. Consistently, the production of TGF-β1, the expression of alpha-smooth muscle actin (α-SMA) and collagen I (COL1A1), as well as the elevation of hydroxyproline were suppressed in GPR81 deficient mice. Supplementation with DHBA enhanced CCl4-induced liver fibrogenesis in WT mice but not in GPR81 KO mice. DHBA also promoted TGF-β1-induced LX-2 activation. Mechanistically, GPR81 suppressed cAMP/CREB and then inhibited the expression of Smad7, a negative regulator of Smad3, which resulted in increased phosphorylation of Smad3 and enhanced activation of HSCs. Conclusion GPR81 might be a detrimental factor that promotes the development of liver fibrosis by regulating CREB/Smad7 pathway.

This paper aims to analyse the ambiguous relationship with modernity of the holiday spaces in the Third Reich. The Kraft durch Freude (KdF) and the Hitlerjugend, the two major Nazi organisations dedicated to normalising the leisure time of the Reich's subjects, were protagonists of architectural experiences characterised by opposing conceptions of modernity. Two radically opposed architectural models seem to emerge from the KdF Seebad Prora seaside resort and from the ideal layout of the camp recommended by the Hitlerjugend manuals: the machine and the camp. The analysis and comparison of these two models define an opportunity to investigate the complexity of the totalitarian spatial ecosystem by analysing its two-faced approach to modernity, its structural link with the regime and the contemporary perception of its difficult heritage, attempting to dispel certain prejudices and oversimplifications regarding Nazi Germany's planning.

Bacterial biofilms have been implicated in several chronic infections. After initial attachment, a critical first step in biofilm formation is a cell inducing a surface-sensing response. In the Gram-negative opportunistic pathogen Pseudomonas aeruginosa, two second messengers, cyclic diguanylate monophosphate (c-di-GMP) and cyclic adenosine monophosphate (cAMP), are produced by different surface-sensing mechanisms. However, given the disparate cellular behaviors regulated by these second messengers, how newly attached cells coordinate these pathways remains unclear. Some of the uncertainty relates to studies using different strains, experimental systems, and usually focusing on a single second messenger. In this study, we developed a tricolor reporter system to simultaneously gauge c-di-GMP and cAMP levels in single cells. Using PAO1, we show that c-di-GMP and cAMP are selectively activated in two commonly used experimental systems to study surface sensing. By further examining the conditions that differentiate a c-di-GMP or cAMP response, we demonstrate that an agarose-air interface activates cAMP signaling through type IV pili and the Pil-Chp system. However, a liquid-agarose interface favors the activation of c-di-GMP signaling. This response is dependent on flagellar motility and correlated with higher swimming speed. Collectively, this work indicates that c-di-GMP and cAMP signaling responses are dependent on the surface context. [ABSTRACT FROM AUTHOR]

Many types of cancer have infectious origins. Gastric cancer patients can demonstrate high seroprevalence of Helicobacter pylori (H. pylori). The aim of the present study was to assess the expression of SMOX gene in the group of Polish patients with gastric cancer. SMOX is believed to promote H. pylori -induced carcinogenesis via inflammation, DNA damage and activation of β-catenin signaling. We also assessed the mRNA expression of selected pro-inflammatory cytokines, i.e. IL-2, IFN-γ, TNF-α , and antimicrobial peptide, cathelicidin. The study material consisted of gastric tissue samples collected during total gastrectomy from three different places in stomach: from primary tumor, 3 ​cm away from the primary lesion, and from the wall opposite to the primary tumor. After RNA isolation, qPCR reactions were performed for the relevant genes. The obtained results confirmed an increased level of SMOX expression in gastric cancer patients with the history of H. pylori infection. And, as far as we know, this is the first study on SMOX gene expression conducted on tissue taken from a patient, not on a cell line. The levels of pro-inflammatory cytokines, i.e. IL-2, IFN-γ, TNF-α , were also increased, thus indicating their contribution to the specific inflammatory microenvironment of the tumor. Interestingly, the levels of CAMP , encoding antimicrobial peptide, were reduced in all tissue types. The findings confirm that SMOX plays a role in gastric carcinogenesis. However, further research is needed on the role of inflammatory and other factors involved in this process to identify targets for cancer immunotherapy. [Display omitted] [ABSTRACT FROM AUTHOR]

This research revisits the iconic film Victor/Victoria (Edwards, 1982), in order to illuminate how the comedic humiliation of archetypal women characters reinstates patriarchal dominance. By highlighting archetypes that I have labeled the "legitimate" woman, fat lady, scolding mother, and sexy ditz, this interdisciplinary research contributes to critical feminist scholarship and communication study that rarely engages the rhetorical significance of women who perform drag. The specific aim of this research is to reexamine the regressive effects of seemingly progressive films like Victor/Victoria in order to foment meaningful discourse about the subversive, and conversely, anxiety-inducing effects of drag in this precarious political moment, when many conservative lawmakers identify drag as a cultural threat. [ABSTRACT FROM AUTHOR]

Background: Phosphodiesterase (PDE) inhibitors are gaining interest in the context of pulmonary pathologies. In particular, the PDE3 inhibitor enoximone (ENXM) has shown potential relative to the cure of asthma, chronic obstructive pulmonary disease (COPD), and acute respiratory distress syndrome (ARDS). Despite its administration via inhalation being planned for use against COVID-19 related ARDS (C-ARDS), presently, no inhalable medicine containing ENXM is available. Objectives: This study aims to develop a new formulation suitable for pulmonary administration of ENXM. Methods: A solution for nebulization, based on the complex between ENXM and Hydroxypropyl-β-Cyclodextrin (HPβCD) (ENXM/HPβCD) is developed. The obtained solution is characterized in terms of aerodynamic distributions and biopharmaceutical features. Results: The evaluation of the aerosol droplets indicates a good bronchi–lung distribution of the drug. Biological evaluations of the air–liquid interface (ALI) in an in vitro lung cell model demonstrates that ENXM/HPβCD is capable of a local direct effect, increasing intracellular cyclic adenosine monophosphate (cAMP) levels and protecting from oxidative stress. Conclusions: This study offers a promising advance in the optimization of enoximone delivery to the lungs. [ABSTRACT FROM AUTHOR]

In Sa'adat Hasan Manto's short story "Toba Tek Singh", readers are introduced to Sikh inmate Bishan Singh living in an asylum in pre-Partition India.1 The disfigured, swollen, babbling body of Bishan Singh is redolent of Giorgio Agamben's representation of the " Muselmann ", the abject camp prisoners of Auschwitz, in his Remnants of Auschwitz: The Witness and the Archive. Drawing on Agamben's insights, this article reads the figure of Bishan Singh as the Agambenian " Muselmann " and Partition witness, caught in the space of the camp under the guise of an asylum for the mentally ill. This article also traces this space or holding centre for the mentally ill as a site of production of an ab-humanity marked not so much by a lack of speech, but by its provocative disorder. The figure of Bishan Singh as " Muselmann " emerges as marked out by his garbled, traumatized language that signals both his ab-humanity and his exposure to the violence that attends the making of the human subject. This study argues that Bishan Singh's wounded body and speech constitute traces of the unsayable, and that what is perceptible emerges from what is not. [ABSTRACT FROM AUTHOR]

Multidrug resistance proteins type 4 (MRP4) and 5 (MRP5) play pivotal roles in the transport of cyclic nucleotides in various tissues. However, their specific functions within the lower urinary tract remain relatively unexplored. This study aimed to investigate the effect of pharmacological inhibition of MRPs on cyclic nucleotide signaling in isolated pig bladder. The relaxation responses of the bladder were assessed in the presence of the MRP inhibitor, MK571. The temporal changes in intra- and extracellular levels of cAMP and cGMP in stimulated tissues were determined by mass spectrometry. The gene (ABCC4) and protein (MRP4) expression were also determined. MK571 administration resulted in a modest relaxation effect of approximately 26% in carbachol-precontracted bladders. The relaxation induced by phosphodiesterase inhibitors such as cilostazol, tadalafil, and sildenafil was significantly potentiated in the presence of MK571. In contrast, no significant potentiation was observed in the relaxation induced by substances elevating cAMP levels or stimulators of soluble guanylate cyclase. Following forskolin stimulation, both intracellular and extracellular cAMP concentrations increased by approximately 15.8-fold and 12-fold, respectively. Similarly, stimulation with tadalafil + BAY 41-2272 resulted in roughly 8.2-fold and 3.4-fold increases in intracellular and extracellular cGMP concentrations, respectively. The presence of MK571 reduced only the extracellular levels of cGMP. This study reveals the presence and function of MRP4 transporters within the porcine bladder and paves the way for future research exploring the role of this transporter in both underactive and overactive bladder disorders. NEW & NOTEWORTHY: This study investigates the impact of pharmacological inhibition of MRP4 and MRP5 transporters on cyclic nucleotide signaling in isolated pig bladders. MK571 administration led to modest relaxation, with enhanced effects observed in the presence of phosphodiesterase inhibitors. However, substances elevating cAMP levels remained unaffected. MK571 selectively reduced extracellular cGMP levels. These findings shed light on the role of MRP4 transporters in the porcine bladder, opening avenues for further research into bladder disorders. [ABSTRACT FROM AUTHOR]

Small molecules that stimulate cAMP production in Mycobacterium tuberculosis (Mtb) block the ability of the bacterium to metabolize cholesterol. Perturbing cAMP levels in Mtb hold promise for shortening the duration of combination treatments. Mtb pathogenesis and physiology are impacted by cAMP signaling, including host immune responses, intrinsic drug resistance, and metabolism. The large number of cAMP synthetic and cAMP responsive proteins in Mtb represent additional opportunities to chemically manipulate cAMP signaling in the bacterium. Chemically altering cAMP levels in other bacterial pathogens could be used to combat drug tolerance and/or enhance treatment strategies. Mycobacterium tuberculosis (Mtb) replicates within host macrophages by adapting to the stressful and nutritionally constrained environments in these cells. Exploiting these adaptations for drug discovery has revealed that perturbing cAMP signaling can restrict Mtb growth in macrophages. Specifically, compounds that agonize or stimulate the bacterial enzyme, Rv1625c/Cya, induce cAMP synthesis and this interferes with the ability of Mtb to metabolize cholesterol. In murine tuberculosis (TB) infection models, Rv1625c/Cya agonists contribute to reducing relapse and shortening combination treatments, highlighting the therapeutic potential for this class of compounds. More recently, cAMP signaling has been implicated in regulating fatty acid utilization by Mtb. Thus, a new model is beginning to emerge in which cAMP regulates the utilization of host lipids by Mtb during infection, and this could provide new targets for TB drug development. Here, we summarize the current understanding of cAMP signaling in Mtb with a focus on our understanding of how cAMP signaling impacts Mtb physiology during infection. We also discuss additional cAMP-related drug targets in Mtb and other bacterial pathogens that may have therapeutic potential. [ABSTRACT FROM AUTHOR]

The article questions the paradigmatic nature ascribed to "the zone"—and the concomitant dismissal of the camp's—by some analyses of the politics of capital's operations, and problematizes the very notion of the paradigm. Elaborating on previous reflections concerning contemporary agro-industrial zones in Italy, the article rethinks camps against state-centric and exceptionalist readings that consider them purely as sites of exclusion. At the same time, it retains a stress on the symbolic dimension of forms of containment and extraction, going beyond a narrow political-economic approach. The zone and the camp, it is argued, are mutually imbricated "infrastructure spaces" of present-day agro-capital's operations, which, however, result from the sedimentation of spatialized techniques for labor disciplining, reproduction, and containment that have developed alongside capitalist forms of agriculture throughout the contemporary period. The camp is thus defined as a function of the political, sovereign dimensions of extraction, that may operate within but also beyond the state. Furthermore, it is underlain by differential attributions of humanness, and therefore by a specific biopolitical anthropology. Engaging in a genealogy of the (humanitarian and/as labor) camps that today proliferate in agro-industrial zones, I argue that to understand the spatial formations emerging from and sustaining the politics of contemporary capital operations a recursive analytics is necessary, that thus questions the purchase of paradigms on the grounds of their atemporality and complicates the positing of mere historical continuities. [ABSTRACT FROM AUTHOR]

The premiere of Joe DiPietro's Fucking Men in Greece, in November 2018, sparked intense interest, particularly in the local gay community. Adapted from Arthur Schnitzler's controversial La Ronde, the play delves into the emotional and sexual dynamics of gay men within late capitalism, exploring themes such as promiscuity, fear of outing, HIV/AIDS, closeted lives, and the complex nature of relationships. Antónis Galéos translated the play, offering insights into Greece's modern gay landscape. This article addresses the underexplored intersection of gender, sexuality, and theatre translation, focusing on the construction of gay identities through verbal camp. Using Keith Harvey's descriptive framework on surface features of camp, it examines how verbal camp is translated into Greek, highlighting its impact on stage effects and on broader societal implications. This study aims to shed light on the nuanced construction of gay identities across languages and cultures, emphasizing visibility and representation within the local gay community. [ABSTRACT FROM AUTHOR]

The study presents a review of the Geology of the Senegalo-Mauritanian (S-M) sedimentary basin with a glance on stratigraphy, tectonic evolution, and integrated petroleum systems. The S-M basin is a typical Mesozoic-Cenozoic passive margin which opened westward from the Northwest African craton into the Atlantic Ocean. The basin overlies a Paleozoic sequence which represents part of the Taoudeni basin. Rifting and tectonic movements associated with the breakup of Gondwana and the formation of the Atlantic Ocean began in the Triassic and have led to a subdivision of the basin into three stages: pre-rift (Proterozoic-Paleozoic), syn-rift (Late Triassic-Middle Jurassic), and post-rift (Middle Jurassic-Present). Pre-rifting phase, made of sediments deposited between the Precambrian and Devonian, is mainly continental detrital rocks. The main deposits of the syn-rift stage are Triassic evaporites and Jurassic volcanic intrusion from the Central Atlantic Magmatic Province (CAMP). The post-rift segment consists of an Upper Jurassic-Lower Cretaceous carbonate platform overlain by a predominantly progradation and transgressive Cretaceous-Tertiary clastic sequence, up to 12,000 m thick in places. The S-M basin exhibits oil and gas potential. Indeed a total of three petroleum systems exist in the basin: the Lower Paleozoic Petroleum System (LPPS), the Subsalt Petroleum System (SSPS), and the Cretaceous-Tertiary Petroleum System (CTPS). Previous source rock analyses have shown a good quantity of total organic content (TOC) and type I kerogen; type I, II, and III for the LPPS and CTPS, respectively. The main reservoirs comprised fractured sandstone of Cambrian to Ordovician and Devonian, with good porosity up to 20%, karstified Oligocene limestone, and Maastrichtian and Miocene sandstones. The primary seals include the Upper Cretaceous and Tertiary marine mudstone and shale for these petroleum systems. Both stratigraphic and structural traps were derived from seismic profiles and included growth faults, slope truncation, turbidite-related traps, salt-related structures, carbonate bank deposits, and structures related to volcanism. Preserved extensional structures before the rifting and especially normal faults along the Paleozoic section have served as migration pathways for hydrocarbon in the Southern sub-basin. [ABSTRACT FROM AUTHOR]

Bacterial lipopolysaccharides belong to the group of pathogen-associated molecular patterns such as alarmins. They can cause various dysfunctions of the cardiovascular system, including arrhythmia, myocardial hypertrophy, myocarditis, and heart failure. The damaging effect of lipopolysaccharides on the myocardium can be a result of their direct action or ensured by uncontrolled secretion of endogenous alarmins and cytotoxic shock. Lipopolysaccharides are perceived by specific caspases of host cells and activate the release of interleukins, and in maximum stimulation they lead to necrosis and/or pyroptosis of cells. The mechanism of the action of bacterial lipopolysaccharide on the functional activity of the heart was studied in vitro using an isolated frog heart model. By the method of pharmacological blockade, the participation of calcium and potassium channels, phosphodiesterase and Na+-K+-ATPase in the mechanism of the lipopolysaccharide influence on the inotropic and chronotropic activity of the heart was revealed. In our experiments, we observed a dose-dependent negative effect of lipopolysaccharide on the inotropic and chronotropic functions of isolated frog heart, as well as a significant reduction in its viability. It is assumed that the mechanism of the action of lipopolysaccharide on the heart involves calcium and potassium ions, Na+-K+-ATPase and cAMP. The study investigated the role of the calcium-regulating hormonal system (including parathyroid hormone, parathyroid hormone-related protein, calcitonin, and vitamin D3) in preventing disturbances in the functional parameters of the isolated heart induced by bacterial lipopolysaccharide. The protective role of these hormones in preserving the pacemaker and contractile functions of the heart under the influence of bacterial lipopolysaccharide has been shown. A particularly significant effect is exerted by vitamin D3, parathyroid hormone and parathyroid hormone-related protein, which maintain the functional activity of the isolated heart for a long time. [ABSTRACT FROM AUTHOR]

Introduction: Air pollution from diesel combustion is linked in part to the generation of diesel exhaust particles (DEP). DEP exposure induces various processes, including inflammation and oxidative stress, which ultimately contribute to a decline in lung function. Cyclic AMP (cAMP) signaling is critical for lung homeostasis. The impact of DEP on cAMP signaling is largely unknown. Methods: We exposed human bronchial epithelial (BEAS-2B) cells to DEP for 24-72 h and evaluated mitochondrial bioenergetics, markers of oxidative stress and inflammation and the components of cAMP signaling. Mitochondrial bioenergetics was measured at 72 h to capture the potential and accumulative effects of prolonged DEP exposure on mitochondrial function. Results: DEP profoundly altered mitochondrial morphology and network integrity, reduced both basal and ATP-linked respiration as well as the glycolytic capacity of mitochondria. DEP exposure increased gene expression of oxidative stress and inflammation markers such as interleukin-8 and interleukin-6. DEP significantly affected mRNA levels of exchange protein directly activated by cAMP-1 and -2 (Epac1, Epac2), appeared to increase Epac1 protein, but left phospho-PKA levels unhanged. DEP exposure increased A-kinase anchoring protein 1, β2-adrenoceptor and prostanoid E receptor subtype 4 mRNA levels. Interestingly, DEP decreased mRNA levels of adenylyl cyclase 9 and reduced cAMP levels stimulated by forskolin (AC activator), fenoterol (β2-AR agonist) or PGE2 (EPR agonist). Discussion: Our findings suggest that DEP induces mitochondrial dysfunction, a process accompanied by oxidative stress and inflammation, and broadly dampens cAMP signaling. These epithelial responses may contribute to lung dysfunction induced by air pollution exposure. [ABSTRACT FROM AUTHOR]

Melanoma, a cancer arising from melanocytes, requires a novel treatment strategy because of the ineffectiveness of conventional therapies in certain patients. Fustin is a flavanonol found in young fustic (Cotinus coggygria). However, little is known about its antimelanoma effects. Our study demonstrates that fustin suppresses the growth of B16 melanoma cells. Phalloidin staining of cytoskeletal actin revealed that fustin induced a conformational change in the actin structure of melanoma cells, accompanied by suppressed phosphorylation of myosin regulatory light chain 2 (MLC2), a regulator of actin structure. Furthermore, the protein kinase A (cAMP-dependent protein kinase) inhibitor H89 completely attenuated fustin-induced downregulation of phosphorylated myosin phosphatase targeting subunit 1, which is involved in dephosphorylation of MLC2. In a mouse model, administration of fustin suppressed tumor growth in B16 melanoma cells without adverse effects. In conclusion, our findings suggest that fustin effectively suppresses melanoma cell growth both in vitro and in vivo. [ABSTRACT FROM AUTHOR]

We analyzed the effects of olfactory receptors (ORs) on transient receptor potential vanilloid 1 (TRPV1) activation using HEK293T cells co-expressing TRPV1 and OR51E1. We demonstrate here that the effect of OR51E1 on TRPV1 activation varies depending on the two TRPV1 ligands: capsaicin and eugenol. Notably, both of these ligands are vanilloid analogs. OR51E1 enhanced the response of TRPV1 to capsaicin but diminished that to eugenol. OR51E2 also showed similar effects. Based on the susceptibility to the OR's modulatory effects, various TRPV1 ligands could be classified into capsaicin and eugenol types. Activation of OR51E1 enhanced cAMP production. In addition, forskolin exhibited almost identical effects as ORs on TRPV1 responses to both types of ligands. These results suggest that OR51E1-induced cAMP elevation leads to a modification of TRPV1, presumably phosphorylation of TRPV1, which amplifies the susceptibility of TRPV1 to the two types of ligands differently. [ABSTRACT FROM AUTHOR]

Antidepressants, including duloxetine, are a significant cause of drug-induced hyponatremia, which can disrupt the continuation of medication. Tolvaptan is beneficial for correcting hyponatremia caused by the syndrome of inappropriate antidiuresis, but its impact on duloxetine-induced hyponatremia remains unknown. We used male Sprague-Dawley rats to examine the impact of duloxetine treatment on lithium-induced nephrogenic diabetes insipidus (Li-NDI) and to evaluate whether the results were reversed by co-treatment with tolvaptan. To induce Li-NDI, lithium chloride (40 mmol lithium/kg dry food) was administered for 2 weeks. Duloxetine (50 mg/kg/day) and tolvaptan (10 mg/kg/day) were also administered in food to assess their individual effects over the same period. At the end of each animal experiment, kidneys were harvested to measure levels of cAMP, vasopressin-2 receptor (V2R), cAMP-responsive element binding protein 1 (CREB-1), aquaporin-2 (AQP2), and prostaglandin E2 (PGE2). Water diuresis was induced in the Li-NDI rats, and duloxetine treatment reduced polyuria while increasing urine osmolality. Duloxetine treatment prevented the decrease in total AQP2, AQP2 phosphorylation at serine 256, and CREB-1 phosphorylation in Li-NDI rats. The V2R mRNA level was also reduced in Li-NDI rats and restored by duloxetine treatment. In the subsequent experiment, the decreased water diuresis in Li-NDI rats treated with duloxetine was reversed by co-treatment with tolvaptan. Tolvaptan co-treatment also reversed the changes in AQP2 protein and CREB-1 phosphorylation in the renal cortex and medulla. The decreased cAMP levels in Li-NDI rat kidneys were elevated by duloxetine treatment, and this elevation was reversed by co-treatment with tolvaptan. However, the elevated PGE2 levels in Li-NDI rat kidneys were not affected by either duloxetine alone or tolvaptan co-treatment. In conclusion, antidiuresis was induced by duloxetine in Li-NDI and reversed by tolvaptan co-treatment through alterations in the V2R-cAMP-AQP2 pathway. These findings could underlie the mechanism of duloxetine-induced hyponatremia and suggest the potential usefulness of tolvaptan in treating drug-induced hyponatremia. [ABSTRACT FROM AUTHOR]

Osteocrin (OSTN) is an endogenous protein sharing structural similarities with the natriuretic peptides [NPs; atrial (ANP), B‐type (BNP) and C‐type (CNP) NP], which are hormones known for their crucial role in maintaining pressure/volume homeostasis. Osteocrin competes with the NPs for binding to the receptor involved in their clearance (NPR‐C). In the present study, having identified, for the first time, the major circulating form of OSTN in human and ovine plasma, we examined the integrated haemodynamic, endocrine and renal effects of vehicle‐controlled incremental infusions of ovine proOSTN (83–133) and its metabolism in eight conscious normal sheep. Incremental i.v. doses of OSTN produced stepwise increases in circulating concentrations of the peptide, and its metabolic clearance rate was inversely proportional to the dose. Osteocrin increased plasma levels of ANP, BNP and CNP in a dose‐dependent manner, together with concentrations of their intracellular second messenger, cGMP. Increases in plasma cGMP were associated with progressive reductions in arterial pressure and central venous pressure. Plasma cAMP, renin and aldosterone were unchanged. Despite significant increases in urinary cGMP levels, OSTN administration was not associated with natriuresis or diuresis in normal sheep. These results support OSTN as an endogenous ligand for NPR‐C in regulating plasma concentrations of NPs and associated cGMP‐mediated bioactivity. Collectively, our findings support a role for OSTN in maintaining cardiovascular homeostasis. What is the central question of this study?What role does osteocrin (OSTN) have in integrated cardiovascular, renal and neurohumoral function in normal health?What is the main finding and its importance?Osteocrin is structurally similar to natriuretic peptides (NPs) that play a crucial role in cardiovascular homeostasis and binds to the NP receptor‐C (NPR‐C). Stepped doses of OSTN raised plasma atrial NP, B‐type NP, C‐type NP and cGMP and reduced arterial and venous pressures. Collectively, these findings provide strong evidence that increased NP levels result from competitive displacement from NPR‐C, not from increased NP secretion, suggesting that OSTN might play a role in maintaining cardiovascular homeostasis. [ABSTRACT FROM AUTHOR]

Calcium serves as a widespread second messenger in almost every human and animal cell. The regulation of various cellular processes, such as transcriptional control and the kinetics of membrane channels, is significantly influenced by intracellular calcium ions (Ca 2 + ), and linkages between Ca 2 + and other second messengers should activate signaling networks. The passage of ions across the cell membrane regulates Ca 2 + levels in pancreatic β -cells and requires the coordinated interaction of various ion transport mechanisms and organelles. The signaling of Ca 2 + in β -cells and its interactions with the intracellular dynamics of cyclic adenosine monophosphate (cAMP) is poorly understood. Therefore, the current investigation proposes a mathematical model to illustrate the spatiotemporal dynamical interaction between Ca 2 + and cAMP. In order to construct a one-dimensional mathematical model, the fundamental initial and boundary conditions derived from the physiological characteristics of the β -cell are incorporated. The numerical results were obtained by MATLAB simulations using the finite element method and the Crank-Nicolson method. The current study aims to offer an update on regulation between Ca 2 + and cAMP signaling circuits, with a focus on interactions that occur in localized areas of the β -cell. The model gives the individual effect of each parameter on the regulation of Ca 2 + and cAMP profiles in a β -cell. Evidently, impairments in the regulation of messenger pathways contribute to the pathological conditions, as demonstrated by the results obtained. [ABSTRACT FROM AUTHOR]

The cyclic nucleotides 3′,5′-cAMP/cGMP are now established as essential components of cellular processes in plants. The discovery of 2′,3′-cAMP/cGMP synthetases in Toll/interleukin-1 receptor (TIR) proteins supports an increasing recognition of both isomers as signaling molecules. Amino acid motifs diagnostic for adenylate cyclases (ACs) and guanylate cyclases (GCs) have enabled the discovery of moonlighting catalytic activities in both well-characterized and new proteins. 3′,5′-cAMP/cGMP operate as intramolecular tuners in microenvironments, while the 2′,3′ isoforms operate at the systems level in defense responses. Certain phosphodiesterases (PDEs) that hydrolyze 3′,5′-cAMP/cGMP function in the same protein as the enzymes that generate it. The twin AC-PDE domain architecture enables the tuning of cyclic nucleotide activities in a transient, dynamic, and compartmentalized manner. Research on cyclic nucleotide moonlighting enzymes is expected to drive biotechnological innovations and crop improvements. Cyclic nucleotides 3′,5′-cAMP and 3′,5′-cGMP are now established signaling components of the plant cell while their 2′,3′ positional isomers are increasingly recognized as such. 3′,5′-cAMP/cGMP is generated by adenylate cyclases (ACs) or guanylate cyclases (GCs) from ATP or GTP, respectively, whereas 2′,3′-cAMP/cGMP is produced through the hydrolysis of double-stranded DNA or RNA by synthetases. Recent evidence suggests that the cyclic nucleotide generating and inactivating enzymes moonlight in proteins with diverse domain architecture operating as molecular tuners to enable dynamic and compartmentalized regulation of cellular signals. Further characterization of such moonlighting enzymes and extending the studies to noncanonical cyclic nucleotides promises new insights into the complex regulatory networks that underlie plant development and responses, thus offering exciting opportunities for crop improvement. [ABSTRACT FROM AUTHOR]

Background and Purpose: Calcitonin gene‐related peptide (CGRP) is a potent vasodilator. While its signalling is assumed to be mediated via increases in cAMP, this study focused on elucidating the actual intracellular signalling pathways involved in CGRP‐induced relaxation of human isolated coronary arteries (HCA). Experimental Approach: HCA were obtained from heart valve donors (27 M, 25 F, age 54 ± 2 years). Concentration–response curves to human α‐CGRP or forskolin were constructed in HCA segments, incubated with different inhibitors of intracellular signalling pathways, and intracellular cAMP levels were measured with and without stimulation. Results: Adenylyl cyclase (AC) inhibitors SQ22536 + DDA and MDL‐12330A, and PKA inhibitors Rp‐8‐Br‐cAMPs and H89, did not inhibit CGRP‐induced relaxation of HCA, nor did the guanylyl cyclase inhibitor ODQ, PKG inhibitor KT5823, EPAC1/2 inhibitor ESI09, potassium channel blockers TRAM‐34 + apamin, iberiotoxin or glibenclamide, or the Gαq inhibitor YM‐254890. Phosphodiesterase inhibitors induced a concentration‐dependent decrease in the response to KCl but did not potentiate relaxation to CGRP. Relaxation to forskolin was not blocked by PKA or AC inhibitors, although AC inhibitors significantly inhibited the increase in cAMP. Inhibition of Gβγ subunits using gallein significantly inhibited the relaxation to CGRP in human coronary arteries. Conclusion: While CGRP signalling is generally assumed to act via cAMP, the CGRP‐induced vasodilation in HCA was not inhibited by targeting this intracellular signalling pathway at different levels. Instead, inhibition of Gβγ subunits did inhibit the relaxation to CGRP, suggesting a different mechanism of CGRP‐induced relaxation than generally believed. [ABSTRACT FROM AUTHOR]

The morphology, internal architecture, and emplacement mechanisms of the Central Atlantic Magmatic Province (CAMP) lava flows of the Hartford and Deerfield basins (USA) are presented. The Talcott, Holyoke, and Hampden formations within the Hartford basin constitute distinct basaltic units, each exhibiting chemical, mineralogical, and structural differences corresponding to flow fields. Each flow field was the result of several sustained eruptions that produced both inflated pahoehoe flows and subaquatic extrusions: 1–5 eruptions in the Talcott formation and 1–2 in Holyoke and Hampden basalts, where simple flows are dominant. The Deerfield basin displays the Deerfield basalt unit, characterized by pillow lavas and sheet lobes, aligning chemically and mineralogically with the Holyoke basalt unit. Overall, the studied flow fields are composed of thick, simple pahoehoe flows that display the entire range of pahoehoe morphology, including inflated lobes. The three-partite structure of sheet lobes, vertical distribution of vesicles, and segregation structures are typical. The characteristics of the volcanic pile suggest slow emplacement during sustained eruptive episodes and are compatible with a continental basaltic succession facies model. The studied CAMP basalts of the eastern United States are correlated with the well-exposed examples on both sides of the Atlantic Ocean (Canada, Portugal, and Morocco). [ABSTRACT FROM AUTHOR]