Intrinsic Stimuli Research Articles

Prenylcysteine oxidase 1 like protein is required for neutrophil bactericidal activities

The bactericidal function of neutrophils is dependent on a myriad of intrinsic and extrinsic stimuli. Using systems immunology approaches we identify microbiome- and infection-induced changes in neutrophils. We focus on investigating the Prenylcysteine oxidase 1 like (Pcyox1l) protein function. Murine and human Pcyox1l proteins share ninety four percent aminoacid homology revealing significant evolutionary conservation and implicating Pcyox1l in mediating important biological functions. Here we show that the loss of Pcyox1l protein results in significant reductions in the mevalonate pathway impacting autophagy and cellular viability under homeostatic conditions. Concurrently, Pcyox1l CRISPRed-out neutrophils exhibit deficient bactericidal properties. Pcyox1l knock-out mice demonstrate significant susceptibility to infection with the gram-negative pathogen Psuedomonas aeruginosa exemplified through increased neutrophil infiltrates, hemorrhaging, and reduced bactericidal functionality. Cumulatively, we ascribe a function to Pcyox1l protein in modulation of the prenylation pathway and suggest connections beween metabolic responses and neutrophil functionality.

Neutrophil Extracellular Traps and Their Possible Implications in Ocular Herpes Infection.

Neutrophil extracellular traps (NETs) are net-like structures released from neutrophils. NETs predominantly contain cell-free deoxyribonucleic acid (DNA) decorated with histones and neutrophil granule proteins. Numerous extrinsic and intrinsic stimuli can induce the formation of NETs such as pathogens, cytokines, immune complexes, microcrystals, antibodies, and other physiological stimuli. The mechanism of NETosis induction can either be ROS-dependent or independent based on the catalase producing activity of the pathogen. NADPH is the source of ROS production, which in turn depends on the upregulation of Ca2+ production in the cytoplasm. ROS-independent induction of NETosis is regulated through toll-like receptors (TLRs). Besides capturing and eliminating pathogens, NETs also aggravate the inflammatory response and thus act as a double-edged sword. Currently, there are growing reports of NETosis induction during bacterial and fungal ocular infections leading to different pathologies, but there is no direct report suggesting its role during herpes simplex virus (HSV) infection. There are innumerable independent reports showing that the major effectors of NETosis are also directly affected by HSV infection, and thus, there is a strong possibility that HSV interacts with these facilitators that can either result in virally mediated modulation of NETosis or NETosis-mediated suppression of ocular HSV infection. This review focuses on the mechanism of NETs formation during different ocular pathologies, with its prime focus on highlighting their potential implications during HSV ocular infections and acting as prospective targets for the treatment of ocular diseases.

Hepcidin and ferritin levels as markers of immune cell activation during septic shock, severe COVID-19 and sterile inflammation.

Major clinically relevant inflammatory events such as septic shock and severe COVID-19 trigger dynamic changes in the host immune system, presenting promising candidates for new biomarkers to improve precision diagnostics and patient stratification. Hepcidin, a master regulator of iron metabolism, has been intensively studied in many pathologies associated with immune system activation, however these data have never been compared to other clinical settings. Thus, we aimed to reveal the dynamics of iron regulation in various clinical settings and to determine the suitability of hepcidin and/or ferritin levels as biomarkers of inflammatory disease severity. To investigate the overall predictive ability of hepcidin and ferritin, we enrolled the patients suffering with three different diagnoses - in detail 40 patients with COVID-19, 29 patients in septic shock and eight orthopedic patients who were compared to nine healthy donors and all cohorts to each other. We showed that increased hepcidin levels reflect overall immune cell activation driven by intrinsic stimuli, without requiring direct involvement of infection vectors. Contrary to hepcidin, ferritin levels were more strongly boosted by pathogen-induced inflammation - in septic shock more than four-fold and in COVID-19 six-fold in comparison to sterile inflammation. We also defined the predictive capacity of hepcidin-to-ferritin ratio with AUC=0.79 and P = 0.03. Our findings confirm that hepcidin is a potent marker of septic shock and other acute inflammation-associated pathologies and demonstrate the utility of the hepcidin-to-ferritin ratio as a predictor of mortality in septic shock, but not in COVID-19.

Oxidative Stress and Antioxidants in Chronic Rhinosinusitis with Nasal Polyps.

Oxidative stress results from an imbalance between the production of reactive oxygen species and the body's antioxidant defense system. It plays an important role in the regulation of the immune response and can be a pathogenic factor in various diseases. Chronic rhinosinusitis (CRS) is a complex and heterogeneous disease with various phenotypes and endotypes. Recently, an increasing number of studies have proposed that oxidative stress (caused by both environmental and intrinsic stimuli) plays an important role in the pathogenesis and persistence of CRS. This has attracted the attention of several researchers. The relationship between the presence of reactive oxygen species composed of free radicals and nasal polyp pathology is a key topic receiving attention. This article reviews the role of oxidative stress in respiratory diseases, particularly CRS, and introduces potential therapeutic antioxidants that may offer targeted treatment for CRS.

Nanoparticle-mediated stimulus-responsive antibacterial therapy.

The limitations associated with conventional antibacterial therapies and the subsequent amplification of multidrug-resistant (MDR) microorganisms have increased, necessitating the urgent development of innovative antibacterial techniques. Accordingly, nanoparticle-mediated therapeutics have emerged as potential candidates for antibacterial treatment due to their suitable dimensions, penetration capacity, and high efficiency in targeted drug delivery. However, although nanoparticle-based drug delivery systems have been demonstrated to be effective, they are limited by their overuse and unwanted side effects. Thus, to overcome these drawbacks, stimulus-responsive antibiotic delivery has been extended as a promising strategy for site-specific restricted drug exemption. Nano-formulations that are triggered by various stimuli, such as intrinsic, extrinsic, and bacterial stimuli, have been developed. Thus, by harnessing the physicochemical properties of various nanoparticles, the selective release of therapeutic cargoes can be achieved through the application of a variety of local stimuli such as light, sound, irradiation, pH, and magnetic field. In this review, we also highlight the progress and perspectives of stimulus-responsive combination therapy, with special emphasis on the eradication of MDR strains and biofilms. Hence, this review addresses the advancement and challenges in the applications of stimulus-responsive nanoparticles together with the various future prospects of this technique.

Recent advances in responsive antibacterial materials: design and application scenarios.

Bacterial infection is one of the leading causes of death globally, although modern medicine has made considerable strides in the past century. As traditional antibiotics are suffering from the emergence of drug resistance, new antibacterial strategies are of great interest. Responsive materials are appealing alternatives that have shown great potential in combating resistant bacteria and avoiding the side effects of traditional antibiotics. In this review, the responsive antibacterial materials are introduced in terms of stimulus signals including intrinsic (pH, enzyme, ROS, etc.) and extrinsic (light, temperature, magnetic fields, etc.) stimuli. Their biomedical applications in therapeutics and medical devices are then discussed. Finally, the author's perspective of the challenge and the future of such a system is provided.

The Emerging Role of Tumor Microenvironmental Stimuli in Regulating Metabolic Rewiring of Liver Cancer Stem Cells

Primary liver cancer (PLC) is one of the most devastating cancers worldwide. Extensive phenotypical and functional heterogeneity is a cardinal hallmark of cancer, including PLC, and is related to the cancer stem cell (CSC) concept. CSCs are responsible for tumor growth, progression, relapse and resistance to conventional therapies. Metabolic reprogramming represents an emerging hallmark of cancer. Cancer cells, including CSCs, are very plastic and possess the dynamic ability to constantly shift between different metabolic states depending on various intrinsic and extrinsic stimuli, therefore amplifying the complexity of understanding tumor heterogeneity. Besides the well-known Warburg effect, several other metabolic pathways including lipids and iron metabolism are altered in PLC. An increasing number of studies supports the role of the surrounding tumor microenvironment (TME) in the metabolic control of liver CSCs. In this review, we discuss the complex metabolic rewiring affecting liver cancer cells and, in particular, liver CSCs. Moreover, we highlight the role of TME cellular and noncellular components in regulating liver CSC metabolic plasticity. Deciphering the specific mechanisms regulating liver CSC-TME metabolic interplay could be very helpful with respect to the development of more effective and innovative combinatorial therapies for PLC treatment.

Clinical and Sociodemographic Profile of Psychomotor Agitation in Mental Health Hospitalisation: A Multicentre Study.

Psychomotor agitation is characterised by an increase in psychomotor activity, restlessness and irritability. People with psychomotor agitation respond by over-reacting to both intrinsic and extrinsic stimuli, experiencing stress and/or altered cognition. The objective of this study is to assess the clinical and sociodemographic profile of psychomotor agitation in patients with severe mental disorders. The study was carried out in Spain by means of multicentre cross-sectional convenience sampling involving 140 patients who had been admitted to psychiatric hospital units and had experienced an episode of psychomotor agitation between 2018 and 2021.Corrigan's Agitated Behaviour Scale was used to assess psychomotor agitation. The results show that the predominant characteristic in psychomotor agitation is aggressiveness, which is also the most reported factor in patients with severe mental disorder. Patients who also have anxiety develop psychomotor agitation symptoms of moderate/severe intensity. The clinical and sociodemographic profile found in our study is consistent with other studies on the prevalence of psychomotor agitation.

Immuno(T)herapy for age-related diseases.

During the last decade, the stimulation of T-cell function by the blockage of immunosuppressive checkpoints has experienced an outstanding impact in the treatment of cancer. Development of the chimeric antigen receptor T-cell technology has also emerged as a powerful alternative for patients suffering from oncological processes, especially those affected by hematological neoplasms. Recent evidence suggest that the use of immunotherapy could be extended to non-oncological diseases and could be especially relevant for age-associated disorders, opening exciting therapeutic options for a wide range of diseases of the elderly. Here we comment on the emergence of T-cell-based immunotherapies as feasible approaches that could revolutionize the future of GeroScience.

Transgenerational effects of maternal corticosterone across early life in a viviparous snake

Glucocorticoids (GCs) are central mediators of vertebrate responses to intrinsic and extrinsic stimuli. Among the sources of variation in circulating GCs are transgenerational effects mediated by mothers. Here we studied potential maternal effects mediated by GCs on offspring phenotype in a live-bearing reptile, the western terrestrial garter snake (Thamnophis elegans). We evaluated the association between baseline corticosterone (CORT) levels during gestation (i.e., preparturition) in field-captured mothers and 1) reproductive success and offspring sex ratios, 2) birth phenotypic traits of offspring born under common-garden laboratory conditions, and 3) neonate (age 3 months) and juvenile (age 12 months) traits of offspring raised under two thermal regimes (‘warm’ and ‘cool’) during their first year of life. Reproductive success and offspring sex ratios were not associated with preparturition maternal CORT, but pregnant snakes with higher CORT levels gave birth to smaller, lighter offspring, which tended to grow faster to age three months. Neonate baseline CORT varied with preparturition maternal CORT in a sex-specific manner (positive trend for females, negative for males). Maternal CORT effects on offspring phenotype were no longer detectable in juveniles at age one year. Instead, juvenile phenotypes were most influenced by rearing environment, with offspring raised under the cool regime showing higher baseline CORT and slower growth than those raised under warmer conditions. Our findings support the notion that offspring phenotype might be continuously adjusted in response to environmental cues —both pre- and post-natal— and that the strength of maternal CORT effects declines as offspring develop and experience unique environmental challenges. Our results contribute to a growing literature on transgenerational effects of hormones and help to fill a gap in our knowledge of these effects in ectothermic amniotes.

Task Demands Differentially Affect Processing of Intrinsic and Extrinsic Object Features in Working Memory

Some argue that visual working memory operates on integrated object representations. Here, we contend that obligatory feature integration occurs with intrinsic but not extrinsic object features. Working memory for shapes and colors was assessed using a change-detection task with a central test probe, while recording event-related potentials (ERPs). Color was either an intrinsic surface feature of a shape or connected to the shape via a proximal but spatially disjunct extrinsic frame. There were two types of test: The direct test required memory for shape and color; the indirect test required only shape memory. Study-test changes of color were therefore either task-relevant or task-irrelevant. We assessed performance costs and event-related potential (ERP) effects arising from color changes. In the direct test, performance was poorer for extrinsic than intrinsic stimuli; task-relevant color changes elicited enhanced frontal negativity (N2, FN400) for both intrinsic and extrinsic stimuli. In the indirect test, performance costs and ERP effects associated with irrelevant color change were larger for intrinsic than extrinsic stimuli. This suggests intrinsic information is more readily integrated into the working-memory representation and evaluated against the test probe. Findings imply that feature integration is not obligatory under all conditions but influenced by stimulus-driven and task-related focus of attention.

Epigenetics and environment in breast cancer: New paradigms for anti-cancer therapies.

Breast cancer remains the most frequently diagnosed cancer in women worldwide. Delayed presentation of the disease, late stage at diagnosis, limited therapeutic options, metastasis, and relapse are the major factors contributing to breast cancer mortality. The development and progression of breast cancer is a complex and multi-step process that incorporates an accumulation of several genetic and epigenetic alterations. External environmental factors and internal cellular microenvironmental cues influence the occurrence of these alterations that drives tumorigenesis. Here, we discuss state-of-the-art information on the epigenetics of breast cancer and how environmental risk factors orchestrate major epigenetic events, emphasizing the necessity for a multidisciplinary approach toward a better understanding of the gene-environment interactions implicated in breast cancer. Since epigenetic modifications are reversible and are susceptible to extrinsic and intrinsic stimuli, they offer potential avenues that can be targeted for designing robust breast cancer therapies.

A sister's search for the seeds of psychosis

Dr. Dolores Malaspina sought a better way to understand the origins of psychosis than a schizophrenogenic mother, as her family had been informed upon her sisters illness. She moved her attention from environmental biology and zoology, to medical science and assembled knowledge on the multilevel components purported to underpin severe mental illness. Her studies cross levels to consider connections among exposures and genetic etiologies, intrinsic homeostatic mechanisms, stimuli perception and clinical illness features. Original contributions include associating later paternal age with increasing risk for schizophrenia in offspring and proposing that de novo mutations with shorter cell cycles explained the association, showing increased resting hippocampal blood flow in psychosis and that it was associated with inflammation, and that autonomic nervous system dysfunction was related to hippocampal inflammation, plausibly reflecting vascular abnormalities. She has been a professor of psychiatry in medical schools at Columbia University, New York University and at Mount Sinai in New York, USA.

Aging, testosterone, and neuroplasticity: friend or foe?

Neuroplasticity or neural plasticity implicates the adaptive potential of the brain in response to extrinsic and intrinsic stimuli. The concept has been utilized in different contexts such as injury and neurological disease. Neuroplasticity mechanisms have been classified into neuroregenerative and function-restoring processes. In the context of injury, neuroplasticity has been defined in three post-injury epochs. Testosterone plays a key yet double-edged role in the regulation of several neuroplasticity alterations. Research has shown that testosterone levels are affected by numerous factors such as age, stress, surgical procedures on gonads, and pharmacological treatments. There is an ongoing debate for testosterone replacement therapy (TRT) in aging men; however, TRT is more useful in young individuals with testosterone deficit and more specific subgroups with cognitive dysfunction. Therefore, it is important to pay early attention to testosterone profile and precisely uncover its harms and benefits.In the present review, we discuss the influence of environmental factors, aging, and gender on testosterone-associated alterations in neuroplasticity, as well as the two-sided actions of testosterone in the nervous system. Finally, we provide practical insights for further study of pharmacological treatments for hormonal disorders focusing on restoring neuroplasticity.

Porcine Enteric Coronavirus PEDV Induces the ROS-ATM and Caspase7-CAD-γH2AX Signaling Pathways to Foster Its Replication.

DNA damage response (DDR) is an evolutionarily conserved mechanism by which eukaryotic cells sense DNA lesions caused by intrinsic and extrinsic stimuli, including virus infection. Although interactions between DNA viruses and DDR have been extensively studied, how RNA viruses, especially coronaviruses, regulate DDR remains unknown. A previous study showed that the porcine epidemic diarrhea virus (PEDV), a member of the genus Alphacoronavirus in the Coronaviridae family, induces DDR in infected cells. However, the underlying mechanism was unclear. This study showed that PEDV activates the ATM-Chk2 signaling, while inhibition of ATM or Chk2 dampens the early stage of PEDV infection. Additionally, we found that PEDV-activated ATM signaling correlates with intracellular ROS production. Interestingly, we showed that, unlike the typical γH2AX foci, PEDV infection leads to a unique γH2AX staining pattern, including phase I (nuclear ring staining), II (pan-nuclear staining), and III (co-staining with apoptotic bodies), which highly resembles the apoptosis process. Furthermore, we demonstrated that PEDV-induced H2AX phosphorylation depends on the activation of caspase-7 and caspase-activated DNAse (CAD), but not ATM-Chk2. Finally, we showed that the knockdown of H2AX attenuates PEDV replication. Taken together, we conclude that PEDV induces DDR through the ROS-ATM and caspase7-CAD-γH2AX signaling pathways to foster its early replication.

Targeting senescent cells for a healthier longevity: the roadmap for an era of global aging.

Aging is a natural but relentless process of physiological decline, leading to physical frailty, reduced ability to respond to physical stresses (resilience) and, ultimately, organismal death. Cellular senescence, a self-defensive mechanism activated in response to intrinsic stimuli and/or exogenous stress, is one of the central hallmarks of aging. Senescent cells cease to proliferate, while remaining metabolically active and secreting numerous extracellular factors, a feature known as the senescence-associated secretory phenotype. Senescence is physiologically important for embryonic development, tissue repair, and wound healing, and prevents carcinogenesis. However, chronic accumulation of persisting senescent cells contributes to a host of pathologies including age-related morbidities. By paracrine and endocrine mechanisms, senescent cells can induce inflammation locally and systemically, thereby causing tissue dysfunction, and organ degeneration. Agents including those targeting damaging components of the senescence-associated secretory phenotype or inducing apoptosis of senescent cells exhibit remarkable benefits in both preclinical models and early clinical trials for geriatric conditions. Here we summarize features of senescent cells and outline strategies holding the potential to be developed as clinical interventions. In the long run, there is an increasing demand for safe, effective, and clinically translatable senotherapeutics to address healthcare needs in current settings of global aging.

Molecular and biochemical regulation of skeletal muscle metabolism.

Skeletal muscle hypertrophy is a culmination of catabolic and anabolic processes that are interwoven into major metabolic pathways, and as such modulation of skeletal muscle metabolism may have implications on animal growth efficiency. Muscle is composed of a heterogeneous population of muscle fibers that can be classified by metabolism (oxidative or glycolytic) and contractile speed (slow or fast). Although slow fibers (type I) rely heavily on oxidative metabolism, presumably to fuel long or continuous bouts of work, fast fibers (type IIa, IIx, and IIb) vary in their metabolic capability and can range from having a high oxidative capacity to a high glycolytic capacity. The plasticity of muscle permits continuous adaptations to changing intrinsic and extrinsic stimuli that can shift the classification of muscle fibers, which has implications on fiber size, nutrient utilization, and protein turnover rate. The purpose of this paper is to summarize the major metabolic pathways in skeletal muscle and the associated regulatory pathways.

PSYCHOLOGICAL DETERMINANTS OF ECONOMIC GROWTH

This study aimed to examine the psychological determinants of economic growth. The study sample was taken from Tanzania in two regions- Mwanza and Kagera. The cross-sectional survey research design was used. The self-checklist questionnaires were used to collect the primary data from 211 individuals. The analysis-weighted automatic linear modelling (AW-ALM) and probit model were used to examine the linear and non-linear behaviour of the psychological determinants (Hube) on economic growth respectively. The study found that the main psychological determinant of economic growth is the motivation of the individual. Moreover, the study evidenced the concavity and convexity of functional/relational behaviour of the Hube on economic growth in the Mwanza and Kagera regions respectively. The study concluded that the effective motivation packages for economic growth are that involve both bounded choices or self-interested (intrinsic) and unbounded choices or induced-interest (extrinsic) motives. Consequently, the study recommended that appropriate motivational strategies should be involved both intrinsic and extrinsic stimuli of the individual. Keywords: Cognitive Psychology, Intrinsic and Extrinsic Motives, Lifestyle, Metacognition.

The Influence of Vicarious Fear-Learning in "Infecting" Reactive Action Inhibition.

Since the dawn of cognitive neuroscience, emotions have been recognized to impact on several executive processes, such as action inhibition. However, the complex interplay between emotional stimuli and action control is not yet fully understood. One way to measure inhibitory control is the stop-signal task (SST), which estimates the ability to cancel outright an action to the presentation of a stop signal by means of the stop-signal reaction times (SSRTs). Impaired as well as facilitated action control has been found when faced with intrinsic emotional stimuli as stop signals in SSTs. Here, we aimed at investigating more deeply the power of negative stimuli to influence our action control, testing the hypothesis that a previously neutral stimulus [i.e., the image of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)], which has been conditioned through vicarious fear learning, has the same impact on reactive action inhibition performance as an intrinsically negative stimulus (i.e., a fearful face or body). Action control capabilities were tested in 90 participants by means of a SST, in which the stop signals were represented by different negative stimuli. Results showed that the SARS-CoV-2 image enhanced the ability to suppress an ongoing action similarly to observing fearful facial expressions or fearful body postures. Interestingly, we found that this effect was predicted by impulsivity traits: for example, the less self-control the participants had, the less they showed emotional facilitation for inhibitory performance. These results demonstrated that vicarious fear learning has a critical impact on cognitive abilities, making a neutral image as threatening as phylogenetically innate negative stimuli and able to impact on our behavioral control.

Microenvironmental Behaviour of Nanotheranostic Systems for Controlled Oxidative Stress and Cancer Treatment.

The development of smart, efficient and multifunctional material systems for diseases treatment are imperative to meet current and future health challenges. Nanomaterials with theranostic properties have offered a cost effective and efficient solution for disease treatment, particularly, metal/oxide based nanotheranostic systems already offering therapeutic and imaging capabilities for cancer treatment. Nanoparticles can selectively generate/scavenge ROS through intrinsic or external stimuli to augment/diminish oxidative stress. An efficient treatment requires higher oxidative stress/toxicity in malignant disease, with a minimal level in surrounding normal cells. The size, shape and surface properties of nanoparticles are critical parameters for achieving a theranostic function in the microenvironment. In the last decade, different strategies for the synthesis of biocompatible theranostic nanostructures have been introduced. The exhibition of therapeutics properties such as selective reactive oxygen species (ROS) scavenging, hyperthermia, antibacterial, antiviral, and imaging capabilities such as MRI, CT and fluorescence activity have been reported in a variety of developed nanosystems to combat cancer, neurodegenerative and emerging infectious diseases. In this review article, theranostic in vitro behaviour in relation to the size, shape and synthesis methods of widely researched and developed nanosystems (Au, Ag, MnOx, iron oxide, maghemite quantum flakes, La2O3−x, TaOx, cerium nanodots, ITO, MgO1−x) are presented. In particular, ROS-based properties of the nanostructures in the microenvironment for cancer therapy are discussed. The provided overview of the biological behaviour of reported metal-based nanostructures will help to conceptualise novel designs and synthesis strategies for the development of advanced nanotheranostic systems.