Suppression Of Response Research Articles

Peak response regularization for localization

Deep convolutional neural networks approaches often assume that the feature response has a Gaussian distribution with target-centered peak response, which can be used to guide the target location and classification. Nevertheless, such an assumption is implausible when there is progressive interference from other targets and/or background noise, which produces sub-peaks on the tracking response map and causes model drift. In this paper, we propose a feature response regularization approach for sub-peak response suppression and peak response enforcement and aim to handle progressive interference systematically. Our approach, referred to as Peak Response Regularization (PRR), applies simple-yet-efficient method to aggregate and align discriminative features, which convert local extremal response in discrete feature space to extremal response in continuous space, which enforces the localization and representation capability of convolutional features. Experiments on human pose detection, object detection, object tracking, and image classification demonstrate that PRR improves the performance of image tasks with a negligible computational cost.

Gentiopicroside improves NASH and liver fibrosis by suppressing TLR4 and NLRP3 signaling pathways

BackgroundNon-alcoholic steatohepatitis (NASH) and liver fibrosis are progressive conditions associated with non-alcoholic fatty liver disease (NAFLD), characterized by hepatocyte pyroptosis and hepatic stellate cell (HSC) activation. Gentiopicroside (GPS) has emerged as a potential treatment for NASH, yet its underlying mechanism remains unclear. AimTo confirm that GPS can improve NASH and liver fibrosis by blocking the NLRP3 signaling pathway Study designInitially, different animal models were used to study the effects and mechanisms of GPS on NASH and fibrosis. Subsequent in vitro experiments utilized co-cultures and other techniques to delve deeper into its mechanism, followed by validation of the findings in mouse liver tissues. MethodsC57BL/6 mice were fed high-fat, high-cholesterol (HFHC), or methionine-choline-deficient (MCD) diets to induce NASH and fibrosis. RAW264.7 cells and born marrow bone marrow-derived macrophages (BMDMs) were stimulated with LPS and ATP to induce inflammation, then co-cultured with primary hepatocytes and HSCs, treated with GPS, and its efficacy and mechanism were analyzed. ResultsIn vivo, GPS alleviated NASH and liver fibrosis by inhibiting the NLRP3 pathway. In vitro, GPS attenuated inflammation induced by BMDMs by inhibiting TLR4 and NLRP3 signaling pathways, and Co-culture studies suggested that GPS reduced hepatocyte pyroptosis and HSC activation, which was also confirmed in liver tissues ConclusionGPS improves NASH and liver fibrosis by inhibiting the TLR4 and NLRP3 signaling pathways. The specific mechanism may be related to the suppression of macrophage-mediated inflammatory responses, thereby reducing hepatocyte pyroptosis and HSC activation.

WTAP and m6A-modified circRNAs modulation during stress response in acute myeloid leukemia progenitor cells

N6-methyladenosine (m6A) is one of the most prevalent and conserved RNA modifications. It controls several biological processes, including the biogenesis and function of circular RNAs (circRNAs), which are a class of covalently closed-single stranded RNAs. Several studies have revealed that proteotoxic stress response induction could be a relevant anticancer therapy in Acute Myeloid Leukemia (AML). Furthermore, a strong molecular interaction between the m6A mRNA modification factors and the suppression of the proteotoxic stress response has emerged. Since the proteasome inhibition leading to the imbalance in protein homeostasis is strictly linked to the stress response induction, we investigated the role of Bortezomib (Btz) on m6A regulation and in particular its impact on the modulation of m6A-modified circRNAs expression. Here, we show that treating AML cells with Btz downregulated the expression of the m6A regulator WTAP at translational level, mainly because of increased oxidative stress. Indeed, Btz treatment promoted oxidative stress, with ROS generation and HMOX-1 activation and administration of the reducing agent N-acetylcysteine restored WTAP expression. Additionally, we identified m6A-modified circRNAs modulated by Btz treatment, including circHIPK3, which is implicated in protein folding and oxidative stress regulation. These results highlight the intricate molecular networks involved in oxidative and ER stress induction in AML cells following proteotoxic stress response, laying the groundwork for future therapeutic strategies targeting these pathways.

Sorbremnoids A and B: NLRP3 Inflammasome Inhibitors Discovered from Spatially Restricted Crosstalk of Biosynthetic Pathways.

Crosstalk-oriented chemical evolution of natural products (NPs) is an efficacious strategy for generating novel skeletons through coupling reactions between NP fragments. In this study, two NOD-like receptor protein 3 (NLRP3) inflammasome inhibitors, sorbremnoids A and B (1 and 2), with unprecedented chemical architectures were identified from a fungus Penicillium citrinum. Compounds 1 and 2 exemplify rare instances of hybrid NPs formed via a major facilitator superfamily (MFS)-like enzyme by coupling reactive intermediates from two separate biosynthetic gene clusters (BGCs), pcisor and pci56. Both sorbremnoids A and B are NLRP3 inflammasome inhibitors. Sorbremnoid A demonstrated strong inhibition of IL-1β by directly binding to the NLRP3 protein, inhibiting the assembly and activation of the NLRP3 inflammasome in vitro, with potential application in diabetic refractory wound healing through the suppression of excessive inflammatory responses. This research will inspire the development of anti-NLRP3 inflammasome agents as lead treatments and enhance knowledge pertaining to NPs derived from biosynthetic crosstalk.

Acute effects of a vigorous-intensity warm-up on response suppression and decision-making of football referees

ABSTRACT This study investigates the acute effect of physical exercise simulating a standard pre-competitive warm-up on the response suppression and decision-making of football referees. Thirty-four referees (n = 17 – regional level; n = 17 – national level) participated in the study. A Stop-Signal Task (SST) and a decision-making video test were used to evaluate the referees’ perceptual-cognitive functions. The findings revealed that the vigorous aerobic exercise acutely impacted basic cognitive functions, as indicated by decreased reaction time and decreased choice accuracy. However, higher-order cognitive functions such as response suppression and decision-making did not exhibit significant changes post-exercise. Based on these results, there is no evidence to suggest that a vigorous-intensity warm-up is likely to favour response suppression and decision-making factors in the initial phases of the game. National referees showed superior response suppression abilities (shorter stop-signal reaction times and lower probability of responding to the stop-signal) than regional referees, indicating that higher-level referees possess enhanced perceptual-cognitive skills, likely influenced by their experience. Further studies are required to determine whether these variables can be acutely improved through physical exercise. In this regard, our results suggest the need for alternative strategies in pre-competitive referee warm-ups if aiming to improve perceptual-cognitive skills in the initial phases of the game.

The Role of Satellites in the Evolution of Begomoviruses.

Begomoviruses have emerged as destructive pathogens of crops, particularly in the tropics and subtropics, causing enormous economic losses and threatening food security. Epidemics caused by begomoviruses have even spread in regions and crops that were previously free from these viruses. The most seriously affected crops include cassava; cotton; grain legumes; and cucurbitaceous, malvaceous, and solanaceous vegetables. Alphasatellites, betasatellites, and deltasatellites are associated with the diseases caused by begomoviruses, but begomovirus-betasatellite complexes have played significant roles in the evolution of begomoviruses, causing widespread epidemics in many economically important crops throughout the world. This article provides an overview of the evolution, distribution, and approaches used by betasatellites in the suppression of host plant defense responses and increasing disease severity.

A bacterial effector manipulates plant metabolism, cell death, and immune responses via independent mechanisms.

Bacterial pathogens inject effector proteins inside plant cells to manipulate cellular functions and achieve a successful infection. The soil-borne pathogen Ralstonia solanacearum (Smith), the causal agent of bacterial wilt disease, secretes > 70 different effectors inside plant cells, although only a handful of them have been thoroughly characterized. One of these effectors, named RipI, is required for full R. solanacearum pathogenicity. RipI associates with plant glutamate decarboxylases (GADs) to promote the accumulation of gamma-aminobutyric acid (GABA), which serves as bacterial nutrient. In this work, we found that RipI can also suppress plant immune responses to bacterial elicitors, which seems to be unrelated to the ability of RipI to induce GABA accumulation and plant cell death. A detailed characterization of the RipI features that contribute to its virulence activities identified two residues at the C-terminal domain that mediate RipI interaction with plant GADs and the subsequent promotion of GABA accumulation. These residues are also required for the appropriate homeostasis of RipI in plant cells and the induction of cell death, although they are partially dispensable for the suppression of plant immune responses. Altogether, we decipher and uncouple the virulence activities of an important bacterial effector at the biochemical level.

Role of Regulatory T Cells in Intracerebral Hemorrhage.

Intracerebral hemorrhage (ICH) is a common cerebrovascular disease that can lead to severe neurological dysfunction in surviving patients, resulting in a heavy burden on patients and their families. When ICH occurs, the blood‒brain barrier is disrupted, thereby promoting immune cell migration into damaged brain tissue. As important immunosuppressive T cells, regulatory T (Treg) cells are involved in the maintenance of immune homeostasis and the suppression of immune responses after ICH. Treg cells mitigate brain tissue damage after ICH in a variety of ways, such as inhibiting the neuroinflammatory response, protecting against blood‒brain barrier damage, reducing oxidative stress damage and promoting nerve repair. In this review, we discuss the changes in Treg cells in ICH clinical patients and experimental animals, the mechanisms by which Treg cells regulate ICH and treatments targeting Treg cells in ICH, aiming to support new therapeutic strategies for clinical treatment.

Extracorporeal organ support for critically ill patients: Overcoming the past, achieving the maximum at present, and redefining the future

Extracorporeal organ support (ECOS) has made remarkable progress over the last few years. Renal replacement therapy, introduced a few decades ago, was the first available application of ECOS. The subsequent evolution of ECOS enabled the enhanced support to many other organs, including the heart [veno-arterial extracorporeal membrane oxygenation (ECMO), slow continuous ultrafiltration], the lungs (veno-venous ECMO, extracorporeal carbon dioxide removal), and the liver (blood purification techniques for the detoxification of liver toxins). Moreover, additional indications of these methods, including the suppression of excessive inflammatory response occurring in severe disorders such as sepsis, coronavirus disease 2019, pancreatitis, and trauma (blood purification techniques for the removal of exotoxins, endotoxins, or cytokines), have arisen. Multiple organ support therapy is crucial since a vast majority of critically ill patients present not with a single but with multiple organ failure (MOF), whereas, traditional therapeutic approaches (mechanical ventilation for acute respiratory failure, antibiotics for sepsis, and inotropes for cardiac dysfunction) have reached the maximum efficacy and cannot be improved further. However, several issues remain to be clarified, such as the complexity and cost of ECOS systems, standardization of indications, therapeutic protocols and initiation time, choice of the patients who will benefit most from these interventions, while evidence from randomized controlled trials supporting their use is still limited. Nevertheless, these methods are currently a part of routine clinical practice in intensive care units. This editorial presents the past, present, and future considerations, as well as perspectives regarding these therapies. Our better understanding of these methods, the pathophysiology of MOF, the crosstalk between native organs resulting in MOF, and the crosstalk between native organs and artificial organ support systems when applied sequentially or simultaneously, will lead to the multiplication of their effects and the minimization of complications arising from their use.

SARS-CoV-2 Protein Nsp9 Is Involved in Viral Evasion through Interactions with Innate Immune Pathways.

The suppression of the host's innate antiviral immune response by SARS-CoV-2, a contributing factor to the severity of disease, has been considerably studied in recent years. Many of these studies have focused on the actions of the structural proteins of the virus because of their accessibility to host immunological components. However, less is known about SARS-CoV-2 nonstructural and accessory proteins in relation to viral evasion. Herein, we study SARS-CoV-2 nonstructural proteins Orf3a, Orf6, and Nsp9 in a mimicked virus-infected state using poly(I:C), a synthetic analog of viral dsRNA, that elicits the antiviral immune response. Through genome-wide expression profiling, we determined that Orf3a, Orf6, and Nsp9 all modulate the host antiviral signaling transcriptome to varying extents, uniquely suppressing aspects of innate immune signaling. Our data suggest that SARS-CoV-2 Nsp9 hinders viral detection through suppression of RIG-I expression and antagonizes the interferon antiviral cascade by downregulating NF-kB and TBK1. Our data point to unique molecular mechanisms through which the different SARS-CoV-2 proteins suppress immune signaling and promote viral evasion. Nsp9 in particular acts on major elements of the host antiviral pathways to impair the antiviral immune response.

H7 modulation of the L3 auditory neuron and phonotaxis in the cricket Acheta domesticus

AbstractSeveral studies have implicated the L3 auditory interneuron in the regulation of syllable period selective phonotaxis in female cricket Acheta domesticus. The L3's response to model calls of conspecific males comprises of an immediate and a prolonged response. The kinetics of activation of these electrical activities are consistent with sequential activation of ionotropic and metabotropic mechanisms. In this study, we used electrophysiological and pharmacological tools to investigate the cellular mechanisms underlying L3's response. Bath application of the synthetic protein kinase inhibitor 1‐(5‐isoquinolinesul‐fonyl)‐2‐methylpiperazine (H7), results in the suppression of L3's spiking response, and this effect can be reversed by saline wash. Additionally, when female A. domesticus that were previously nano‐injected with H7 were tested for phonotaxis on a non‐compensating treadmill, they demonstrated suppression of syllable period‐dependent phonotaxis. These findings implicate protein kinase in the regulation of L3's spiking rhythm and the associated phonotaxis in A. domesticus.

The advances on oral tolerance induction for prevention of egg allergy in infants

The prevalence of food allergy is increasing worldwide and seriously affects the living quality of patients and their families. Egg allergy is one of the commonest forms of food allergy. The traditional regimen is to delay the introduction of eggs to infant complementary foods, which is not able to reduce the prevalence of egg allergies and causes negative effects on infants' physical and psychological conditions. Oral tolerance therapy is an approach to establish immune tolerance by the active suppression of specific immune responses to antigens in the gastrointestinal tract. The development of oral tolerance through early introduction of eggs to infant complementary has proven effective in randomized controlled trials, which has been incorporated into infant feeding guidelines in many countries. This article focuses on the mechanism, efficacy and safety of oral tolerance induction in the prevention of egg allergy.

Juvenile Hormone as a contributing factor in establishing midgut microbiota for fecundity and fitness enhancement in adult female Aedes aegypti

Understanding the factors influencing mosquitoes’ fecundity and longevity is important for designing better and more sustainable vector control strategies, as these parameters can impact their vectorial capacity. Here, we address how mating affects midgut growth in Aedes aegypti, what role Juvenile Hormone (JH) plays in this process, and how it impacts the mosquito’s immune response and microbiota. Our findings reveal that mating and JH induce midgut growth. Additionally, the establishment of a native bacterial population in the midgut due to JH-dependent suppression of the immune response has important reproductive outcomes. Specific downregulation of AMPs with an increase in bacteria abundance in the gut results in increased egg counts and longer lifespans. Overall, these findings provide evidence of a cross-talk between JH response, gut epithelial tissue, cell cycle regulation, and the mechanisms governing the trade-offs between nutrition, immunity, and reproduction at the cellular level in the mosquito gut.

Opposing effects of pre-existing antibody and memory T cell help on the dynamics of recall germinal centers

Re-exposure to an antigen generates abundant antibody responses and drives the formation of secondary germinal centers (GCs). Recall GCs in mice consist almost entirely of naïve B cells, whereas recall antibodies derive overwhelmingly from memory B cells. Here, we examine this division between cellular and serum compartments. After repeated immunization with the same antigen, tetramer analyses of recall GCs revealed a marked decrease in the ability of B cells in these structures to bind the antigen. Boosting with viral variant proteins restored antigen binding in recall GCs, as did genetic ablation of primary-derived antibody-secreting cells through conditional deletion of Prdm1, demonstrating suppression of GC recall responses by pre-existing antibodies. In hapten-carrier experiments in which B and Tcell specificities were uncoupled, memory Tcell help allowed B cells with undetectable antigen binding to access GCs. Thus, antibody-mediated feedback steers recall GC B cells away from previously targeted epitopes and enables specific targeting of variant epitopes, with implications for vaccination protocols.

Testing the response suppression mechanism of working memory.

Many working memory (WM) paradigms involve recalling multiple items from the same memory set. Participants rarely repeat items they have already recalled, avoiding repetition errors. To prevent these errors, WM models incorporate a response suppression mechanism that removes recalled items from the set of response options. Despite its importance for our understanding of WM, response suppression has received limited direct testing. To address this gap, we used computational models implementing two hypothetical mechanisms of response suppression to derive predictions and tested these predictions experimentally. Participants were asked to recall the same items multiple times during a single trial. If already recalled items are removed from the response set to prevent repetition errors, memory performance should be impaired when the same item is tested again. Contrary to this, we found that memory performance was unimpaired when the same item was tested a second time, and even displayed a recall advantage. Therefore, this study demonstrates the implausibility of response suppression to account for how people avoid repetition errors. We discuss alternative explanations. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

INHIBITORY CONTROL IN CHILDREN WITH ATTENTİON DEFİCİT AND HYPERACTİVİTY DİSORDER

The article talks about inhibitory control, which is one of the executive functions in children with ADHD. These children always have impaired executive functions. However, executive dysfunction does not always mean ADHD. Evaluation of executive functions can help diagnose this neurodevelopmental disorder. One of the most common executive function deficits associated with ADHD is problems with inhibitory control. They find it difficult to control inappropriate or impulsive behavior, external interference, and therefore have trouble concentrating. Inhibition plays an important role in successful behavior, requiring the suppression of extraneous interference to focus attention, the ignoring of irrelevant cues to recall stored information, and the suppression of habitual responses to adaptive decision making. Impaired response inhibition directly affects four executive functions: working memory, self-regulation, language internalization, and restructuring. This, in turn, leads to difficulties with complex movements and goal-directed behavior, especially those related to motor control, verbal fluency, and syntax. Given the influence of inhibitory control on ADHD, the author argues that training that enhances inhibition may improve ADHD symptoms. A number of studies in this area have demonstrated the effectiveness of trainings designed to enhance inhibitory control.

Enhanced suppression of vibration response and energy transfer by using nonlinear hysteresis friction damper

Enhanced suppression of vibration response and energy transfer by using nonlinear hysteresis friction damper

Pars Opercularis Underlies Efferent Predictions and Successful Auditory Feedback Processing in Speech: Evidence From Left-Hemisphere Stroke.

Hearing one's own speech allows for acoustic self-monitoring in real time. Left-hemisphere motor planning regions are thought to give rise to efferent predictions that can be compared to true feedback in sensory cortices, resulting in neural suppression commensurate with the degree of overlap between predicted and actual sensations. Sensory prediction errors thus serve as a possible mechanism of detection of deviant speech sounds, which can then feed back into corrective action, allowing for online control of speech acoustics. The goal of this study was to assess the integrity of this detection-correction circuit in persons with aphasia (PWA) whose left-hemisphere lesions may limit their ability to control variability in speech output. We recorded magnetoencephalography (MEG) while 15 PWA and age-matched controls spoke monosyllabic words and listened to playback of their utterances. From this, we measured speaking-induced suppression of the M100 neural response and related it to lesion profiles and speech behavior. Both speaking-induced suppression and cortical sensitivity to deviance were preserved at the group level in PWA. PWA with more spared tissue in pars opercularis had greater left-hemisphere neural suppression and greater behavioral correction of acoustically deviant pronunciations, whereas sparing of superior temporal gyrus was not related to neural suppression or acoustic behavior. In turn, PWA who made greater corrections had fewer overt speech errors in the MEG task. Thus, the motor planning regions that generate the efferent prediction are integral to performing corrections when that prediction is violated.

The role of CRMP4 in LPS-induced neuroinflammation

Neuroinflammation has been gaining attention as one of the potential causes of neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis in recent years. The suppression of excessive proinflammatory responses is expected to be a target for the treatment and prevention of neurodegenerative diseases. Collapsin response mediator protein 4 (CRMP4) is involved in cytoskeleton-associated axonal guidance in the developing brain. Recently, the involvement of CRMP4 in several pathological conditions, including inflammation induced by lipopolysaccharide (LPS), a widely used inflammatory molecule, has been reported. However, the role of CRMP4 in LPS-induced inflammation in vivo remains largely unknown.In this study, we generated microglia-specific CRMP4 knockout mice for the first time and examined the role of CRMP4 in an LPS-induced brain inflammation model. We found that microglia after LPS injection in substantia nigra was significantly reduced in Crmp4-/- mice compared to Crmp4+/+mice. The increased expression of IL-10 in striatum samples was downregulated in Crmp4-/- mice. A significant reduction in Iba1 expression was also observed in microglia-specific Crmp4 knockout mice compared with that in control mice. In contrast, the expression of IL-10 did not change in these mice, whereas arginase 1 (Arg1) expression was significantly suppressed. These results demonstrate the involvement of CRMP4 in LPS-induced inflammation in vivo, that CRMP4 suppresses microglial proliferation in a cell-autonomous manner.

Amniotic fluid stem cell‐derived extracellular vesicles educate type 2 conventional dendritic cells to rescue autoimmune disorders in a multiple sclerosis mouse model

AbstractDendritic cells (DCs) are essential orchestrators of immune responses and represent potential targets for immunomodulation in autoimmune diseases. Human amniotic fluid secretome is abundant in immunoregulatory factors, with extracellular vesicles (EVs) being a significant component. However, the impact of these EVs on dendritic cells subsets remain unexplored. In this study, we investigated the interaction between highly purified dendritic cell subsets and EVs derived from amniotic fluid stem cell lines (HAFSC‐EVs). Our results suggest that HAFSC‐EVs are preferentially taken up by conventional dendritic cell type 2 (cDC2) through CD29 receptor‐mediated internalization, resulting in a tolerogenic DC phenotype characterized by reduced expression and production of pro‐inflammatory mediators. Furthermore, treatment of cDC2 cells with HAFSC‐EVs in coculture systems resulted in a higher proportion of T cells expressing the regulatory T cell marker Foxp3 compared to vehicle‐treated control cells. Moreover, transfer of HAFSC‐EV‐treated cDC2s into an EAE mouse model resulted in the suppression of autoimmune responses and clinical improvement. These results suggest that HAFSC‐EVs may serve as a promising tool for reprogramming inflammatory cDC2s towards a tolerogenic phenotype and for controlling autoimmune responses in the central nervous system, representing a potential platform for the study of the effects of EVs in DC subsets.