Inhibition Of Function Research Articles

CD59 double knockout mice express a CD59ba hybrid fusion protein that mediates insulin secretion.

CD59 is a cell-surface inhibitor of the terminal step in the complement cascade. However, in addition to its complement inhibitory function, a non-canonical role of CD59 in pancreatic beta cells has been identified. Two recently discovered intracellular alternative splice forms of CD59, IRIS-1 and IRIS-2, are involved in insulin exocytosis through interactions with SNARE-complex components. In mice, the CD59 gene has undergone duplication and to further explore the role of CD59 in insulin secretion, blood glucose homeostasis was studied in a CD59 double knockout (CD59abKO) mouse model. However, no phenotypic deviation related to insulin secretion or blood glucose homeostasis was observed for the CD59abKO mice. Instead, a CD59ba hybrid transcript formed as a consequence of the mutation induced to generate the model was identified. This hybrid transcript is expressed in pancreatic islets of the CD59abKO mice and is comprised of the remaining exons of the two CD59 genes spliced together. Similar to canonical CD59, the CD59ba hybrid was found to be glycosylated and present on the cell surface when exogenously expressed in INS-1 832/13 cells. Furthermore, INS-1 832/13 cells over-expressing the mouse CD59ba hybrid retained normal insulin secretion following siRNA-mediated knockdown of canonical CD59. Hence, although the CD59ba hybrid has lost the complement inhibitory function, the intracellular insulin secretory function remains. These results provide further information concerning the structural requirements of CD59 in its intracellular role relative to its role as a complement inhibitor. It also highlights the importance of carefully assessing plausible consequences of induced mutations in research models.

Concurrent oculomotor hyperactivity and deficient anti-saccade performance in obsessive-compulsive disorder

Existing studies mainly focused on the inhibition of the task-interfering response to understand the inhibitory deficits of obsessive-compulsive disorder (OCD). However, recent studies suggested that inhibitory function is broadly involved in response preparation and implementation. It is yet unknown if the inhibition dysfunction in OCD extends beyond the task-interfering response to the general inhibitory function. Here we address this issue based on the multidimensional eye-movement measurements, which can better capture the inhibitory deficits than manual responses. Thirty-one OCD patients and 32 healthy controls (HCs) completed the anti-saccade task where multidimensional eye-movement features were developed. Confirmatory factor analysis (CFA) suggested two components of inhibitory function that negatively correlated with each other: one component of oculomotor hyperactivity in generating oculomotor output which is characterized with early premature saccades, early cross rates and saccade number; the other component of task-specific oculomotor efficiency which is characterized with task accuracy, saccade latency, correction rate, and amplitude gain. Importantly, OCD showed both stronger oculomotor hyperactivity and deficient oculomotor efficiency than HCs, and the machine-learning-based classifications showed that the features of oculomotor hyperactivity had higher prediction accuracy than the features of oculomotor efficiency in distinguishing OCD from HCs. Our results suggested that OCD has concurrent deficits in oculomotor hyperactivity and oculomotor efficiency, which may originate from a common inhibitory dysfunction.

GABA in early brain development: A dual role review.

This comprehensive review examines the multifaceted roles of gamma-aminobutyric acid (GABA) in early brain development. GABA, traditionally recognized for its inhibitory functions in the mature brain, also exhibits excitatory effects during early neural development. This article explores the mechanisms behind GABA's dual roles, detailing its impact on the properties of the immature brain, the mechanisms of GABA-mediated excitation, the role of GABA-mediated presynaptic inhibition, the trophic actions of GABA during early development, GABA regulation of neurite growth and GABA-mediated cell differentiation in the immature brain. Emphasizing recent research findings, the review highlights the significance of GABAergic signalling in shaping the developing brain and its potential implications for understanding neurodevelopmental disorders.

IFITM1 is a host restriction factor that inhibits porcine epidemic diarrhea virus infection.

Porcine epidemic diarrhea virus (PEDV) infection and transmission pose a serious threat to the global swine industry. The search for a new host factor with anti-PEDV effect may be an effective potential target for the development of novel antiviral drugs. Interferon-induced transmembrane proteins (IFITMs) play a crucial role in the innate immune response triggered by viral infection, and it has been suggested that IFITMs can block the early stages of viral replication, but the mechanism of action is currently unclear. The current study sheds light on the role of IFITM1 in PEDV infection. Specifically, overexpression of IFITM1 suppresses PEDV proliferation in IPEC-J2 cells, while knockdown of IFITM1 has the opposite effect. Collectively, these findings underscore IFITM1's inhibitory role in PEDV infection, with critical implications for the residues and structural motifs within its CTD. The study demonstrates that IFITM1, an interferon-induced transmembrane protein, plays a critical role in the antiviral response against Porcine Epidemic Diarrhea Virus (PEDV). Notably: Overexpression of IFITM1 suppresses PEDV proliferation.IFITM1 co-localizes with PEDV virions in the cytoplasm surrounding the nucleus.Immunocolloidal gold electron microscopy reveals IFITM proteins embedded on the surface of PEDV virions.IFITM1 directly interacts with the N protein of PEDV.C-terminal domain mutations in IFITM1 compromise its inhibitory function against PEDV, with specific amino acid residues playing a pronounced role.These findings enhance our understanding of innate immunity and antiviral defense mechanisms, with potential implications for therapeutic strategies against PEDV infection. The study establishes IFITM1 as a key player in the antiviral response against PEDV. Its inhibitory function, co-localization with virions, and interaction with the N protein provide valuable insights. Notably, the CTD mutations of IFITM1 have a fundamental impact on its modulatory action. These findings contribute to our understanding of innate immunity and antiviral defense mechanisms, with potential implications for therapeutic strategies against PEDV infection.

Prenatal Exposure to MAM Impairs mPFC and Hippocampal Inhibitory Function in Mice during Adolescence and Adulthood.

Neurodevelopmental abnormalities are considered to be one of the important causes of schizophrenia. The offspring of methylazoxymethanol acetate (MAM)-exposed mice are recognized for the dysregulation of neurodevelopment and are well-characterized with schizophrenia-like phenotypes. However, the inhibition-related properties of the medial prefrontal cortex (mPFC) and hippocampus throughout adolescence and adulthood have not been systematically elucidated. In this study, both 10 and 15 mg/kg MAM-exposed mice exhibited schizophrenia-related phenotypes in both adolescence and adulthood, including spontaneous locomotion hyperactivity and deficits in prepulse inhibition. We observed that there was an obvious parvalbumin (PV) loss in the mPFC and hippocampus of MAM-exposed mice, extending from adolescence to adulthood. Moreover, the frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) in pyramidal neurons at mPFC and hippocampus was significantly dampened in the 10 and 15 mg/kg MAM-exposed mice. Furthermore, the firing rate of putative pyramidal neurons in mPFC and hippocampus was increased, while that of putative inhibitory neurons was decreased during both adolescence and adulthood. In conclusion, PV loss in mPFC and hippocampus of MAM-exposed mice may contribute to the impaired inhibitory function leading to the attenuation of inhibition in the brain both in vitro and in vivo.

Involvement of neurons in the non-human primate anterior striatum in proactive inhibition.

Behaving as desired requires selecting the appropriate behavior and inhibiting the selection of inappropriate behavior. This inhibitory function involves multiple processes, such as reactive and proactive inhibition, instead of a single process. In this study, two male macaque monkeys were required to perform a task in which they had to sequentially select (accept) or refuse (reject) a choice. Neural activity was recorded from the anterior striatum, which is considered to be involved in behavioral inhibition, focusing on the distinction between proactive and reactive inhibitions. We identified neurons with significant activity changes during the rejection of bad objects. Cluster analysis revealed three distinct groups, of which only one showed increased activity during object rejection, suggesting its involvement in proactive inhibition. This activity pattern was consistent irrespective of the rejection method, indicating a role beyond saccadic suppression. Furthermore, minimal activity changes during the fixation task indicated that these neurons were not primarily involved in reactive inhibition. In conclusion, these findings suggest that the anterior striatum plays a crucial role in cognitive control and orchestrates goal-directed behavior through proactive inhibition, which may be critical in understanding the mechanisms of behavioral inhibition dysfunction that occur in patients with basal ganglia disease.Significance statement This study revealed a group of neurons in the anterior striatum that plays a crucial role in cognitive control by actively participating in the rejection of unfavorable choices. Contrary to previous belief, these neurons were involved in proactive inhibition (i.e., the process of discarding unnecessary options), instead of suppressing automatic responses, to achieve a goal. This distinction is vital for understanding the mechanisms by which the brain makes decisions and may have implications for addressing neurological disorders associated with impaired decision-making and inhibitory control. Our findings provide new insights into the neural mechanisms underlying goal-directed behavior and highlight the importance of the anterior striatum in orchestrating complex cognitive functions.

Transcutaneous spinal cord stimulation neuromodulates pre- and postsynaptic inhibition in the control of spinal spasticity.

Aside from enabling voluntary control over paralyzed muscles, a key effect of spinal cord stimulation is the alleviation of spasticity. Dysfunction of spinal inhibitory circuits is considered a major cause of spasticity. These circuits are contacted by Ia muscle spindle afferents, which are also the primary targets of transcutaneous lumbar spinal cord stimulation (TSCS). We hypothesize that TSCS controls spasticity by transiently strengthening spinal inhibitory circuit function through their Ia-mediated activation. We show that 30min of antispasticity TSCS improves activity in post- and presynaptic inhibitory circuits beyond the intervention in ten individuals with traumatic spinal cord injury to normative levels established in 20 neurologically intact individuals. These changes in circuit function correlate with improvements in muscle hypertonia, spasms, and clonus. Our study opens the black box of the carryover effects of antispasticity TSCS and underpins a causal role of deficient post- and presynaptic inhibitory circuits in spinal spasticity.

Drug Repurposing and Screening for Multiple Sclerosis Targeting Microglia and Macrophages.

Microglia/macrophages (MG/Mφ) play a central role in the pathogenesis of multiple sclerosis (MS). However, the intricacies of the immunomodulatory microenvironment in MS, particularly the heterogeneity and regulatory mechanisms of MG/Mφ subpopulations, remain elusive. The commonly used treatment options for MS have several drawbacks, such as significant side effects and uncertain efficacy. The exploration of developing new drugs targeting MG/Mφ for the treatment of MS remains to be investigated. We identified three distinct subpopulations of MG/Mφ, among which MG/Mφ_3 significantly increased as the experimental autoimmune encephalomyelitis (EAE) progressed. Ifenprodil and RO-25-6981 demonstrated notable inhibition of inflammatory factor expression, accompanied by reduced cytotoxicity. The interaction modes of these compounds with the common binding pocket in the GluN1b-GluN2B amino terminal domain heterodimer were elucidated. Virtual docking, based on the N-methyl-D-aspartate (NMDA) receptor, showed that homo-skeleton compounds of ifenprodil potentially exhibit low binding free energy with the receptor, including eliprodil and volinanserin. In vitro cell models corroborated the effective inhibition of inflammatory factor expression and minimal cytotoxicity of eliprodil and volinanserin. CoMFA (standard error of estimate = 0.378, R2 = 0.928, F values = 241.255, Prob. of R2 = 0) and topomer CoMFA (q2 = 0.553, q2 stderr = 0.77, intercept = - 1.48, r2 = 0.908, r2 stderr = 0.35) were established based on the inhibitors of NMDA receptor. The contour maps of CoMFA and topomer CoMFA models give structural information to improve the inhibitory function. This study underscores the involvement of MG/Mφ in inflammatory pathways during MS progression and offers promising compound candidates for MS therapy targeting MG/Mφ.

The Mechanism of the Nucleus Accumbens-Ventral Pallidum Pathway Mediated by Drug Withdrawal-Induced High-Seeking Motivation in Cocaine Addiction.

The reinforcement of drug-seeking motivation following drug withdrawal is recognized as a significant factor contributing to relapse. The ventral pallidum (VP) plays a crucial role in encoding and translating motivational aspects of reward. However, current research lacks a clear understanding of how the VP mediates drug-seeking motivation and the feedback modulation between the VP and the nucleus accumbens (NAc) following drug withdrawal. Therefore, utilizing a rat model of cocaine self-administration, we investigated the circuitry mechanisms underlying drug-seeking behavior post-drug withdrawal involving the NAc-VP pathway. Initially, we observed a significant enhancement in drug-seeking behavior 14 days after cocaine withdrawal. Subsequently, we identified the feedback mechanism through which the NAc-VP regulates this behavior. Immunofluorescence results indicated an increase in c-Fos expression levels in the ventral pallidum ventromedial (VPvm) and ventrolateral ventral pallidum (VPvl) following drug withdrawal. Calcium fiber photometry further elucidated that during the expression of high motivational drug-seeking behavior, there was a specific enhancement in VPvm neuronal activity, and retrograde tracing techniques suggested a weakened transmission function in the NAc-VPm pathway. Additionally, chemical genetic techniques demonstrated that inhibiting the activity of the NAc-VP pathway could increase the motivational level of drug-seeking behavior. These findings indicate that the reduced inhibitory function of the NAc-VP pathway following prolonged cocaine withdrawal forms the basis for heightened reactivity in VPvm neurons, thus regulating the expression of high motivational behavior triggered by drug-related cues. Our study results suggest that maintaining normal NAc-VP pathway functionality may decrease drug-seeking motivation post long-term drug withdrawal, offering new insights for interventions targeting relapse.

Prolonged Hyperactivity Elicits Massive and Persistent Chloride Ion Redistribution in Subsets of Cultured Hippocampal Dentate Granule Cells.

Maintaining low [Cl - ] in is important for inhibitory function, however, hyperactivity, such as that seen in epilepsy, may lead to elevated [Cl - ] in. Pilocarpine induces hyperactivity in dentate granule cells (DGCs) in hippocampal organotypic slice cultures. Multicellular imaging using a chloride sensing dye with a fluorescence lifetime imaging approach revealed that [Cl - ] in is elevated in a subpopulation of DGCs. Gaussian mixture model analysis is a powerful tool for studying the emergence of cellular heterogeneity in a pathological condition.

Mechanism of APC truncation involved in colorectal cancer tumorigenesis (Review).

Adenomatous polyposis coli (APC) is widely recognized as a heavily mutated gene that suppresses tumor growth in colorectal cancer (CRC). Its mutation is considered to be the primary and early event that occurs in the development of CRC. In addition, APC has a crucial role in inhibiting the canonical Wnt signaling pathway. APC mutations in CRC result in the production of shortened gene products. This impairment of β-catenin destruction complexes causes an accumulation of active β-catenin in the cytoplasm and nucleus. In these compartments, β-catenin can bind with DNA-binding proteins of the transcription factor/lymphoid enhancer-binding factor family, thereby activating the Wnt signaling pathway. Consequently, the balance of numerous cellular processes is disrupted, ultimately driving the formation of tumors. There is a growing body of evidence indicating the prevalent occurrence of APC truncation in the majority of CRC cases. Furthermore, it has been observed that these truncated proteins have a crucial role in the activation of the Wnt signaling pathway and the subsequent loss of tumor inhibitory function. This review aimed to provide an overview of the recent advancements in understanding the mechanism behind APC truncation and its association with the onset and progression of CRC.

Translational research on cognitive impairment in chronic kidney disease.

Cognitive decline is common in patients with acute or chronic kidney disease. Several areas of brain function can be affected, including short and long-term memory, attention and inhibitory control, sleep, mood, eating control and motor function. Cognitive decline in kidney disease shares risk factors with cognitive dysfunction in people without kidney disease, such as diabetes, high blood pressure, sedentary lifestyle and unhealthy diet. However, additional kidney-specific risk factors may contribute, such as uremic toxins, electrolyte imbalances, chronic inflammation, acid-base disorders or endocrine dysregulation. Traditional and kidney-specific risk factors may interact to cause damage to the blood-brain barrier, induce vascular damage in the brain, and cause neurotoxicity or neuroinflammation. Here, we discuss recent insights into the pathomechanisms of cognitive decline from animal models and novel avenues for prevention and therapy. We focus on a several areas that influence cognition: blood-brain barrier disruption, the role of skeletal muscle, physical activity and the endocrine factor irisin, and the emerging therapeutic role of sodium-glucose transporter 2 (SGLT2) inhibitors and glucagon-like peptide 1 (GLP-1) receptor agonists. Taken together, these studies demonstrate the importance of animal models in providing a mechanistic understanding of this complex condition and their potential to explain the mechanisms of novel therapies.

A molecular dynamics investigation into the inhibitory function of hydroxypropyl-beta-cyclodextrin (HPBCD) in its interaction with amyloid-beta (Aβ) plaques near the cell membrane in the context of Alzheimer's disease.

Although Alzheimer`s disease has been known for a long time, it is interesting that scientists are still doing widespread research on it. Meanwhile, in parallel with experimental research, computational research is also yielding interesting results. In this study, we investigated the inhibitory behavior of hydroxypropyl-beta-cyclodextrin (HPBCD) drug candidates, which are more soluble than beta-cyclodextrin (BCD), using molecular dynamics simulations and compared them with AC0107 new drug. Parameters such as cell membrane stability, protein stability, drug inhibition rate, protein permeability, hydrogen bonding agents, the study of the energy content of interactions between different groups, and interactions between different species were of interest. The outcomes indicate that the drug candidate HPBCD has a role in inhibiting protein membrane penetration and has better performance than new AC0107 drug. In other words, HPBCD not only act as a drug carrier of Alzheimer's disease, but also as an inhibitor of it and can play a double role in its improvement.

Disruptive compensatory mechanisms in fibromyalgia syndrome and their association with pharmacological agents.

Fibromyalgia syndrome (FMS) is a chronic disorder characterized commonly by widespread musculoskeletal pain and fatigue, predominantly affecting women, with its complexity often leading to underdiagnosis and complicating treatment effectiveness. Transcranial magnetic stimulation (TMS) metrics are potential markers to optimize FMS treatments; however, evidence is limited. Our study aimed to explore the relationship between cortical excitability and inhibition, assessed through TMS markers, and clinical characteristics in patients with FMS. This presented cross-sectional study employed baseline data from a clinical trial with 108 FMS patients, mostly female (88.8%), and mean age of 47.3 years old (SD = 12.06). Our analysis showed that decreased short-intracortical inhibition (SICI) was associated with gabapentinoids use, nicotine history, and increased fatigue levels, suggesting its connection with compensatory mechanisms for non-painful FMS features. Increased motor intracortical facilitation (ICF) was linked with greater pain severity and shorter FMS duration, implying its relationship with a reorganization of sensorimotor pathways due to chronic pain. Additionally, higher resting motor threshold (rMT) was associated with less effective pain modulation (lower conditioned pain modulation [CPM]), indicating a disruption of pain compensatory mechanism. Given the role of SICI in indexing homeostatic brain mechanisms and its association with fatigue, a hallmark characteristic of FMS-induced behavioral changes, these results suggest that FMS likely has a deleterious effect on brain inhibitory function, thus providing a potential novel insight for FMS mechanisms. In addition, it seems that this compensatory mechanism's disruption is enhanced by pharmacological agents such as gabapentioids and nicotine.

Single-cell landscape of bronchoalveolar immune cells in patients with immune checkpoint inhibitor-related pneumonitis

The pathophysiology of immune checkpoint inhibitor-related pneumonitis remains incompletely understood. We conducted single-cell and T-cell receptor transcriptomic sequencing on the bronchoalveolar lavage fluid from five patients with grade ≥2 immune checkpoint inhibitor-related pneumonitis. Our analyses revealed a prominent enrichment of T cells in the bronchoalveolar lavage fluid of patients with immune checkpoint inhibitor-related pneumonitis. Within the CD4 + T cell subset, Tfh-like T cells were highly enriched and exhibited signatures associated with inflammation and clonal expansion. Regulatory T cells were also enriched and displayed enhanced inhibitory functions. Within the CD8 + T-cell subset, effector memory/tissue-resident memory T cells with an elevated cytotoxic phenotype were highly infiltrated. Among myeloid cells, alveolar macrophages were depleted, while pro-inflammatory intermediate monocytes were elevated. Dendritic cells demonstrated enhanced antigen presentation capabilities. Cytokines CXCR4, CXCL13, TNF-α, IFN-α, IFN-γ, and TWEAK were elevated. Through a comprehensive single-cell analysis, we depicted the landscape of immune checkpoint inhibitor-related pneumonitis.

A cofactor-induced repressive type of transcription factor condensation can be induced by synthetic peptides to suppress tumorigenesis.

Transcriptional factors (TFs) act as key determinants of cell death and survival by differentially modulating gene expression. Here, we identified many TFs, including TEAD4, that form condensates in stressed cells. In contrast to YAP-induced transcription-activating condensates of TEAD4, we found that co-factors such as VGLL4 and RFXANK alternatively induced repressive TEAD4 condensates to trigger cell death upon glucose starvation. Focusing on VGLL4, we demonstrated that heterotypic interactions between TEAD4 and VGLL4 favor the oligomerization and assembly of large TEAD4 condensates with a nonclassical inhibitory function, i.e., causing DNA/chromatin to be aggregated and entangled, which eventually impede gene expression. Based on these findings, we engineered a peptide derived from the TEAD4-binding motif of VGLL4 to selectively induce TEAD4 repressive condensation. This "glue" peptide displayed a strong antitumor effect in genetic and xenograft mouse models of gastric cancer via inhibition of TEAD4-related gene transcription. This new type of repressive TF phase separation exemplifies how cofactors can orchestrate opposite functions of a given TF, and offers potential new antitumor strategies via artificial induction of repressive condensation.

Human IL-22 receptor-targeted small protein antagonist suppress murine DSS-induced colitis

BackgroundHuman interleukin-22 (IL-22) is known as a “dual function” cytokine that acts as a master regulator to maintain homeostasis, structural integrity of the intestinal epithelial barrier, and shielding against bacterial pathogens. On the other hand, the overexpression of IL-22 is associated with hyper-proliferation and recruitment of pathologic effector cells, leading to tissue damage and chronic inflammation in specific diseases including inflammatory bowel disease (IBD). To study a role of IL-22-mediated signaling axis during intestinal inflammation, we generated a set of small protein blockers of IL-22R1 and verified their inhibitory potential on murine model of colitis.MethodsWe used directed evolution of proteins to identify binders of human IL-22 receptor alpha (IL-22R1), designated as ABR ligands. This approach combines the assembly of a highly complex combinatorial protein library derived from small albumin-binding domain scaffold and selection of promising protein variants using ribosome display followed by large-scale ELISA screening. The binding affinity and specificity of ABR variants were analyzed on transfected HEK293T cells by flow cytometry and LigandTracer. Inhibitory function was further verified by competition ELISA, HEK-Blue IL-22 reporter cells, and murine dextran sulfate sodium (DSS)-induced colitis.ResultsWe demonstrate that ABR specifically recognizes transgenic IL-22R1 expressed on HEK293T cells and IL-22R1 on TNFα/IFNγ-activated HaCaT cells. Moreover, some ABR binders compete with the IL-22 cytokine and function as IL-22R1 antagonists in HEK-Blue IL22 reporter cells. In a murine model of DSS-induced acute intestinal inflammation, daily intraperitoneal administration of the best IL-22R1 antagonist, ABR167, suppressed the development of clinical and histological markers of colitis including prevention of mucosal inflammation and architecture deterioration. In addition, ABR167 reduces the DSS-induced increase in mRNA transcript levels of inflammatory cytokines such as IL-1β, IL-6, IL-10, and IL-17A.ConclusionsWe developed small anti-human IL-22R1 blockers with antagonistic properties that ascertain a substantial role of IL-22-mediated signaling in the development of intestinal inflammation. The developed ABR blockers can be useful as a molecular clue for further IBD drug development.

Effects of total sleep deprivation on functional connectivity of the anterior cingulate cortex: Insights from resting-state fMRI in healthy adult males

Inadequate sleep significantly impacts an individual's health by compromising inhibitory control and self-regulation abilities. This study employed resting-state functional magnetic resonance imaging (fMRI) to assess the functional connectivity between the anterior cingulate cortex (ACC) and the whole brain in 16 healthy adult males after 36 h of total sleep deprivation. Additionally, this study investigated alterations in individuals' inhibitory control functions and physiological mechanisms following sleep deprivation. The results showed a significant increase in functional connectivity between the ACC, the left angular gyrus, and the right hippocampus following 36 h of continuous sleep deprivation. Conversely, functional connectivity was notably decreased between the ACC and the right insular cortex, right paracingulate gyrus, and bilateral putamen. Furthermore, changes in ACC functional connectivity were significantly correlated with alterations in behavioral performance in the go/no-go task after sleep deprivation. This study contributes to understanding brain network mechanisms in the anterior cingulate gyrus after sleep deprivation. It clarifies the relationship between functional connectivity changes in the anterior cingulate gyrus and inhibitory control post-sleep deprivation.

The mechanism of MMP14-positive tumor-associated fibroblast subsets in inhibiting PD-1 immunotherapy for esophageal cancer through exosomal tsRNA-10522

Esophageal cancer (EC) continues to pose a significant health risk. Cancer-associated fibroblasts (CAFs), an essential part of the tumor microenvironment (TME), are viewed as potential therapeutic targets. However, their role in tumor mechanisms specific to esophageal cancer remains to be elucidated. This study identified MMP14+ CAFs and MMP14- CAFs using immunofluorescence staining. The cytotoxic activity of CD8 T cells was assessed via western blot and ELISA. Using a transwell test, the migratory potential of MMP14+ CAFs was evaluated. Using flow cytometry, apoptosis was found in the esophageal squamous cell carcinoma cell line KYSE30. To determine the important tsRNAs released by MMP14+ CAFs, tsRNA-seq was used. Two subgroups of EC receiving PD-1 immunotherapy were identified by our research: MMP14+ CAFs and MMP14- CAFs. MMP14+ CAFs showed improved migratory capacity and released more inflammatory factors linked to cancer. Through exosomes, these CAFs may prevent anti-PD-1-treated CD8 T cells from being cytotoxic. Furthermore, exosomal tsRNA from MMP14+ CAFs primarily targeted signaling pathways connected with cancer. Notably, it was discovered that tsRNA-10522 plays a critical role within inhibiting CD8 T cell tumor cell death. The tumor cell killing of CD8 T cells by exosomal tsRNA-10522 is inhibited by a subgroup of cells called MMP14+ CAFs inside the EC microenvironment during PD-1 immunotherapy. This reduces the effectiveness of PD-1 immunotherapy for EC. Our findings demonstrate the inhibitory function of MMP14+ CAFs within EC receiving PD-1 immunotherapy, raising the prospect that MMP14+ CAFs might serve as predictive indicators in EC receiving PD-1 immunotherapy.

Executive functions involved in thought suppression: An attempt to integrate research in two paradigms

There are two main thought suppression research paradigms: the White Bear and Think/No-Think paradigms. In Think/No-Think research, thought suppression is effective and is considered to be mediated by prepotent response inhibition. Conversely, in White Bear studies, thought suppression is counterproductive and appears to engage resistance to proactive interference. However, findings regarding the involvement of these executive functions in each task are mixed. In the current study, two thought suppression procedures were compared. Using Friedman and Miyake’s inhibitory functions model (2004) it was investigated whether the differences between thought suppression tasks can be explained by involvement of different executive functions. The results showed that the suppression phases of both procedures were correlated, but the outcomes of suppression were unrelated. There was no evidence supporting the involvement of the examined executive functions in either thought suppression task. Commonalities and discrepancies of the two tasks are discussed along with their external validity.