Mutual Activation Research Articles

Infiltrated monocyte and T cell interaction drives immunopathology in the brain during cryptococcal meningoencephalitis

Abstract Cryptococcal meningoencephalitis (CM) is a major cause of central nervous system (CNS)-linked mortality worldwide. High mortality frequently occurs despite antifungal drug treatment and pathogen elimination, and increasing evidence suggests over-exuberant host immune responses promote CM pathogenesis. Our goal was to dissect the role of two major groups of cells recruited to CNS (myeloid cell and T cell) and determine whether and how their crosstalk drives CM immunopathology. To study this, we developed a murine model that reproduces major features of human CM. Using this model, we found mice mortality did not directly correlate with CNS fungal burden, but instead was synchronized with the accumulation of ultra-Th1 polarized CD4 T cells and CCR2+ monocytes (Mo). Recruitment of Mo into the CNS was impaired in CCR2−/− mice, and these mice survived significantly longer and displayed fewer neurological symptoms despite higher brain fungal burden compared to WT mice. Mechanistically, we found that 1) CCR2+ Mo contributed to CXCR3+IFNγhi CD4 T cell accumulation and their ultra-Th1 polarization through modulating CXCL9/CXCL10 production. 2) CXCR3 deletion resulted in diminished CD4 T cell recruitment, Th1 polarization and conferred markedly protection against CM mortality; 3) robust IFNγ production by CD4 T cells corresponded to massive iNOS expression in Mo, which propose excessive NO production potentially contributes to neuronal injury. Collectively, we showed CCR2+ Mo and CXCR3+ CD4 T cells interact to promote mutual recruitment and activation, causing profound CNS damage during CM. Regulation of Mo and T cell function may become therapeutic strategy to aid current anti-fungal drug treatment that is frequently ineffective.

A mutual activation loop between the Ca2+-activated chloride channel TMEM16A and EGFR/STAT3 signaling promotes breast cancer tumorigenesis.

The Ca2+-activated chloride channel TMEM16A (anoctamin 1) is overexpressed in breast cancer. It remains unclear how TMEM16A overexpression plays a role in carcinogenesis in breast cancer. In this study, we found that high TMEM16A expression in combination with high EGFR or STAT3 expression was significantly associated with shorter overall survival in ER-positive breast cancer patients without tamoxifen treatment, and longer overall survival in patients with tamoxifen treatment. EGFR/STAT3 signaling activation by EGF promoted TMEM16A expression, and TMEM16A overexpression activated EGFR/STAT3 signaling in breast cancer cells. Both in vitro and in animal studies showed that TMEM16A overexpression promoted, and TMEM16A knockdown inhibited breast cancer cell proliferation and tumor growth. In addition, TMEM16A overexpression-induced cell proliferation was blocked by EGFR/STAT3 inhibitors, and TMEM16A knockdown reduced EGF-induced proliferation and tumorigenesis in breast cancer. Furthermore, inhibition of TMEM16A channel function effectively reduced breast cancer cell proliferation, especially in combination with EGFR inhibitors. Our findings identify a mutual activation loop between TMEM16A and EGFR/STAT3 signaling, which is important for breast cancer proliferation and growth. TMEM16A inhibition may represent a novel therapy for EGFR-expressing breast cancer.

B cell primary immune responses.

B cell primary immune responses.

Dynamics of Xavi Hernández’s game: A vectorial study through polar coordinate analysis

The evolution of soccer over the past 30 years has brought about a faster pace of play and more demanding player dynamics that have led to a paradigm shift in how the game is analyzed. Classic, purely descriptive studies of midfielder performance paint a disjointed picture that is far from the reality of the complex network of relationships and interactions that mark modern-day soccer. The aim of this study was to investigate the relationships established by Xavier “Xavi” Hernández, captain of FC Barcelona and a member of the Spanish national team for many years, during his participation in the final stages of the 2012 UEFA European Football Championship. The authors studied Xavi’s relationship with other players on the pitch, the areas in which his interventions started and ended, his use of technical–tactical skills, and his involvement in set plays. A modified version of a purpose-designed observation instrument was used within an observational methodology study. The data were analyzed by polar coordinate analysis, which is a powerful data reduction technique that reveals significant prospective and retrospective relationships between a focal behavior (Xavi) and other behaviors of interest. The results show that Xavi presents a mutual activation with behaviors from J6 (Iniesta) and J21 (Silva) and significant relationships in attack set-up zones. He is also the most important player in set piece situations, when he uses technical behaviors of control and passing. Studies on tactical performance should analyze all inputs of play and focus on a deep, layered analysis of results to facilitate the work of soccer coaches and educators.

Dual inhibitors of RAF-MEK-ERK and PI3K-PDK1-AKT pathways: Design, synthesis and preliminary anticancer activity studies of 3-substituted-5-(phenylamino) indolone derivatives.

The dysfunction and mutual compensatory activation of RAF-MEK-ERK and PI3K-PDK1-AKT pathways have been demonstrated as the hallmarks in several primary and recurrent cancers. The strategy of concurrent blocking of these two pathways shows clinical merits on effective cancer therapy, such as combinatory treatments and dual-pathway inhibitors. Herein, we report a novel prototype of dual-pathway inhibitors by means of merging the core structural scaffolds of a MEK1 inhibitor and a PDK1 inhibitor. A library of 43 compounds that categorized into three series (Series I-III) was synthesized and tested for antitumor activity in lung cancer cells. The results from structure-activity relationship (SAR) analysis showed the following order of antitumor activity that 3-hydroxy-5-(phenylamino) indolone (Series III) > 3-alkenyl-5-(phenylamino) indolone (Series I) > 3-alkyl-5-(phenylamino) indolone (Series II). A lead compound 9za in Series III showed most potent antitumor activity with IC50 value of 1.8 ± 0.8 µM in A549 cells. Moreover, antitumor mechanism study demonstrated that 9za exerted significant apoptotic effect, and cellular signal pathway analysis revealed the potent blockage of phosphorylation levels of ERK and AKT in RAF-MEK-ERK and PI3K-PDK1-AKT pathways, respectively. The results reported here provide robust experimental basis for the discovery and optimization of dual pathway agents for anti-lung cancer therapy.

Construction of a Ce3+doped CeO2/Bi2MoO6heterojunction with a mutual component activation system for highly enhancing the visible-light photocatalytic activity for removal of TC or Cr(vi)

A synergetic effect of a mutual activation system enhancing the photo-oxidation and reduction ability of a C-BMO heterojunction.

P.2.28 Mutual activation of muscarinic and mGlu2 receptors as a new treatment of schizophrenia-related cognitive deficits

There is little known about real world psychopharmacological prescribing practices in managing pregnant women with severe mental illness (SMI). This study utilised a sample of 535 women with a SMI across two hospitals in Australia. This included women with psychotic disorders, bipolar disorder and a range of non-psychotic disorders. The majority of women with a SMI in pregnancy were prescribed psychotropic medication as part of their management. Furthermore, more than one class of agent was prescribed for 31% of women with psychotic disorders and 30% of women with bipolar disorder. Differences between sites were identified in prescribing practices across the mental disorders. This included the variation in rates of use of multiple agents and pattern of use across pregnancy. This study also identified that women with a SMI had elevated rates of gestational hypertension, gestational diabetes mellitus, smoking and obesity in pregnancy and neonates admitted following delivery compared with the Australian average. These findings suggest that studies that examine associated risks for severe mental disorders or their treatments on pregnancy and infant outcomes should take into account the prescribing practices including the likelihood of exposure to polypharmacy and a range of potential confounding co-morbidities and exposures. The discrepancies in reported findings for pregnancy and infant outcomes following use of antipsychotic and mood stabiliser agents such as lithium may be at least partially accounted for by the complexity of multiple exposures that includes use of multiple psychopharmacological agents, co-exposures such as smoking and co-morbid conditions such as obesity.

Mutual activation of glutamatergic mGlu4 and muscarinic M4 receptors reverses schizophrenia-related changes in rodents

RationaleMetabotropic glutamate receptors and muscarinic M4 receptors have been proposed as novel targets for various brain disorders, including schizophrenia. Both receptors are coupled to Go/i proteins and are expressed in brain circuits that are important in schizophrenia. Therefore, their mutual activation may be an effective treatment and allow minimizing the doses of ligands required for optimal activity.ObjectivesIn the present studies, subactive doses of mGlu4 and M4 activators (LSP4-2022 and VU152100, respectively) were administered to investigate the mutual interaction between mGlu4 and M4 receptors in animal models of schizophrenia.MethodsThe behavioral tests used were MK-801-induced hyperactivity, (±)-2.5-dimethoxy-4-iodoamphetamine hydrochloride (DOI)-induced head twitches, the modified forced swim test, and MK-801-induced disruptions of social interactions and novel object recognition. DOI-induced spontaneous excitatory postsynaptic currents (sEPSCs) in brain slices and positron emission tomography (PET) in were used to establish the ability of these compounds to modulate the glutamatergic and dopaminergic systems. Rotarod was used to assess putative adverse effects.ResultsThe mutual administration of subactive doses of LSP4-2022 and VU152100 exerted similar antipsychotic-like efficacy in animals as observed for active doses of both compounds, indicating their additive actions. VU152100 inhibited the DOI-induced frequency (but not amplitude) of sEPSCs in the frontal cortex, confirming presynaptic regulation of glutamate release. Both compounds reversed amphetamine-induced decrease in D2 receptor levels in the striatum, as measured with [18F]fallypride. The compounds did not induce any motor impartments when measured in rotarod test.ConclusionsBased on our results, the simultaneous activation of M4 and mGlu4 receptors is beneficial in reversing MK-801- and amphetamine-induced schizophrenia-related changes in animals.

Tescalcin/c-Src/IGF1R\u03b2-mediated STAT3 activation enhances cancer stemness and radioresistant properties through ALDH1

Tescalcin (TESC; also known as calcineurin B homologous protein 3, CHP3) has recently reported as a regulator of cancer progression. Here, we showed that the elevation of TESC in non-small cell lung cancer (NSCLC) intensifies epithelial-mesenchymal transition (EMT) and cancer stem cell (CSC) properties, consequently enhancing the cellular resistance to γ-radiation. TESC expression and the phosphorylation (consequent activation) of signal transducer and activator of transcription 3 (STAT3) were upregulated in CSC-like ALDH1high cells than in ALDH1low cells sorted from A549 NSCLC cells. Knockdown of TESC suppressed CSC-like properties as well as STAT3 activation through inhibition of insulin-like growth factor 1 receptor (IGF1R), a major signaling pathway of lung cancer stem cells. TESC activated IGF1R by the direct recruitment of proto-oncogene tyrosine kinase c-Src (c-Src) to IGF1Rβ complex. Treatment of IGF1R inhibitor, AG1024, also suppressed c-Src activation, implicating that TESC mediates the mutual activation of c-Src and IGF1R. STAT3 activation by TESC/c-Src/IGF1R signaling pathway subsequently upregulated ALDH1 expression, which enhanced EMT-associated CSC-like properties. Chromatin immunoprecipitation and luciferase assay demonstrated that STAT3 is a potential transcription activator of ALDH1 isozymes. Ultimately, targeting TESC can be a potential strategy to overcome therapeutic resistance in NSCLC caused by augmented EMT and self-renewal capacity.

Highly Efficient and Diastereoselective Construction of Trifluoromethyl-Containing Spiro[pyrrolidin-3,2'-oxindole] by a Catalyst-free Mutually Activated [3+2] Cycloaddition Reaction.

A catalyst-free self-catalyzed [3+2] cycloaddition reaction of isatin-derived α-(trifluoromethyl)imines with vinylpyridines is reported. The reaction offers a straightforward and atom-economical procedure for the preparation of a series of 5'-trifluoromethyl-spiro[pyrrolidin-3,2'-oxindoles] in excellent yields and diastereoselectivities. The reaction mechanism has been investigated by control experiments, DFT calculation of pKa values and the kinetic profiles, revealing that this reaction featured the mutual activation between isatin-derived α-(trifluoromethyl)imines and vinylpyridine to generate the reactive species.

The association of motor information and verbal information: a new perspective on the mechanism of the SPT effect

ABSTRACTCurrent perspectives on the mechanism underlying the Subject Performed Task (SPT) effect have not yet reached a consensus. This study investigated whether the association between motor and verbal information is a key factor that explains the SPT effect. Experiment 1 and 2 tested whether motor and verbal retrieval memory performance were different when the association level was varied. Results showed that when subjects used low association learning materials, memory performance in either motor or verbal retrieval condition was significantly better than performance in the combined retrieval condition. Experiment 3 examined whether the level of association between motor and verbal information affects the SPT effect. Results revealed that the SPT effect disappeared when low association learning materials were used. Our findings imply that the high association level between motor and verbal information enables mutual activation of the two information types, leading to improved memory performance.

Nature-Inspired 2D-Mosaic 3D-Gradient Mesoporous Framework: Bimetal Oxide Dual-Composite Strategy toward Ultrastable and High-Capacity Lithium Storage.

In allusion to traditional transition-metal oxide (TMO) anodes for lithium-ion batteries, which face severe volume variation and poor conductivity, herein a bimetal oxide dual-composite strategy based on two-dimensional (2D)-mosaic three-dimensional (3D)-gradient design is proposed. Inspired by natural mosaic dominance phenomena, Zn1-xCoxO/ZnCo2O4 2D-mosaic-hybrid mesoporous ultrathin nanosheets serve as building blocks to assemble into a 3D Zn-Co hierarchical framework. Moreover, a series of derivative frameworks with high evolution are controllably synthesized, based on which a facile one-pot synthesis process can be developed. From a component-composite perspective, both Zn1-xCoxO and ZnCo2O4 provide superior conductivity due to bimetal doping effect, which is verified by density functional theory calculations. From a structure-composite perspective, 2D-mosaic-hybrid mode gives rise to ladder-type buffering and electrochemical synergistic effect, thus realizing mutual stabilization and activation between the mosaic pair, especially for Zn1-xCoxO with higher capacity yet higher expansion. Moreover, the inside-out Zn-Co concentration gradient in 3D framework and rich oxygen vacancies further greatly enhance Li storage capability and stability. As a result, a high reversible capacity (1010 mA h g-1) and areal capacity (1.48 mA h cm-2) are attained, while ultrastable cyclability is obtained during high-rate and long-term cycles, rending great potential of our 2D-mosaic 3D-gradient design together with facile synthesis.

Deep networks with non-static activation function

Deep neural networks typically with a fixed activation function at each neuron, have shown breakthrough performances. The fixed activation function is not the optimal choice for different data distributions. Toward this end, this work improves the deep neural networks by proposing a novel and efficient activation scheme called “Mutual Activation” (MAC). A non-static activation function is adaptively learned in the training phase of deep network. Furthermore, the proposed activation neuron cooperating with maxout is a potent higher-order function approximator, which can break through the convex curve limitation. Experimental results on object recognition benchmarks demonstrate the effectiveness of the proposed activation scheme.

Intraspinal microstimulation for respiratory muscle activation

A complex propriospinal network is synaptically coupled to phrenic and intercostal motoneurons, and this makes it difficult to predict how gray matter intraspinal microstimulation (ISMS) will recruit respiratory motor units. We therefore mapped the cervical and high thoracic gray matter at locations which ISMS activates diaphragm (DIA) and external intercostal (EIC) motor units. Respiratory muscle electromyography (EMG) was recorded in anesthetized female spinally intact adult rats while a stimulating electrode was advanced ventrally into the spinal cord in 600μm increments. At each depth, single biphasic stimuli were delivered at 10–90μA during both the inspiratory and expiratory phase independently. Twenty electrode tracks were made from C2-T1 at medial and lateral gray matter locations. During inspiration, ISMS evoked DIA and EIC activity throughout C2-T1 gray matter locations, with mutual activation occurring at 17±9% of sites. During inspiratory phase ISMS the average latency for DIA activation was 4.40±0.70ms. During the expiratory phase, ISMS-induced DIA activation required electrodes to be in close proximity to the phrenic motoneuron pool, and average activation latency was 3.30±0.50ms. We conclude that appropriately targeted ISMS can co-activate DIA and EIC motor units, and endogenous respiratory drive has a powerful impact on ISMS-induced respiratory motor unit activation. The long latency diaphragm motor unit activation suggests the presence of a complex propriospinal network that can modulate phrenic motor output.

Methane activation over a boron nitride catalyst driven by in situ formed molecular water

Boron nitride converts methane to valuable chemicals through a H2O-assisted O2 and CH4 synergetic mutual activation mechanism.

Interaction and Mutual Activation of Different Innate Immune Cells Is Necessary to Kill and Clear Hepatitis C Virus-Infected Cells

Innate immune cells can sense hepatitis C virus (HCV)-infected cells and respond with anti-viral actions including secretion of interferons (IFNs). In previous studies, the response of individual innate immune cells against HCV was analyzed in detail. We hypothesized that interaction of multiple innate immune cells increases the magnitude of the immune response and eventually leads to clearance of HCV-infected cells. To investigate this, we co-cultured Huh-7 HCV subgenomic replicon (SGR) cells with peripheral blood mononuclear cells (PBMCs). We confirm secretion of IFNα by plasmacytoid dendritic cells (pDCs) and IFNγ by natural killer (NK) cells in the co-culture setup. Moreover, we observed that also monocytes contribute to the anti-viral response. Flow cytometry and ImageStream analysis demonstrated that monocytes take up material from HCV SGR cells in co-culture with PBMCs. Preceding the uptake, PBMCs caused apoptosis of HCV SGR cells by tumor necrosis factor-related apoptosis inducing ligand (TRAIL) expression on NK cells. We observed that only the interplay of monocytes, pDCs, and NK cells resulted in efficient clearance of HCV SGR cells, while these cell populations alone did not kill HCV SGR cells. Despite similar TRAIL receptor expression on Huh-7 control cells and HCV SGR cells, HCV activated PBMCs specifically killed HCV SGR cells and did not target Huh-7 control cells. Finally, we showed that HCV replicating cells per se are sensitive toward TRAIL-induced apoptosis. Our results highlight the importance of the interplay of different innate immune cells to initiate an efficient, rapid, and specific response against HCV-infected cells.

Intergroup dissimilarity predicts physiological synchrony and affiliation in intergroup interaction

Interpersonal similarity attracts. In intergroup contexts, however, similarity between groups potentiates bias. The current study examined whether intergroup similarity versus dissimilarity engenders cross-group friendship formation. We used an essay-writing paradigm to manipulate perceived intergroup similarity or dissimilarity between the ethnic groups of participants prior to a dyadic interaction that involved a competitive party game. During the interaction, we continuously recorded physiological and behavioral responses from both participants. We used the physiological responses to derive a measure of physiological synchrony: the mutual activation of partners' sympathetic nervous systems. People primed with dissimilarity, not similarity, experienced physiological synchrony with their partner. Moreover, the partners of people primed with dissimilarity acted more affiliative than the partners of people primed with similarity, which in turn predicted friendship initiation by participants. We discuss the seemingly counter-intuitive value of emphasizing differences between groups to foster positive intergroup relations.

Mathematical comparison of memory functions between mutual activation and repression networks in a stochastic environment

Biological memory is a ubiquitous function that can generate a sustained response to a transient inductive stimulus. To better understand this function, we must consider the mechanisms by which different structures of genetic networks achieve memory. Here, we investigated two competitive gene regulatory network models: the regulated mutual activation network (MAN) and the regulated mutual repression network (MRN). Stochasticity deteriorated the persistence of memory of both the MAN and the MRN. Mathematical comparison by simulation and theoretical analysis identified functional differences in the stochastic memory between the competitive models: specifically, the MAN provided much more robust, persistent memory than the MRN. The stochastic persistent memory pattern of the MAN can be adjusted by changing the binding strength of the activators, whereas the MRN required highly cooperative and strong binding repressors for robust memory.

The antagonistically bifunctional retinoid oxidoreductase complex is required for maintenance of all-trans-retinoic acid homeostasis

All-trans-retinoic acid (RA), a bioactive derivative of vitamin A, exhibits diverse effects on gene transcription and non-genomic regulatory pathways. The steady-state levels of RA are therefore tightly controlled, but the mechanisms responsible for RA homeostasis are not fully understood. We report a molecular mechanism that allows cells to maintain a stable rate of RA biosynthesis by utilizing a biological circuit generated by a bifunctional retinoid oxidoreductive complex (ROC). We show that ROC is composed of at least two subunits of NAD+-dependent retinol dehydrogenase 10 (RDH10), which catalyzes the oxidation of retinol to retinaldehyde, and two subunits of NADPH-dependent dehydrogenase reductase 3 (DHRS3), which catalyzes the reduction of retinaldehyde back to retinol. RDH10 and DHRS3 also exist as homo-oligomers. When complexed, RDH10 and DHRS3 mutually activate and stabilize each other. These features of ROC ensure that the rate of RA biosynthesis in whole cells is largely independent of the concentration of the individual ROC components. ROC operates in various subcellular fractions including microsomes, mitochondria, and lipid droplets; however, lipid droplets display weaker mutual activation between RDH10 and DHRS3, suggesting reduced formation of ROC. Importantly, disruption of the ROC-generated circuit by a knockdown of DHRS3 results in an increased flux through the RA biosynthesis pathway and elevated RA levels despite the decrease in RDH10 protein destabilized by the absence of DHRS3, hence demonstrating a loss of control. Thus, the bifunctional nature of ROC provides the RA-based signaling system with robustness by safeguarding appropriate RA concentration despite naturally occurring fluctuations in RDH10 and DHRS3.

Structural Insight into Allosteric Inhibition of Mycobacterium tuberculosis Tryptophan Synthase

The rise of antibiotic‐resistant pathogens requires redirecting drug discovery effort toward new cellular targets to provide new treatment options. Such alternative, yet unexplored opportunities exist in central metabolism, where many enzymes are only conditionally essential and thus their successful exploitation requires understanding of metabolic fluxes and pathway regulations under certain environmental conditions. In Mycobacterium tuberculosis, tryptophan biosynthesis represents one such promising pathway that could be targeted. In Mtb, the multistep L‐Trp synthesis involves several enzymes: TrpEG, TrpD, TrpC and TrpAB, which is validated as conditionally essential in vivo. The whole‐cell screening of a diversity‐oriented synthetic library identified a novel bactericidal azetidine derivative, BRD4592, that specifically inhibits TrpAB (tryptophan synthase). TrpAB is a heterotetrameric, PLP‐dependent complex catalyzing two last reactions in L‐Trp synthesis: the conversion of indole‐3‐glycerol phosphate to indole and glyceraldehyde 3‐phosphate (TrpA) followed by indole and L‐Ser condensation to yield L‐Trp (TrpB). During the catalytic cycle, indole is transferred from the TrpA to TrpB active site through 25 Å hydrophobic channel to react with the L‐Ser‐PLP adduct. The enzymatic activities and substrate channeling are coordinated by complex allosteric communication between the subunits. This regulation involves cycling between various conformational states, with both subunits adopting either an open (inactive) or closed (active) state. Detailed kinetic, biophysical and structural evidence reveals that BRD4592 is an allosteric, mixed‐type inhibitor, which binds specifically to a novel site within the intersubunit channel, at the TrpA‐TrpB interface. The molecule promotes closed, active state of the TrpB subunit and increases enzyme affinity for the L‐Ser substrate. BRD4592 acts on three levels: it limits flexibility of the interface potentially disrupting mutual activation of the subunits, prevents indole translocation, and increases product inhibition providing means to successfully inhibit both, TrpA and TrpB reactions. Our results indicate that allosteric binders may represent an effective tool to deactivate central metabolism enzymes, which often are allosterically regulated and might be predisposed for this type of inhibition.Support or Funding InformationThis work was supported by the Broad Institute Tuberculosis donor group, the Pershing Square Foundation, the Bill & Melinda Gates Foundation under grant OPP1032518, the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, under contracts HHSN272200700058C and HHSN272201200026C and the U. S. Department of Energy, Office of Biological and Environmental Research, under contract DE‐AC02‐06CH11357. For this work, University of Chicago is a subgrantee of Structural Genomics Consortium under a Bill & Melinda Gates Foundation grant for the Structure‐Guided Drug Discovery Coalition.