Modulator Of Activity Research Articles

Discovery of new AMR drugs targeting modulators of antimicrobial activity using in vivo silkworm screening systems.

Global concerns about drug-resistant bacteria have underscored the need for new antimicrobial drugs. Emerging strategies in drug discovery include considering the third factors that influence drug activity. These factors include host-derived elements, adjuvants, and drug combinations, which are crucial in regulating antimicrobial efficacy. Traditional in vivo assessments have relied on animal models to study drug absorption, distribution, metabolism, excretion, and toxicity (ADMET). Alternative models, such as silkworms, are being explored to overcome the ethical and financial barriers associated with mammalian models. The silkworm has been proven effective in evaluating ADMET and in highlighting the therapeutic potential enhanced by third factors. Host factors (either mammalian or non-mammalian) enhance the antimicrobial activity of antimicrobial agents such as lysocin E. Additionally, using D-cycloserine to potentiate vancomycin has successfully combated vancomycin-resistant infections in silkworms. Leveraging silkworms in drug discovery could establish a novel screening method incorporating interactions with third factors, whether host related or non-host-related, thus promising new pathways for identifying antimicrobial drugs with unique mechanisms of action.

Innovative active terahertz modulator based on dynamic graphene-silicon arrays

This paper presents an innovative active terahertz (THz) modulator that utilizes dynamic graphene-silicon arrays (DGSAs) to overcome the challenges of dynamically manipulating THz waves. The DGSA combines the exceptional electrical properties of graphene with the enhanced optical absorption capabilities of silicon arrays, enabling dual-mode active control through optical pumping and electrical biasing. An 808 nm laser is used to photoexcite carriers in the silicon arrays for optical pumping while a bias voltage modulates the Fermi level of graphene, subsequently varying Si conductivity and influencing the transmission properties of THz waves. Simulations have demonstrated modulation depths of up to 94% at 2.5 THz in the transmission mode and 89% at 1 THz in the reflection mode. Furthermore, this study delves into a theoretical analysis and numerical simulations, exploring the modulation mechanisms, including the role of graphene’s Drude model and PN junction effects. These insights provide a robust theoretical framework for understanding the DGSA’s operation and lay a solid foundation for the design and optimization of high-performance THz modulation devices.

A comprehensive two-hybrid analysis to explore the Legionella pneumophila effector-effector interactome.

Secreted bacterial effector proteins are typically viewed as modulators of host activity, entering the host cytosol to physically interact with and modify the activity of one or more host proteins in support of infection. A growing body of evidence suggests that a subset of effectors primarily function to modify the activities of other effectors inside the host. These "effectors of effectors" or metaeffectors are often identified through experimental serendipity during the study of canonical effector function against the host. We previously performed the first global effector-wide genetic interaction screen for metaeffectors within the arsenal of Legionella pneumophila, an intracellular bacterial pathogen with over 300 effectors. Here, using a high-throughput, scalable methodology, we present the first global interaction network of physical interactions between L. pneumophila effectors. This data set serves as a complementary resource to identify and understand both the scope and nature of non-canonical effector activity within this important human pathogen.

The Particularities of the Structural Components of the Students' Educational Process, for Improving Skills in the Instructive-Tourism Practice

The content of the practice in higher education institutions assumes the position of the worker in the field of tourism, who, in addition to office work, is put in the position to go on the route, and this fact can only be achieved through an instructive-tourism practice. The subject of the research focused on the instructive-tourism practice that can have various structural components must be implemented taking into account various aspects of the tourism industry. The methods that provided us with the expected results included the analysis of the specialized literature and the structural aspects of the tourist instructive practice process. All of this presupposes the implementation of some modules for practical field activities, necessary in the training of students' professional skills. Thus, the obtained results lead us to conclude that the diversification of student practices is essential in their professional training.

IMMU-04. G-AMINOBUTYRIC ACID DRIVES GLIOBLASTOMA IN FEMALES IN AN IMMUNE-DEPENDENT MANNER

Abstract Communication with a neuronal network and accumulation of myeloid-derived suppressive cells (MDSCs) support GBM growth and therapeutic resistance. GBM incidence and outcomes differ between males and females. We previously demonstrated that granulocytic (gMDSCs) drive GBM in females. However, a lack of understanding of the host factors regulating distinct MDSC subset function remains to be a major obstacle for therapeutically targeting these cells in GBM. In this study, we identified γ-aminobutyric acid (GABA) pathway as a modulator of gMDSC activity. gMDSCs from both healthy adults and glioma patients, expressed significantly higher levels of GABA receptor B1 (GABBR1) and GABA receptor B2 (GABBR2) compared to monocytic MDSCs (mMDSCs). On contrary, GABA receptor A (GABAAR) subunits were not expressed in either MDSC subtype. Given these differences, we investigated the effect of GABA on MDSC metabolism and found an increase in L-arginine metabolism specifically in female gMDSCs following GABA treatment while no significant metabolic changes were observed in any other groups. In MDSCs, L-arginine can be metabolized via nitric oxide synthase (NOS2) or Arginase-1 (Arg-1). While treatment with GABA or the GABBR agonist baclofen increased NOS2 production in specifically in female gMDSCs, Arg-1 was not affected. Mechanistically, baclofen enhanced gMDSC-mediated T cell suppression in females. In preclinical models of GBM, baclofen treatment resulted in a truncated survival only in immunocompetent female mice, which was reversed by pharmaceutical inhibition of NOS2. Clinically, female patients on GABA analogs (pregabalin, gabapentin) had significantly lower 12-month survival probabilities compared to control population. This effect was not observed in male patients. Conversely, inhibition of GABBR with CGP35348 prolonged survival in female GBM models and reprogramed the immunosuppressive tumor microenvironment. Collectively, these results highlight that GABA alters anti-tumor immune response in a sex-specific manner. These results support the future assessment of GABA pathway inhibitors as potential immunotherapy agents in GBM.

Common and contrasting effects of 5-HTergic signaling in pyramidal cells and SOM interneurons of the mouse cortex.

Serotonin (5-hydroxytryptamine, 5-HT) is a powerful modulator of neuronal activity within the central nervous system and dysfunctions of the serotonergic system have been linked to several neuropsychiatric disorders such as major depressive disorders or schizophrenia. The anterior cingulate cortex (aCC) plays an important role in cognitive capture of stimuli and valence processing and it is densely innervated by serotonergic fibers from the nucleus raphe. In order to understand how pathophysiological 5-HT signalling can lead to neuropsychiatric diseases, it is important to understand the physiological actions of 5-HT on cortical circuits. Therefore, we combined electrophysiological recordings with pharmacology and immunocytochemistry to investigate the effects of 5-HT on Somatostatin-positive interneurons (SOM-INs) and compared these to supragranular pyramidal cells (PCs). This comparison allowed us to identify common and contrasting effects of 5-HT on SOM-INs and PCs of the aCC resulting in a specific modulation of the excitation-to-inhibition balance in PCs but not in SOM-INs.

Mitochondrial Dynamics Drive Muscle Stem Cell Progression from Quiescence to Myogenic Differentiation.

From quiescence to activation and myogenic differentiation, muscle stem cells (MuSCs) experience drastic alterations in their signaling activity and metabolism. Through balanced cycles of fission and fusion, mitochondria alter their morphology and metabolism, allowing them to affect their decisive role in modulating MuSC activity and fate decisions. This tightly regulated process contributes to MuSC regulation by mediating changes in redox signaling pathways, cell cycle progression, and cell fate decisions. In this review, we discuss the role of mitochondrial dynamics as an integral modulator of MuSC activity, fate, and maintenance. Understanding the influence of mitochondrial dynamics in MuSCs in health and disease will further the development of therapeutics that support MuSC integrity and thus may aid in restoring the regenerative capacity of skeletal muscle.

Plasmonic modulators based on enhanced interaction between graphene and localized transverse-electric plasmonic mode

Active plasmonic modulators with high modulation depth, low energy consumption, ultra-fast speed, and small footprint are of interest and particular significance for nanophotonics and integrated optics. Here by constructing a transverse-electric (TE) plasmonic mode and maximizing the in-plane component localized on the graphene surface, we propose a high-performing plasmonic modulator based on a graphene/split ring-like plasmonic waveguide (SRPW) system with a record high modulation depth (20.46 dB/µm) and suppressed insertion loss (0.248 dB/µm) at telecom wavelength 1310 nm, simultaneously possessing pronounced advantage in broadband ability (800-1650 nm) and superior electrical performance with energy consumption of 0.43 fJ/bit and modulation speed of 200 GHz. This innovative design provides a novel approach and idea for enhancing the interaction between light and matter in the waveguide system and will certainly inspire new schemes for the development of on-chip integrated optoelectronic devices.

An overview of the pathophysiology of agitation in Alzheimer's dementia with a focus on neurotransmitters and circuits.

Alzheimer's dementia (AD) is a progressive, neurodegenerative disease often accompanied by neuropsychiatric symptoms that profoundly impact both patients and caregivers. Agitation is among the most prevalent and distressing of these symptoms and often requires treatment. Appropriate therapeutic interventions depend on understanding the biological basis of agitation and how it may be affected by treatment. This narrative review discusses a proposed pathophysiology of agitation in Alzheimer's dementia based on convergent evidence across research approaches. Available data indicate that agitation in Alzheimer's dementia is associated with an imbalance of activity between key prefrontal and subcortical brain regions. The monoamine neurotransmitter systems serve as key modulators of activity within these brain regions and circuits and are rendered abnormal in AD. Patients with AD who exhibited agitation symptoms during life have alterations in neurotransmitter nuclei and related systems when the brain is examined at autopsy. The authors present a model of agitation in Alzheimer's dementia in which noradrenergic hyperactivity along with serotonergic deficits and dysregulated striatal dopamine release contribute to agitated and aggressive behaviors.

Distinct mechanisms drive divergent phenotypes in hypertrophic and dilated cardiomyopathy associated TPM1 variants.

Hypertrophic and dilated cardiomyopathies (HCM and DCM, respectively) are inherited disorders that may be caused by mutations to the same sarcomeric protein but have completely different clinical phenotypes. The precise mechanisms by which point mutations within the same gene bring about phenotypic diversity remain unclear. Our objective has been to develop a mechanistic explanation of diverging phenotypes in two TPM1 mutations, E62Q (HCM) and E54K (DCM). Drawing on data from the literature and experiments with stem cell-derived cardiomyocytes expressing the TPM1 mutations of interest, we constructed computational simulations that provide plausible explanations of the distinct muscle contractility caused by each variant. In E62Q, increased calcium sensitivity and hypercontractility was explained most accurately by a reduction in effective molecular stiffness of tropomyosin and alterations in its interactions with the actin thin filament that favor the 'closed' regulatory state. By contrast, the E54K mutation appeared to act via long-range allosteric interactions to increase the association rate of the C-terminal troponin I mobile domain to tropomyosin/actin. These mutation-linked molecular events produced diverging alterations in gene expression that can be observed in human engineered heart tissues. Modulators of myosin activity confirmed our proposed mechanisms by rescuing normal contractile behavior in accordance with predictions.

Direct and indirect regulation of β-glucocerebrosidase by the transcription factors USF2 and ONECUT2

Mutations in GBA1 encoding the lysosomal enzyme β-glucocerebrosidase (GCase) are among the most prevalent genetic susceptibility factors for Parkinson’s disease (PD), with 10–30% of carriers developing the disease. To identify genetic modifiers contributing to the incomplete penetrance, we examined the effect of 1634 human transcription factors (TFs) on GCase activity in lysates of an engineered human glioblastoma line homozygous for the pathogenic GBA1 L444P variant. Using an arrayed CRISPR activation library, we uncovered 11 TFs as regulators of GCase activity. Among these, activation of MITF and TFEC increased lysosomal GCase activity in live cells, while activation of ONECUT2 and USF2 decreased it. While MITF, TFEC, and USF2 affected GBA1 transcription, ONECUT2 might control GCase trafficking. The effects of MITF, TFEC, and USF2 on lysosomal GCase activity were reproducible in iPSC-derived neurons from PD patients. Our study provides a systematic approach to identifying modulators of GCase activity and deepens our understanding of the mechanisms regulating GCase.

Active logic modulator of terahertz metamaterial for future 6G communication system

A tunable G-shaped metamaterial (GSM) for the upcoming 6G communication system is presented. GSM device shows polarization-dependent characteristics with three or five resonances. The GSM unit cell is composed of two identical G-shaped structures on a silicon (Si) substrate. By utilizing micro-electro-mechanical system (MEMS) technology to change the vertical height (h) between the two G-shaped structures and the horizontal distance (g) between them or change the polarization angle (PA) of the incident light, the electromagnetic responses of GSM device can be switched three to five resonances. The tuning range of resonant frequency of the GSM device is up to 15 GHz by changing the g value, and the modulation depth can reach 93 % by changing PA and h values. This MEMS-based GSM device exhibits multi-resonance and polarization-dependent characteristics, offering an efficient and economical way to modulate terahertz (THz) signals. Moreover, the GSM device also exhibits good optical switching performance at PA = 0°, 30°, and 75° under the condition of h = 2 μm. These characteristics can be expressed as logic signals 'ON' and 'OFF' states, enabling their application in the logic operation function of the NAND gate and programmable two-bit binary digital coding metamaterials.

Expression Profiles of Fatty Acid Transporters and the Role of n-3 and n-6 Polyunsaturated Fatty Acids in the Porcine Endometrium.

Fatty acids (FAs) are important for cell membrane composition, eicosanoid synthesis, and metabolic processes. Membrane proteins that facilitate FA transport into cells include FA translocase (also known as CD36) and FA transporter proteins (encoded by SLC27A genes). The present study aimed to examine expression profiles of FA transporters in the endometrium of cyclic and early pregnant gilts on days 3 to 20 after estrus and the possible regulation by conceptus signals and polyunsaturated FAs (PUFAs). The effect of PUFAs on prostaglandin (PG) synthesis and transcript abundance of genes related to FA action and metabolism, angiogenesis, and immune response was also determined. Day after estrus and reproductive status of animals affected FA transporter expression, with greater levels of CD36, SLC27A1, and SLC27A4 observed in pregnant than in cyclic gilts. Conceptus-conditioned medium and/or estradiol-17β stimulated SLC27A1 and CD36 expression. Among PUFAs, linoleic acid decreased SLC27A1 and SLC27A6 mRNA expression, while arachidonic, docosahexaenoic, and eicosapentaenoic acids increased SLC27A4 transcript abundance. Moreover, arachidonic acid stimulated ACOX1, CPT1A, and IL1B expression and increased PGE2 and PGI2 secretion. In turn, α-linolenic acid up-regulated VEGFA, FGF2, FABP4, and PPARG mRNA expression. These results indicate the presence of an active transport of FAs in the porcine endometrium and the role of PUFAs as modulators of the uterine activity during conceptus implantation.

Virgin Olive oil Authenticity Assays in a Single Run Using Two-Dimensional Liquid Chromatography-High Resolution Mass Spectrometry.

Sterols and triterpenic alcohol analyses are one of the officially established parameters for assessing the authenticity of virgin olive oil (VOO). Most of the applications described for sterol analysis, including the official method, only allow the determination of the total sterol content but not its distribution in free or esterified form. This work proposes a two-dimensional liquid chromatography/high-resolution mass spectrometry (2D-LC-HRMS) method for the simultaneous analysis of triterpenic alcohols, free sterols and steryl esters. A reversed phase liquid chromatography (RPLC)-RPLC coupling was performed through a multiple heart-cutting interface equipped with an active solvent modulation (ASM) valve. Additionally, a selection valve was coupled to the 2D-LC system, allowing the simultaneous data acquisition from both dimensions in a single analysis. A simplified sample treatment based on solid phase extraction was also proposed to avoid tedious steps such as saponification or derivatization before gas chromatography analysis. To evaluate the content of these compounds in different olive oil categories, the proposed 2D-LC-HRMS system was applied to a set of samples from different commercial olive oil categories (extra virgin olive oil, virgin olive oil, olive oil, pomace olive oil) and sunflower oil. The results revealed significant differences in the distribution of free and esterified sterols of the analyzed samples, highlighting the free/esterified sterol ratio as a powerful tool to unveil olive oil fraud practices and fat manipulation.

WONOEP appraisal: The role of glial cells in focal malformations associated with early onset epilepsies.

Epilepsy represents a common neurological disorder in patients with developmental brain lesions, particularly in association with malformations of cortical development and low-grade glioneuronal tumors. In these diseases, genetic and molecular alterations in neurons are increasingly discovered that can trigger abnormalities in the neuronal network, leading to higher neuronal excitability levels. However, the mechanisms underlying epilepsy cannot rely solely on assessing the neuronal component. Growing evidence has revealed the high degree of complexity underlying epileptogenic processes, in which glial cells emerge as potential modulators of neuronal activity. Understanding the role of glial cells in developmental brain lesions such as malformations of cortical development and low-grade glioneuronal tumors is crucial due to the high degree of pharmacoresistance characteristic of these lesions. This has prompted research to investigate the role of glial and immune cells in epileptiform activity to find new therapeutic targets that could be used as combinatorial drug therapy. In a special session of the XVI Workshop of the Neurobiology of Epilepsy (WONOEP, Talloires, France, July 2022) organized by the Neurobiology Commission of the International League Against Epilepsy, we discussed the evidence exploring the genetic and molecular mechanisms of glial cells and immune response and their implications in the pathogenesis of neurodevelopmental pathologies associated with early life epilepsies.

TrafficPro: A road speed prediction framework for urban signal-controlled road networks

In view of the problem that traditional deep learning models do not consider the active time-varying characteristics of traffic flow (signal control information) when predicting the speed of urban road networks, and have low prediction accuracy, this paper proposes a speed prediction framework based on generative adversarial networks and graph neural networks. In this framework, the generator network simultaneously encodes the road network traffic flow and signal control information through active and passive prediction modules to generate prediction results, and then uses the discriminator network to improve the generalization of the prediction results. This framework can obtain higher prediction accuracy than traditional time series models and deep learning models. In the real road network speed prediction scenario, this framework can reduce the prediction error compared to the best benchmark model 3%-4%.

Quercetin as a Modulator of PTPN22 Phosphomonoesterase Activity: A Biochemical and Computational Evaluation.

Cancer, a group of diseases characterized by uncontrollable cell proliferation and metastasis, remains a global health challenge. This study investigates quercetin, a natural compound found in many fruits and vegetables, for its potential to inhibit the phosphomonoesterase activity of protein tyrosine phosphatase nonreceptor type 22 (PTPN22), a key immune response regulator implicated in cancer and autoimmune diseases. We started by screening seven (7) natural compounds against the activities of PTPN22 in vitro. The initial screening identified quercetin with the highest percentage inhibition (81%) among the screened compounds when compared with ursolic acid that has 84%. After the identification of quercetin, we proceeded by investigating the effect of increasing concentrations of the compound on the activity of PTPN22. In vitro studies showed that quercetin inhibited PTPN22 with an IC50 of 29.59 μM, outperforming the reference standard ursolic acid, which had an IC50 of 37.19 μM. Kinetic studies indicated a non-competitive inhibition by quercetin with a Ki of 550 μM. In silico analysis supported these findings, showing quercetin's better binding affinity (ΔGbind -24.56 kcal/mol) compared to ursolic acid, attributed to its higher reactivity and electron interaction capabilities at PTPN22's binding pocket. Both quercetin and ursolic acid improved the structural stability of PTPN22 during simulations. These results suggest quercetin's potential as an anticancer agent, meriting further research. However, in vivo studies and clinical trials are necessary to fully assess its efficacy and safety, and to better understand its mechanisms of action.

Synthesis and characterization of 7-diethylamino-4-Chloromethyl coumarin: Spectroscopic analysis, molecular docking, and anticancer activity on large intestine carcinoma cells

Cancer, characterized by uncontrolled cell growth and metastasis, poses a significant global health burden, ranking as a leading cause of mortality worldwide. Colorectal cancer (CRC) specifically accounts for a substantial portion of cancer cases, with increasing incidence projected over the coming decades. While conventional treatments exist, they often entail adverse effects and limited efficacy, driving interest in natural remedies like coumarin derivatives due to their diverse biological activities and perceived safety profile. This study focuses on the synthesis and characterization of a novel compound, 7-diethylamino-4-chloromethyl coumarin (referred to as 7D4C), derived from coumarin. Structural elucidation employed Fourier transform infrared spectroscopy (FT-IR), proton and carbon-13 nuclear magnetic resonance spectroscopy (1H and 13C NMR), and mass spectrometry (MALDI-TOF-MS). Molecular docking studies were conducted to explore potential biological interactions. Furthermore, the anti-cancer potential of 7D4C was assessed using human epithelial adenocarcinom (LoVo) and healthy fibroblast (CCD-18Co) cell lines. Viability analysis, comet assay for DNA damage, and evaluation of cancer biomarkers including apoptosis, intracellular reactive oxygen species (iROS) levels, mitochondrial membrane potential (MMP), intracellular glutathione (GSH) concentration, and intracellular calcium (iCa2+) levels were performed. The synthesis of 7D4C was successfully completed, and its structure was confirmed. Molecular docking results indicate that 7D4C exhibits strong binding affinity to the p53 protein, highlighting its potential as a novel modulator of p53 activity. Subsequent investigations revealed that the synthesized compound induced apoptosis in cancer cells by reducing MMP and triggering DNA damage through the production of iROS. The promising anti-cancer activity of 7D4C in the LoVo cell line highlights its importance in coumarin-based therapies. Introducing 7D4C could significantly enhance future research in this area, leveraging insights from in vitro coumarin studies.

Modified (2′-deoxy)adenosines activate autophagy primarily through AMPK/ULK1-dependent pathway

Autophagy is a conserved self-digestion process, which governs regulated degradation of cellular components. Autophagy is upregulated upon energy shortage sensed by AMP-dependent protein kinase (AMPK). Autophagy activators might be contemplated as therapies for metabolic neurodegenerative diseases and obesity, as well as cancer, considering tumor-suppressive functions of autophagy. Among them, 5-aminoimidazole-4-carboxamide ribonucleoside (AICAr), a nucleoside precursor of the active phosphorylated AMP analog, is the most commonly used pharmacological modulator of AMPK activity, despite its multiple reported “off-target” effects. Here, we assessed the autophagy/mitophagy activation ability of a small set of (2′-deoxy)adenosine derivatives and analogs using a fluorescent reporter assay and immunoblotting analysis. The first two leader compounds, 7,8-dihydro-8-oxo-2′-deoxyadenosine and -adenosine, are nucleoside forms of major oxidative DNA and RNA lesions. The third, a derivative of inactive N6-methyladenosine with a metabolizable phosphate-masking group, exhibited the highest activity in the series. These compounds primarily contributed to the activation of AMPK and outperformed AICAr; however, retaining the activity in knockout cell lines for AMPK (ΔAMPK) and its upstream regulator SIRT1 (ΔSIRT1) suggests that AMPK is not a main cellular target. Overall, we confirmed the prospects of searching for autophagy activators among (2′-deoxy)adenosine derivatives and demonstrated the applicability of the phosphate-masking strategy for increasing their efficacy.

S1486 Pathogenic Crossroads: Viral Defense Genes as Modulators of Crohn's Disease Activity

S1486 Pathogenic Crossroads: Viral Defense Genes as Modulators of Crohn's Disease Activity