Modulation Of Function Research Articles

Pre-selection of solar analogues with differential rotation signature

The light curve of a star allows studying the variation of its brightness over time, being suitable for determining rotation periods, detecting planets, studying binary systems and differential rotation. The light curve analysis can be performed with the autocorrelation function (ACF), a robust mathematical tool in the detection of the stellar rotation period, by finding patterns in the photometric data. In this work, a sample of stars from the CoRoT mission is analyzed. The analysis is carried out with the ACF to carry out a pre-selection of stars that show signs of rotational modulation, a determining characteristic for the study of differential rotation. 17 stars were selected by visual inspection of the curves and by the ACF function. It was found that three stars have an excellent profile of autocorrelation function and rotational modulation, three have a good profile and the remaining eleven have inappropriate profiles for the study of differential rotation. The photometric time series analyzes show that the autocorrelation function method is very suitable as a previous criterion for the selection of candidate stars for the study of differential rotation, when they present exponential decay of the oscillation peaks of the light curve.

The Microbiome in the Obesity-Breast Cancer Axis: Diagnostic and Therapeutic Potential.

A growing body of evidence has demonstrated a relationship between the microbiome, adiposity, and cancer development. The microbiome is emerging as an important factor in metabolic disease and cancer pathogenesis. This review aimed to highlight the role of the microbiome in obesity and its association with cancer, with a particular focus on breast cancer. This review discusses how microbiota dysbiosis may contribute to obesity and obesity-related diseases, which are linked to breast cancer. It also explores the potential of the gut microbiome to influence systemic immunity, leading to carcinogenesis via the modulation of immune function. This review underscores the potential use of the microbiome profile as a diagnostic tool and treatment target, with strategies including probiotics, fecal microbiota transplantation, and dietary interventions. However, this emphasizes the need for more research to fully understand the complex relationship between the microbiome, metabolic disorders, and breast cancer. Future studies should focus on elucidating the mechanisms underlying the impact of the microbiome on breast cancer and exploring the potential of the microbiota profile as a biomarker and treatment target.

Discovery of Novel, First-in-Class Allosteric Modulators of MALT1 Scaffolding Function with Differentiated Pharmacology for NFκB-Driven Malignancies

Constitutive activation of NFκB is an oncogenic driver for many lymphoid and selected solid tumor malignancies. BTK inhibitors, which affect the upstream NFκB pathway, have been successfully used in some diseases, but their utility is limited. The majority of DLBCL patients, for instance, are insensitive to BTK inhibition, supporting the need for alternative mechanisms to block NFκB-driven tumor progression. Knockdown of MALT1, a key component of the CBMT complex (CARD-BCL10-MALT1-TRAF6) involved in direct signal transduction of NFκB, is able to block NFκB-dependent DLBCL tumor growth in BTKi sensitive or resistant tumors, but pharmacologic modulation has been challenged by the dual-functionality of MALT1 in a complexed signalosome. MALT1 functions as the scaffolding component of the CBMT complex. Activated MALT1 recruits multiple proteins and directly activates NFκB canonical signaling. MALT1 also has protease activity that fine-tunes various signaling pathways including NFκB via the cleavage of many substrates. The scaffolding activity of MALT1 is critical for cancer cell survival. Most MALT1 inhibitors discovered so far only block protease activity, which results in incomplete NFκB inhibition, suboptimal anti-tumor activity, and the induction of severe autoimmunity due to protease inhibition. Using our Smart Allostery platform, we elucidated and then drugged a natural hotspot on MALT1 that selectively impacts scaffolding but not protease function. The series of scaffolding modulators demonstrate potent inhibition of MALT1 scaffolding activity with cellular IC 50 values ranging from 15 to 250 nM, while exerting minimal influence on MALT1 protease function. Unlike protease inhibitors, which only partially affect NFκB activity, scaffolding modulators completely inhibit the NFκB downstream signaling manifested by the suppression of NFκB activity with cellular IC 50 values ranging from 2 to 90 nM. Consequently, scaffolding modulators exhibit a superior and broader anti-proliferation profile compared to MALT1 protease inhibitors and BTK inhibitors in a panel of lymphoma cell lines. Pathway and genetic analyses indicate that B-cell lymphoma lines driven by NFκB are especially sensitive to scaffolding modulators. In vivo studies demonstrate a robust, dose-dependent tumor growth inhibition (TGI) by one representative scaffolding modulator in several B-cell lymphoma xenograft models. In a protease inhibitor sensitive ABC-DLBCL model, OCI-LY10, our scaffolding modulator achieved a maximal TGI of 94%, while a clinical MALT1 protease inhibitor showed 62% maximal TGI (p<0.001). In protease resistant NFκB driven DLBCL models, MALT1 scaffolding modulation resulted in tumor regression or stasis. These findings highlight the differentiated pharmacology of our scaffolding modulators. Distinct from protease inhibitors that suppress T cell activation and Treg population in vivo, scaffolding modulators also did not deplete Treg cells nor suppress T cell activation in a 14-day study. This potentially mitigates the risk of development of autoimmune disease caused by chronic MALT1 protease inhibition. In summary, we have discovered novel, first-in-class allosteric modulators of MALT1 scaffolding activities. These scaffolding modulators drive enhanced and broader anti-tumor effect in models resistant to MALT1 protease or BTK inhibitors and do so without immune dysregulation. Scaffolding modulation represents a potential best-in-class therapeutic opportunity to modulate MALT1 in patients with NFκB-driven malignancies.

Ovarian nesfatin-1 in Hemidactylus flaviviridis: Reproductive phase-dependent expression, role and hormonal regulation

Nesfatin-1 has recently emerged as a modulator of ovarian functions in mammals. Studies in non-mammalian vertebrates, though limited and majorly restricted to fishes, have evidenced a role of this peptide in the regulation of ovarian steroidogenesis and oocyte maturation. Interestingly, nesfatin-1 remains completely unexplored in reptiles. Therefore, the present study aimed to identify nesfatin-1 and elucidate its role and regulation in the ovary of Hemidactylus flaviviridis. Ovarian expression of nucb2/nesfatin-1 was highest during late recrudescence and breeding while it was lowest during regression. Follicular stage-dependent expression analysis showed significantly high expression of nucb2/nesfatin-1 in previtellogenic follicles. Further, in vitro treatment of recrudescent wall lizard ovaries with nesfatin-1 resulted in increased expression of anti-apoptotic gene, bcl-2, along with a concomitant decline in the pro-apoptotic gene, caspase-3. In addition, proliferation/differentiation markers like scf, c-kit, pcna, and bmp-15 were stimulated in ovaries incubated with the peptide. Ovarian steroidogenesis was also positively influenced by nesfatin-1 as treatment with the peptide resulted in heightened star expression as well as increased estradiol and progesterone production. Also, all concentrations of nesfatin-1 stimulated glucose uptake and metabolism in wall lizard ovary. Our observations provide the first evidence of ovarian functions of nesfatin-1 in a reptile. Further, ovarian nucb2/nesfatin-1 was differentially regulated by gonadotropin and sex steroids wherein its expression was stimulated by dihydrotestosterone (DHT) and 17β-estradiol (E2) but inhibited by follicle-stimulating hormone (FSH). In summary, this is the first report of the presence, reproductive stage-dependent expression, role, and regulation of ovarian nucb2/nesfatin-1 in H. flaviviridis.

Discovery of a novel cardiac-specific myosin modulator using artificial intelligence-based virtual screening

Direct modulation of cardiac myosin function has emerged as a therapeutic target for both heart disease and heart failure. However, the development of myosin-based therapeutics has been hampered by the lack of targeted in vitro screening assays. In this study we use Artificial Intelligence-based virtual high throughput screening (vHTS) to identify novel small molecule effectors of human β-cardiac myosin. We test the top scoring compounds from vHTS in biochemical counter-screens and identify a novel chemical scaffold called ‘F10’ as a cardiac-specific low-micromolar myosin inhibitor. Biochemical and biophysical characterization in both isolated proteins and muscle fibers show that F10 stabilizes both the biochemical (i.e. super-relaxed state) and structural (i.e. interacting heads motif) OFF state of cardiac myosin, and reduces force and left ventricular pressure development in isolated myofilaments and Langendorff-perfused hearts, respectively. F10 is a tunable scaffold for the further development of a novel class of myosin modulators.

Metabolism of vitamin D, Calcium and Phosphorus and their disorders in goats

The review article presents materials on the metabolism of the mostcommon vitamins of group D ergocalciferol (D2), cholecalciferol (D3), aswell as essential macronutrients Ca and Phosphorus and their disorders ingoats. Since the primary forms of vitamin D (D2 and D3) are biologicallyinactive and must undergo several stages of hydroxylation to be activated,the biological role and importance for the body of active metabolites ofvitamin D3 25OH D3 (synthesised mainly in the liver under the influenceof hepatic cytochromes P450) and 1, 25(OH)2 D3 and 24,25(OH)2 D3 (theirsynthesis occurs via 1α-hydroxylase in the mitochondria of proximal cellsof the convoluted tubules of the kidneys).It is believed that the liver, while playing an important role in themetabolism of vitamin D and its metabolites and producing 25OH D3, isalso the only organ that synthesises DBP, which transports 25OH D3 totissues and maintains its concentration in the circulatory system.Vitamin D becomes biologically active only after the second stageof hydroxylation is completed. Renal 1α-hydroxylase (CYP27B1),regulated by parathyroid hormone (PTH), plays an important role inthe transformation of the extracellular substrate 25OH D3 to 1,25(OH)2D3, which exerts its effect on target cells and tissues by binding to thenuclear vitamin D receptor. Alternatively, 1,25(OH)2 D3 can bind to theplasma membrane VDR and induce non-genomic actions, in particular,stimulation of intestinal calcium transport.Vitamin D is a steroid substance that is essential for all vertebratesto maintain calcium and phosphorus metabolism within optimal limits, ahealthy skeleton, muscle contraction, modulation of cell growth and neuromuscular function. Calciferol also regulates the immune system, inhibits the development of pathological cells, angiogenesis and inflammatoryreactions. The active form of vitamin D, 1,25(OH)2 D3, stimulates intestinal absorption and renal Ca reabsorption and maintains its minimumphysiological level in the blood.Vitamin D deficiency in goats leads to a decrease in productivity, causesa decrease in intestinal and renal calcium reabsorption, which leads to theincrease in parathyroid hormone levels. This process leads to activation ofosteocytes and, as a result, accelerates bone demineralisation, causing thedevelopment of many diseases in adults, including nutritional and fibrousosteodystrophy, secondary osteodystrophy, endocrine dysfunction), as wellas rickets in young animals. The development of non-skeletal pathologies,in particular, inflammatory, neoplastic and autoimmune diseases, is also associated with cholecalciferol deficiency in the body. In addition, disordersof D-vitamin and calcium-phosphorus metabolism in goats cause the development of postpartum hypocalcaemia and postpartum hypophosphatemia.In the animal body, calcium and phosphorus homeostasis is maintained by a coordinated interaction of absorption and reabsorptionthrough the gastrointestinal tract and kidneys, as well as by storage and mobilization from bone tissue and is regulated mainly by biologically active cholecalciferol metabolites - 25OH D3, 1,25(OH)2 D3, as wellas parathyroid hormone (PTH; synthesised by the pineal glands) andcalcitonin (CT; produced by sparafollicular (light) thyroid C cells) andfibroblast growth factor-23 (FGF23).In contrast to monogastric animals, small ruminants do not modulaterenal calcium excretion in response to calcium limitation in the diet. Themobilization of Ca and P from the skeleton is stimulated by PTH throughosteoclast activation mediated by receptor activator of nuclear factor-κB(RANK). Vitamin D maintains Ca (by stimulating CaZB) and P homeostasis (the direct rapid action of 1,25(OH)2 D3 has been proven to have a directeffect on the absorption of these vital elements in the intestine, reabsorptionof these cations in the renal tubules and their mobilization from bone tissue).Phosphorus is a component of adenosine triphosphate (ATP) and nucleotides. Macroergic phosphate compounds, among which the main oneis adenosine triphosphate acid, provide both the accumulation of energyreserves and its consumption (ATP, ADP, creatine phosphate), affectingprotein, lipid, carbohydrate, mineral, and energy metabolism. An interaction between vitamin D and fibroblast growth factor 23 (FGF23), a bonehormone that causes the development of phosphaturia and reduces thesynthesis of 1,25(OH)2 D3, has been identified.Despite the multidirectionality of etiological factors, common to allforms of osteodystrophy is a disruption of the processes of bone formation and renewal, which is manifested by increased mobilization of calcium, phosphorus and other elements from bone tissue, so the pathologyis accompanied by osteomalacia, osteoporosis and osteofibrosis, and aviolation of the mechanism of maintaining their homeostasis.The main factors of osteodystrophy in animals are feeding disordersand physical inactivity, and the leading links in its pathogenesis are theimbalance between bone formation and resorption.The main methods for diagnosing disorders of D-vitamin and calcium-phosphorus metabolism in goats are clinical, physical, biochemical,enzyme-linked immunosorbent assays and pathological and morphological studies. Biochemical analysis in goat serum determines the content oftotal calcium, inorganic phosphorus, activity of alkaline phosphatase andits isozymes, and immunoassay the concentration of 25OH D3, 1,25(OH)2D3, calcitonin and parathyroid hormone. Keywords: goats, vitamin D, metabolites, metabolism, calcium,phosphorus, liver, kidneys.

Modeling ultrasound modulation of neural function in a single cell

BackgroundLow intensity ultrasound stimulation has been shown to non-invasively modulate neural function in the central nervous system (CNS) and peripheral nervous system (PNS) with high precision. Ultrasound sonication is capable of either excitation or inhibition, depending on the ultrasound parameters used. On the other hand, the mode of interaction of ultrasonic waves with the neural tissue for effective neuromodulation remains ambiguous. New methodHere within we propose a numerical model that incorporates the mechanical effects of ultrasound stimulation on the Hodgkin-Huxley (HH) neuron by incorporating the relation between increased external pressure and the membrane induced tension, with a stress on the flexoelectric effect on the neural membrane. The external pressure causes an increase in the total tension of the membrane thus affecting the probability of the ion channels being open after the conformational changes that those channels undergo. ResultsThe interplay between varying the acoustic intensities and frequencies depicts different action potential suppression rates, whereby a combination of low intensity and low frequency ultrasound sonication proved to be the most effective in modulating neural function.Comparison with Existing Methods: Our method solely depends on the HH model of a single neuron and the linear flexoelectric effect of the dielectric neural membrane, when under an ultrasound-induced mechanical strain, while varying the ion-channels conductances based on different sonication frequencies and intensities. We study the effect of ultrasound parameters on the firing rate, latency, and action potential amplitude of a HH neuron for a better understanding of the neuromodulation modality of ultrasound stimulation (in the continuous and pulsed modes). ConclusionsThis simulation work confirms the published experimental data that low intensity and low frequency ultrasound sonication has a higher success rate of modulating neural firing.

Early-Life Exposure to Dietary Large Phospholipid-Coated Lipid Droplets Improves Markers of Metabolic and Immune Function in Adipose Tissue Later in Life in a Mouse Model.

Human milk (HM) is considered optimal nutrition for infants, beneficially programming adult health outcomes including reduced obesity risk. Early life exposure to infant formula with lipid droplets closely resembling the structural properties of HM lipid globules (Nuturis) attenuated white adipose tissue (WAT) accumulation in mice upon adult western-style diet (WSD) feeding. Here, the study aims to elucidate underlying mechanisms. Mice are raised on control or Nuturis diets between postnatal days 16-42 followed by either standard diet or WSD for 16 weeks. While the adult body composition of mice on a standard diet is not significantly affected, Nuturis reduced adiposity in mice on WSD. Morphologically, mean adipocyte size is reduced in Nuturis-raised mice, independent of adult diet exposure, and WAT macrophage content is reduced, albeit not significantly. Transcriptomics of epididymal WAT indicate potential beneficial effects on energy metabolism and macrophage function by Nuturis. Reduced adult adiposity by early life exposure to Nuturis appears to be associated with smaller adipocytes and alterations in WAT immune and energy metabolism. These results suggest that early modulation of WAT structure and/or function may contribute to the protective programming effects of the early-life Nuturis diet on later-life adiposity.

SISTEM MONITORING SKRIPSI BERBASIS PROGESSIVE WEB APPLICATION DENGAN PUSH NOTIFICATION

The Covid-19 pandemic requires thesis guidance activities to be carried out online. If the tertiary institution does not have a proper thesis monitoring system, the guidance process will not run smoothly and on time. This study aims to create a thesis monitoring system using Progressive Web Application (PWA) technology with a software development method using mobile-D. The development stage begins with the construction of a system architecture in the form of use cases and activity diagrams. Then the initialize stage is translating the system architecture design into an application interface design. Next is the stage of translating the design into an actual application using lumens and mariaDB on the server side and javascript and indexedDB on the client side. After each module is completed, the system functionality modules are integrated into a whole application into a thesis monitoring system. Then the software functionality testing is carried out, especially when it is run on a smartphone. The test results indicate that there are no bugs or errors found when running on laptop or mobile devices

Leukotriene A4 hydrolase inhibition improves age-related cognitive decline via modulation of synaptic function.

Leukotrienes, a class of inflammatory bioactive lipids, are well studied in the periphery, but less is known of their importance in the brain. We identified that the enzyme leukotriene A4 hydrolase (LTA4H) is expressed in healthy mouse neurons, and inhibition of LTA4H in aged mice improves hippocampal dependent memory. Single-cell nuclear RNA sequencing of hippocampal neurons after inhibition reveals major changes to genes important for synaptic organization, structure, and activity. We propose that LTA4H inhibition may act to improve cognition by directly inhibiting the enzymatic activity in neurons, leading to improved synaptic function. In addition, LTA4H plasma levels are increased in both aging and Alzheimer's disease and correlated with cognitive impairment. These results identify a role for LTA4H in the brain, and we propose that LTA4H inhibition may be a promising therapeutic strategy to treat cognitive decline in aging related diseases.

Role of dysregulated macrophage subpopulation ratios and functional changes in the development of coronary atherosclerosis.

Coronary heart disease is one of the most significant risk factors affecting human health worldwide. Its pathogenesis is intricate, with atherosclerosis being widely regarded as the leading cause. Aberrant lipid metabolism in macrophages is recognized as one of the triggering factors in atherosclerosis development. To investigate the role of macrophages in the formation of coronary artery atherosclerosis, we utilized single-cell data from wild-type mice obtained from the aortic roots and ascending aortas after long-term high-fat diet feeding, as deposited in GSE131776. Seurat software was employed to refine the single-cell data in terms of scale and cell types, facilitating the identification of differentially expressed genes. Through the application of differential expression genes, we conducted Gene Ontology and Kyoto Encyclopedia of Genes and Genomes functional enrichment analyses at 0, 8 and 16 weeks, aiming to uncover pathways with the most pronounced functional alterations as the high-fat diet progressed. The AddModuleScore function was employed to score the expression of these pathways across different cell types. Subsequently, macrophages were isolated and further subdivided into subtypes, followed by an investigation into intercellular communication within these subtypes. Subsequent to this, we induced THP-1 cells to generate foam cells, validating critical genes identified in prior studies. The results revealed that macrophages underwent the most substantial functional changes as the high-fat diet progressed. Furthermore, two clusters were identified as potentially playing pivotal roles in macrophage functional regulation during high-fat diet progression. Additionally, macrophage subtypes displayed intricate functionalities, with mutual functional counterbalances observed among these subtypes. The proportions of macrophage subtypes and the modulation of anti-inflammatory and pro-inflammatory functions played significant roles in the development of coronary artery atherosclerosis.

Autophagy Intervened by MicroRNAs Causes Gliomas

miRNAs are found in organisms like animals, plants and a few viruses. They play a role in the modulation of post-transcriptional genome function and in the suppression of RNA. Glial cells, which support the functioning of the neuron (the alternative major type of brain cell), are the cause of brain tumors known as gliomas. Gliomagenesis is the process of the formation and growth of gliomas. A solitary miRNA has the ability to regulate several receptors at distinct stages of autophagy. Numerous miRNAs associated to autophagy were implicated in various phases of the development and advancement of carcinoma. These regulate a number of crucial metabolic processes, such as the cancer autophagic reflex. It has been observed that the activity of genes involved in gliomagenesis, tumor growth, proliferation, apoptosis and posttranscriptional control of anti-oncogenes is impacted by microRNA (miRNA) expression profile. Gliomas may thus deteriorate as a result of compromised miRNAs. The prognosis, therapeutic response and glioma origin may all be determined by miRNA profiling. miRNAs have the ability to be released into circulation and Cerebrospinal Fluid (CSF). They can also be transferred freely or via exosomes between normal and tumor cells, changing them into possible biomarkers for prognosis and/or diagnosis for gliomas.

Effect of high cyclic hydrostatic pressure on osteogenesis of mesenchymal stem cells cultured in liquefied micro-compartments

Bone resident cells are constantly subjected to a range of distinct mechanical loadings, which generates a complex microenvironment. In particular, hydrostatic pressure (HP) has a key impact on modulation of cell function and fate determination. Although HP is a constant mechanical stimulus, its role in regulating the osteogenesis process within a defined 3D microenvironment has not been comprehensively elucidated. Perceiving how environmental factors regulate the differentiation of stem cells is essential for expanding their regenerative potential. Inspired by the mechanical environment of bone, this study attempted to investigate the influence of different ranges of cyclic HP on human adipose-derived mesenchymal stem cells (MSCs) encapsulated within a compartmentalized liquefied microenvironment. Taking advantage of the liquefied environment of microcapsules, MSCs were exposed to cyclic HP of 5 or 50 MPa, 3 times/week at 37 °C. Biological tests using fluorescence staining of F-actin filaments showed a noticeable improvement in cell-cell interactions and cellular network formation of MSCs. These observations were more pronounced in osteogenic (OST) condition, as confirmed by fluorescent staining of vinculin. More interestingly, there was a significant increase in alkaline phosphatase activity of MSCs exposed to 50 MPa magnitude of HP, even in the absence of osteoinductive factors. In addition, a greater staining area of both osteopontin and hydroxyapatite was detected in the 50 MPa/OST group. These findings highlight the benefit of hydrostatic pressure to regulate osteogenesis of MSCs as well as the importance of employing simultaneous biochemical and mechanical stimulation to accelerate the osteogenic potential of MSCs for biomedical purposes.

Molecular dipole regulated surface potential and ferroelectric characteristics in nanoconfined P(VDF-TrFE) architectures

Molecular dipole orientation is crucial to efficiently utilize the piezo- and ferroelectric polarization in polymers. Modern electronic applications of these polymer demand switching of dipoles with low voltage, which requires the dipole orientation to be perpendicular to the substrate (edge-on) rather than parallel (face-on). The 0D, 1D and 2D confinement of polymer architectures into nanoparticles, nanofibers, and thin films is a vital approach to control dipole orientation in ferroelectrics. Our findings show that for 1D (d33 ∼ 18 ± 2.2 pm/V) and 2D nanostructures (d33 ∼ 15 ± 1.5 pm/V) of poly(vinylidenefluoride-trifluoroethylene) (P(VDF-TrFE)), the molecular dipoles are edge-on, whereas for 0D, the dipoles are face-on, which would govern the ferroelectric and piezoelectric behaviour of these confined structures. The subsequent observation concludes that altering the dipole orientation allows precise modulation of surface potential and work function. The work functions of the 0D, 1D and 2D nanostructures are 4.56 ± 0.03 eV, 4.93 ± 0.51 eV and 4.68 ± 0.18 eV, respectively. The tunability of surface potential opens up the possibility of utilizing these nanostructures in single-material triboelectric series. Density functional theory (DFT)-based computations substantially support these experimental findings. This study provides a thorough understanding of the effect of molecule dipole orientation on piezo- and ferroelectric properties of P(VDF-TrFE) nanostructures.

Atomic tracking of thermally‐driven structural evolution in 2D crystals: Case of NbSe2

AbstractAdvanced atomic tracking techniques play a critical role in characterizing structural evolution, elucidating fundamental mechanisms of exotic phenomena and tailoring delicate properties. Thermally driven structural modulation in 2D crystals, such as the charge density wave (CDW), often leads to intriguing quantum properties, making them a valuable platform for exploring fundamental physics and potential device applications. However, despite their significance, experimental studies addressing atomic tracking of thermally‐driven structural evolution in 2D crystals have been limited. Herein, we utilize high‐accuracy variable‐temperature atomic tracking measurements with scanning tunneling microscopy (STM) to directly observe a series of structural transitions in a model 2D crystal, namely NbSe2. With the atomic tracking technique, we confirm the existence of the universal thermally‐driven CDW transition hysteresis between the heating and cooling cycles. This transition hysteresis, characterized by a constant temperature offset, represents a new phenomenon of structural evolution. Our findings provide a feasible method to track CDW transitions at the atomic scale in 2D crystals, significantly contributing to a better understanding and the potential modulation of these materials' functions in nanodevices.image

The Role of Substance P and NK1 Receptors in Mild to Severe Traumatic Brain Injury: From CTE to ICP

Binding of substance P to the tachykinin NK1 receptor is involved in numerous physiological and pathophysiological processes ranging from modulation of sensory and motor function to inflammation, cancer, and brain injury, amongst others. NK1 antagonists therefore have enormous potential as a therapeutic intervention in a wide variety of human disease states, albeit that the clinical potential is yet to be fully realised. In the current review, the role of substance P in the pathophysiology of traumatic brain injury (TBI) will be discussed, summarising both experimental and clinical observations in mild, moderate, and severe TBI. In addition, the potential for NK1 antagonists to be a valuable therapeutic intervention against chronic traumatic encephalopathy (CTE) after repeated concussive brain injury as well as raised intracranial pressure (ICP) following severe TBI will be addressed, highlighting the various pathophysiological processes that are attenuated by the intervention.

Site-selected in situ polymerization for living cell surface engineering

The construction of polymer-based mimicry on cell surface to manipulate cell behaviors and functions offers promising prospects in the field of biotechnology and cell therapy. However, precise control of polymer grafting sites is essential to successful implementation of biomimicry and functional modulation, which has been overlooked by most current research. Herein, we report a biological site-selected, in situ controlled radical polymerization platform for living cell surface engineering. The method utilizes metabolic labeling techniques to confine the growth sites of polymers and designs a Fenton-RAFT polymerization technique with cytocompatibility. Polymers grown at different sites (glycans, proteins, lipids) have different membrane retention time and exhibit differential effects on the recognition behaviors of cellular glycans. Of particular importance is the achievement of in situ copolymerization of glycomonomers on the outermost natural glycan sites of cell membrane, building a biomimetic glycocalyx with distinct recognition properties.

CNSC-43. TARGETING NEURONAL EXCITABILITY FOR NF1 LOW-GRADE GLIOMA THERAPY

Abstract While neuronal activity has previously been implicated in malignant glioma growth control, we recently demonstrated that neuron excitability can also regulate low-grade (optic) glioma initiation and progression. In this prior study, we showed that NF1 germline mutation-dependent neuronal excitability sustains optic glioma growth through HCN channel-mediated midkine activation of a T cell-microglia stromal circuit. Relevant to clinical translation, lamotrigine modulation of HCN channel function reduced neuronal hyperexcitability, midkine production and optic glioma (OPG) growth. To establish an obligate role for neuronal activity and midkine (Mdk) production in OPG growth, we leveraged a series of unique genetically engineered mouse models. First, we demonstrate that midkine is necessary for gliomagenesis, as Nf1-OPG; Mdk-/- mice do not develop tumors and have restored retinal pathology, as evidenced by increased retinal ganglion cell (RGC) numbers and retinal nerve fiber layer thickness. Second, we show that midkine production and neuronal hyperactivity are interdependent, such that only tumor-associated germline Nf1 mutations result in increased RGC excitability and midkine production, whereas those mutations that do not cause optic gliomas lack RGC hyperexcitability or elevated midkine expression. Third, lamotrigine treatment both during and after Nf1-OPG development attenuates midkine levels and tumor proliferation. Moreover, this anti-tumoral effect is durable for months after the cessation of treatment. Fourth, oral treatment of Nf1-OPG-bearing mice with clinically relevant doses of lamotrigine (2.5-7.5mg/kg/day) during OPG development blocks tumor formation. Together, these data establish midkine and neuronal hyperexcitability as key drivers of Nf1 optic glioma growth, relevant to planned clinical trials of this anti-seizure medication for children with NF1-OPG.

Role of Soluble Urokinase-Type Plasminogen Activator Receptor in Cardiovascular Disease.

Chronic inflammation is a major contributor to cardiovascular disease (CVD) risk. Soluble urokinase plasminogen activator receptor (suPAR) is an immune-derived glycoprotein that is strongly associated with atherosclerotic disease. This review summarizes evidence on suPAR's role in CVD pathogenesis and its potential as a prognostic indicator and therapeutic target. Clinical, genetic, and experimental evidence supports suPAR's role as a pathogenic factor in atherosclerosis. suPAR promotes atherosclerosis through modulation of monocyte activation and function. Clinically, elevated suPAR levels are linked to increased cardiovascular risk across diverse populations. Ongoing clinical trials are evaluating therapies targeting suPAR signaling. Current evidence positions suPAR as a regulator of myeloid cell function that contributes to vascular inflammation and subsequent cardiovascular events. Additional research is needed to determine whether suPAR measurement can improve CVD risk prediction and enable personalized management. Overall, suPAR is a promising immune-derived biomarker and target for reducing inflammation and cardiovascular risk.

OptoDyCE-plate as an affordable high throughput imager for all optical cardiac electrophysiology

We present a simple low-cost system for comprehensive functional characterization of cardiac function under spontaneous and paced conditions, in standard 96 and 384-well plates. This full-plate actuator/imager, OptoDyCE-plate, uses optogenetic stimulation and optical readouts of voltage and calcium (parallel recordings from up to 100 wells in 384-well plates are demonstrated). The system is validated with syncytia of human induced pluripotent stem cell derived cardiomyocytes, iPSC-CMs, grown as monolayers, or in quasi-3D isotropic and anisotropic constructs using electrospun matrices, in 96 and 384-well format. Genetic modifications, e.g. interference CRISPR (CRISPRi), and nine compounds of acute and chronic action were tested, including five histone deacetylase inhibitors (HDACis). Their effects on voltage and calcium were compared across growth conditions and pacing rates. We also demonstrated optogenetic point pacing via cell spheroids to study conduction in 96-well format, as well as temporal multiplexing to register voltage and calcium simultaneously on a single camera. Opto-DyCE-plate showed excellent performance even in the small samples in 384-well plates. Anisotropic structured constructs may provide some benefits in drug testing, although drug responses were consistent across tested configurations. Differential voltage vs. calcium responses were seen for some drugs, especially for non-traditional modulators of cardiac function, e.g. HDACi, and pacing rate was a powerful modulator of drug response, highlighting the need for comprehensive multiparametric assessment, as offered by OptoDyCE-plate. Increasing throughput and speed and reducing cost of screening can help stratify potential compounds early in the drug development process and accelerate the development of safer drugs.