Mechanism Of Modulation Research Articles

Hfq influences ciprofloxacin accumulation in Escherichia coli independently of ompC and ompF post-transcriptional regulation.

The antibiotic resistance of pathogenic bacteria is currently one of the major problems in medicine, and finding novel antibacterial agents is one of the most difficult tasks in the field of biomedical sciences. Studies on such tasks can be successful only if genetic and molecular mechanisms leading to antibiotic resistance/sensitivity are understood. Previous reports indicated that the bacterial protein Hfq, discovered as an RNA chaperone but subsequently demonstrated to play also other functions in cells, is involved in the mechanisms of the response of bacterial cells to antibiotics. Recently, it was found that Hfq dysfunction resulted in more effective accumulation of an antibiotic ciprofloxacin in Escherichia coli cells irrespective of the presence or absence of the AcrB efflux pump. However, small RNA-mediated impairment of expression of the ompF gene, which encodes a porin involved in antibiotics influx, reversed the effects of the absence of Hfq on the antibiotic accumulation. This led to the hypothesis that Hfq might influence ciprofloxacin accumulation in the manner independent on its RNA chaperone function, as this protein might also influence cellular membrane structure and functions. Here, we demonstrate that in ompC and ompF mutants of E. coli, accumulation of ciprofloxacin is significantly impaired in the absence of Hfq or its C-terminal domain. These results corroborate the above-mentioned hypothesis on a sRNA-independent mechanism of Hfq-mediated modulation of the antibiotic transmembrane transport. Since fluoroquinolones use both protein- and lipid-mediated pathways to cross the outer membrane, Hfq may influence both processes. This possibility will be discussed herein.

Advances in cannabinoid receptors pharmacology: from receptor structural insights to ligand discovery.

The medicinal and recreational uses of Cannabis sativa have been recognized for thousands of years. Today, cannabis-derived medicines are used to treat a variety of conditions, including chronic pain, epilepsy, multiple sclerosis, and chemotherapy-induced nausea. However, cannabis use disorder (CUD) has become the third most prevalent substance use disorder globally. Cannabinoid receptors are the primary targets that mediate the effects of cannabis and its analogs. Despite their importance, the mechanisms of modulation and the full therapeutic potential of cannabinoid receptors remain unclear, hindering the development of the next generation of cannabinoid-based drugs. This review summarizes the discovery and medicinal potential of phytocannabinoids and explores the distribution, signaling pathways, and functional roles of cannabinoid receptors. It also discusses classical cannabinoid drugs, as well as agonists, antagonists, and inverse agonists, which serve as key therapeutic agents. Recent advancements in the development of allosteric drugs are highlighted, with a focus on positive and negative allosteric modulators (PAMs and NAMs) that target CB1 and CB2 receptors. The identification of multiple allosteric sites on the CB1 receptor and the structural basis for allosteric modulation are emphasized, along with the structure-based discovery of ago-BAMs for CB1. This review concludes by examining the future potential of allosteric modulators in cannabinoid drug development, noting that ongoing progress in cannabinoid-derived drugs continues to open new avenues for therapeutic use and paves the way for future research into their full medicinal potential.

Conversion of human multidrug transporter P-glycoprotein (ABCB1) from drug efflux to uptake pump: Evidence for a switch region modulating the direction of substrate transport.

The multidrug transporter P-glycoprotein (P-gp), is pivotal in exporting various chemically dissimilar amphipathic compounds including anti-cancer drugs, thus causing multidrug resistance during cancer treatment. P-gp is composed of two transmembrane domains (TMDs), each containing six homologous transmembrane helices (TMHs). Among these helices, TMH 6 and 12 align oppositely, lining a drug-binding pocket in the transmembrane region which acts as a pathway for drug efflux. Previously, we demonstrated that specific mutations within TMH 6 and 12 resulted in loss of substrate efflux and altered the transport direction from efflux to uptake for some substrates. This suggested the presence of a regulatory switch that governs the direction of transport. In this study, we sought to elucidate the mechanism of switch modulation of the uptake function by engineering several mutants via substituting specific residues in TMH 6 and 12. We discovered that the alanine substitution of four residues (V974, L975, V977, and F978) within the upper region of TMH 12, along with three residues (V334, F336, and F343) within TMH 6, was sufficient to convert P-gp from an efflux to an uptake pump. Additional mutagenesis of the residues in the middle region of TMH 12 revealed that the uptake function, like efflux, is reversible. Further studies, including molecular dynamics simulations, revealed that the switch region appears to act during the substrate translocation step. We propose that the switch region in TMH 6 and 12, which modulates the direction of transport by P-gp, provides a novel approach to selectively target P-gp-expressing cancer cells.

Resting-state functional connectivity between the frontoparietal network and the default mode network is aberrantly increased in ankylosing spondylitis

Lower back pain comprises the majority of the disease burden of patients with ankylosing spondylitis (AS), while the alterations of the large-scale brain networks could be implicated in the neuropathophysiology of pain. The frontoparietal network (FPN) is known as a pain modulation hub, with key nodes dorsolateral prefrontal cortex (dlPFC) and ventrolateral prefrontal cortex (vlPFC) participating in the pain modulation and reappraisal process. In this study, we adopted the analytical approaches of independent component analysis (ICA) and seed-based correlation analysis (SCA) to examine the resting-state functional connectivity (rsFC) of the large-scale brain networks, notably FPN, between 82 AS patients and 61 healthy controls (HCs). We also investigated the correlation between the rsFC and the clinical measures of AS patients. Both ICA and SCA consistently showed that the rsFC between FPN and mPFC, a key node of the default mode network (DMN), was significantly increased in AS. In addition, SCA also identified a cluster at the right posterior lobe of cerebellum which exhibited increased rsFC with the posterior cingulate cortex, and the right lateral prefrontal cortex also showed increased rsFC with the right dlPFC. Correlation analysis showed that the rsFC between mPFC and the left anterior prefrontal cortex was significantly correlated with C-reactive protein in AS. The increased FPN-DMN connectivity could contribute to the neuropathophysiology of lower back pain in AS, with potential association with faulty pain modulation and reappraisal mechanisms facilitated by the FPN.

A numerical study of unusual flux decreases for cosmic ray protons and electrons observed by Alpha Magnetic Spectrometer in 2017

Alpha Magnetic Spectrometer (AMS), installed on the International Space Station, delivers precision measurements of cosmic proton fluxes and electron fluxes, providing unique inputs to further improve our understanding of the solar modulation of cosmic protons and electrons. The latest measurements published by AMS show significant decreases in daily cosmic proton fluxes and electron fluxes in the second half of 2017 (approximately from June 11, 2017 to December 23, 2017). A special structure, known as a loop, appears in the electron-proton hysteresis during this period. These declining fluxes, as well as their recovery toward solar minimum modulation, could be attributed to solar wind structures such as global merged interaction regions (GMIRs), which can affect cosmic ray flux for several months, as well as coronal mass ejections (CMEs). We aim to find the reason for the decrease and clarify the solar modulation mechanism underlying the loop structure. We developed a 3D numerical model based on Parker transport equation, which is solved as a set of stochastic differential equations, combined with diffusion barriers propagating away from the Sun. Correspondingly, the relevant parameters can be tuned up. The unusual changes in cosmic proton fluxes and electron fluxes in the second half of 2017 could be caused by CMEs and GMIRs. The decreases in these fluxes in 2017, with rigidities below 11 GV, have been successfully reproduced. Daily variations at Earth in terms of the diffusion coefficients (and their mean-free paths) were subsequently obtained. Furthermore, our simulation reveals that the electron-proton hysteresis loop structure in 2017 results from the different responses of protons and electrons to solar modulation, especially with respect to drift and diffusion processes in the heliosphere.

P0017 Single-cell transcriptomic analysis reveals insights into the mechanism of action and immune modulation by granulocyte-monocyte apheresis

Abstract Background Granulocyte-monocyte apheresis (GMA) with Adacolumn® is a non-pharmacological therapy used for ulcerative colitis (UC). Despite its clinical efficacy, the precise immunological mechanisms of GMA have not been completely characterized. This study aimed to uncover the immune cell composition and signalling changes induced by GMA using single-cell RNA sequencing (scRNA-Seq) of peripheral blood mononuclear cells (PBMCs) in UC patients. Methods Patients with steroid-dependent UC receiving GMA were included. scRNA-Seq was performed on PBMCs obtained at a) immediately pre-treatment, b) post-first session (outflow catheter), and c) 1 month after induction GMA. We applied an in-house standard pipeline for quality control, including batch correction and data integration, followed by differential gene expression analyses to ascertain the alterations in immune cell profiles and regulatory pathways induced by GMA. Results Five patients were included and 12 samples were analysed, averaging 8,997 cells and 19,424 genes each. We observed pervasive modulations in immune cell composition, most notably reductions in classical monocytes and expansions in plasmacytoid dendritic cells (pDCs) and Natural Killer (NK) cells. The pathway analyses highlighted downregulation of NF-κB and IL6/JAK/STAT3 signalling across multiple immune cell types, implying widespread decrease in inflammatory activity. This downregulation was particularly pronounced in samples collected immediately after the first session (outflow catheter), suggesting an acute suppression of inflammatory signalling. Classical monocytes showed reduced expression of key pro-inflammatory genes, including TNF, NFKBIZ, and NFKBIA, indicating suppressed pro-inflammatory potential. In turn, non-classical monocytes displayed upregulation of anti-inflammatory markers such as IL1R2, suggesting a reorientation toward balanced immune control. By the second visit (one month after induction), we observed a marked return to homeostasis. This included increased expression of immunoglobulin-related genes, such as IGHA1 and IGKC, across various T cell subsets, such as regulatory T cells (Tregs) and tissue-resident memory T cells (Trm). These patterns suggest a heightened capacity for immune regulation and improved balance within the immune response over time. Conclusion This first single-cell transcriptomic analysis of GMA in UC patients reveals selective impacts on immune cell composition and signalling, with sustained reductions in inflammation and enhanced regulatory balance over time. Our work underscores the potential of GMA as a targeted therapeutic approach to managing immune dysregulation in UC, paving the way for future exploration into its application and optimization in immune-mediated diseases.

Human cornea-derived mesenchymal stromal cells inhibit T cells through indoleamine 2,3 dioxygenase.

Defining the mechanism of immune modulation by mesenchymal stromal cells (MSCs) from distinct anatomical tissues is of great translational interest. The human cornea is an immunologically privileged organ, and the mechanism of immunoregulation of cornea-derived MSCs (cMSCs) is currently unknown. We investigated cMSCs derived from the corneas of 5 independent human donorS for their fitness and mechanism of action in suppressing T cells. cMSCs display the immunophenotype CD45-CD73+CD105+CD90+CD44+ and robust in vitro growth. 30-plex secretome analysis identified that cMSCs innately secrete specific molecules in a dose-dependent manner. cMSCs do not express or upregulate costimulatory but do upregulate coinhibitory molecules upon stimulation with interferon γ (IFNγ). cMSCs inhibit T-cell proliferation in contact-dependent co-cultures, which can be predicted by a unique secretome signature. In addition, co-culturing in a 2-chamber transwell system has demonstrated that cMSCs also inhibit T-cell proliferation in a non-contact-dependent manner. Mechanistic analysis has demonstrated that activated T cells effectively induce indoleamine 2,3-dioxygenase (IDO) but not other enzymes of the tryptophan metabolic pathway in cMSCs. Silencing of IDO in cMSCs reduces their fitness to suppress T cells. These results provide evidence that in cMSCs, one of the principal mechanisms of immunosuppression on T cells is through IDO. These results suggest that MSCs derived from the human cornea display immunoregulatory properties and, thus, may play a role in maintaining the immune-privileged niche of the cornea.

ADARp110 promotes hepatocellular carcinoma progression via stabilization of CD24 mRNA

ADAR is highly expressed and correlated with poor prognosis in hepatocellular carcinoma (HCC), yet the role of its constitutive isoform ADARp110 in tumorigenesis remains elusive. We investigated the role of ADARp110 in HCC and underlying mechanisms using clinical samples, a hepatocyte-specific Adarp110 knock-in mouse model, and engineered cell lines. ADARp110 is overexpressed and associated with poor survival in both human and mouse HCC. It creates an immunosuppressive microenvironment by inhibiting total immune cells, particularly cytotoxic GZMB+CD8+ T cells infiltration, while augmenting Treg cells, MDSCs, and exhausted CD8+ T cells ratios. Mechanistically, ADARp110 interacts with SNRPD3 and RNPS1 to stabilize CD24 mRNA by inhibiting STAU1-mediated mRNA decay. CD24 protects HCC cells from two indispensable mechanisms: macrophage phagocytosis and oxidative stress. Genetic knockdown or monoclonal antibody treatment of CD24 inhibits ADARp110-overexpressing tumor growth. Our findings unveil different mechanisms for ADARp110 modulation of tumor immune microenvironment and identify CD24 as a promising therapeutic target for HCCs.

Conformal reconfigurable holographic metasurface for multifunctional radiation and scattering modulation.

A reconfigurable holographic metasurface (HM) with multifunctional modulation of radiation and scattering for conformal applications is designed in this paper. Based on optical holography theory, a holographic conformal modulation mechanism is proposed, and the conformal surface impedance distribution of HM is derived. To illustrate this mechanism, the designed conformal reconfigurable HM is used to demonstrate a series of radiation and scattering modulation functions, with its reconfigurable property enabling dynamic beam control. In radiation mode, beam scanning with wide angle from -50° to 50° is achieved. In scattering mode, specific responses are generated under different incident angles, including beam steering under oblique incidence within ±60°, multi-beam splitting within ±60° under normal incidence, and diffuse reflection. Low radar cross section (RCS) is exhibited over a wide frequency band from 7.2 to 25 GHz. The designed conformal reconfigurable HM shows high adaptability to cylindrical platforms, insensitivity to oblique incidence, and stability in beam deflection angles, which provides an innovative technical approach for information transmission and stealth in conformal devices.

Study on the modulation mechanism of the optoelectronic properties based on common electrode metal atom adsorption on graphene/MoTe2.

The two-dimensional graphene/MoTe2 heterostructure holds extensive potential applications in optoelectronic devices, sensors, and catalysts. To expand its optical applications, this study systematically investigates the adsorption stability of metal atoms (Au, Pt, Pd, and Fe) on the graphene/MoTe2 and their influence on its optoelectronic properties employing first-principles methods. The findings indicate that after the adsorption of Au and Pd, the structure retains its direct bandgap properties, while the adsorption of Pt and Fe exhibits indirect bandgap characteristics. The work functions for all adsorbed structures are lower compared to the pristine graphene/MoTe2. The total density of states is primarily derived from the C-2p, Mo-4d, Te-5p orbitals, as well as the d and s orbitals of the adsorbed atoms. The pristine graphene/MoTe2 exhibits significant absorption in the ultraviolet range. Once graphene/MoTe2 is adsorbed by metal atoms, it can significantly enhance the optical absorption across the spectrum from infrared to ultraviolet light. These findings provide important theoretical guidance for regulating the application of graphene/MoTe2 in optoelectronics and related fields. All analyses are grounded in density functional theory first principles and computed using CASTEP. Graphene/MoTe2 consists of 4 × 4 × 1 single-layer, graphene single layer, and 3 × 3 × 1 single-layer MoTe2. To prevent interactions between neighboring unit cells, a 20Å vacuum space in the z-direction is employed. The electronic exchange-correlation interactions are treated using the Perdew-Burke-Ernzerhof functional within the framework of the generalized gradient approximation. Van der Waals (vdW) interactions are incorporated using the vdW correction function proposed by Grimme, which effectively describes vdW interactions. During the simulation, the cutoff energy for plane wave expansion is set to 420eV, and the k-point grid is set to 4 × 4 × 1. The atomic displacement convergence standard is 0.002Å, the internal stress convergence standard is 0.1GPa, and the interaction force convergence standard between atoms is 0.05eV/Å. The convergence threshold for the iteration precision is set to ensure that the total energy for each atom is not less than 2 × 10-5eV/atom.

Arginine Metabolism Reprogramming in Perfluorooctanoic Acid (PFOA)-Induced Liver Injury.

Perfluorooctanoic acid (PFOA) is a persistent pollutant that has gained worldwide attention, owing to its widespread presence in the environment. Previous studies have reported that PFOA upregulates lipid metabolism and is associated with liver injury in humans. However, when the fatty acid degradation pathway is activated, lipid accumulation still occurs, suggesting the presence of unknown pathways and mechanisms that remain to be elucidated. In this study, adult C57BL/6N mice were exposed to PFOA at 0.1, 1, and 10 mg/kg/day. Using integrated metabolomics and transcriptomics, it was uncovered that arginine metabolism was differentially downregulated in all three groups. In vitro studies confirmed the downregulation of arginine metabolism in MIHA cell lines treated with PFOA. Supplementation of arginine could effectively rescue liver injury and downregulate the chemokine levels caused by PFOA. This finding highlights the contribution of arginine metabolism in maintaining liver health following PFOA exposure and suggests potential mechanisms of metabolic and immune modulation.

Study on the Electrical and Mechanical Properties of TiC Particle-Reinforced Copper Matrix Composites Regulated by Different Rare Earth Elements.

Copper matrix composites (CMCs) synergistically reinforced with rare earth oxides (Re2O3) and TiC were prepared using a powder metallurgy process with vacuum hot-pressing and sintering technology, aiming to explore new ways to optimize the properties of composites. Through this innovative approach, we propose a new solution strategy and idea for the difficult problem of mutual constraints between electrical and mechanical properties faced by traditional dual-phase reinforced Cu-matrix composites. Meanwhile, the modulation mechanism of Re2O3 in CMCs and the electrical and mechanical properties of the composites were investigated. The compressive yield strength was improved from pure Cu (50 MPa) to TiC/Cu (159 MPa). The yield strength of Eu2O3-TiC/Cu obtained after biphasic strengthening is 213 MPa, which is 326% higher than that of pure Cu, and the ultimate compressive strength reaches 790 MPa. The conductivity was enhanced from TiC/Cu (81.4% IACS) to La2O3-TiC/Cu (87.3% IACS).

Imaging the Brainstem Raphe in Medication-Overuse Headache: Pathophysiological Insights and Implications for Personalized Care.

Background/Objectives: Medication-overuse headache (MOH) is a disabling condition affecting patients with chronic migraine resulting from excessive use of acute headache medication. It is characterized by both pain modulation and addiction-like mechanisms involving the brainstem raphe, a region critical to serotonergic signaling. This study investigates whether alterations in the brainstem raphe, assessed via transcranial sonography (TCS), are associated with MOH and independent of depressive symptoms, aiming to explore their utility as a biomarker. Methods: This prospective case-control study included 60 migraine patients (15 with MOH) and 7 healthy controls. Comprehensive clinical and psychometric assessments were performed to evaluate headache burden, medication use, and depressive symptoms. TCS was used to assess brainstem raphe echogenicity, with findings analyzed using generalized linear models adjusted for depression. Results: Non-visibility of the brainstem raphe was significantly associated with MOH, with an unadjusted odds ratio (OR) of 6.88 (95% CI: 1.32-36.01, p = 0.02). After adjusting for depressive symptoms, this association remained significant, with an adjusted OR of 1.85 (95% CI: 1.02-3.34, p = 0.041). TCS demonstrated good intraclass correlation, highlighting its reproducibility and ability to detect changes relevant to MOH pathophysiology. Conclusions: Brainstem raphe alterations are associated with MOH and may serve as a potential biomarker for its diagnosis and management. TCS offers a non-invasive, cost-effective tool for identifying MOH-specific mechanisms, which could improve clinical decision-making and support personalized care in chronic headache disorders. Further studies are needed to validate these findings and refine the clinical applications of brainstem-focused diagnostics.

The Mechanism of Modulation of Cardiac Force by Temperature.

In maximally Ca2+-activated demembranated fibres from the mammalian skeletal muscle, the depression of the force by lowering the temperature below the physiological level (~35 °C) is explained by the reduction of force in the myosin motor. Instead, cooling is reported to not affect the force per motor in Ca2+-activated cardiac trabeculae from the rat ventricle. Here, the mechanism of the cardiac performance depression by cooling is reinvestigated with fast sarcomere-level mechanics. We determine the changes in the half-sarcomere compliance of maximally Ca2+-activated demembranated rat trabeculae in the range of temperatures of 10-30 °C and analyse the data in terms of a simplified mechanical model of the half-sarcomere to extract the contribution of myofilaments and myosin motors. We find that the changes in the ensemble force are due to changes in the force per motor, while the fraction of actin-attached motors remains constant independent of temperature. The results demonstrate that in the cardiac myosin, as in the skeletal muscle myosin, the force-generating transition is endothermic. The underlying large heat absorption indicates the interaction of extended hydrophobic surfaces within the myosin motor, like those suggested by the crystallographic model of the working stroke.

Involvement of metformin and aging in salivary expression of ACE2 and TMPRSS2.

SARS-CoV-2-related proteins, ACE2 and TMPRSS2, are determinants of SARS-CoV-2 infection. Although these proteins are expressed in oral-related tissues, their expression patterns and modulatory mechanisms in the salivary glands remain unknown. We herein showed that full-length ACE2, which has both a fully functional enzyme catalytic site and high-affinity SARS-CoV-2 spike S1-binding sites, was more highly expressed in salivary glands than in oral mucosal epithelial cells and the lungs. Regarding TMPRSS2, zymogen and the cleaved form were both expressed in the salivary glands, whereas only zymogen was expressed in murine lacrimal glands and the lungs. Metformin, an AMPK activator, increased stimulated saliva secretion and full-length ACE2 expression and decreased cleaved TMPRSS2 expression in the salivary glands, and exerted the same effects on soluble ACE2 (sACE2) and sTMPRSS2 in saliva. Moreover, metformin decreased the expression of beta-galactosidase, a senescence marker, and ADAM17, a sheddase of ACE2 to sACE2, in the salivary glands. In aged mice, the expression of ACE2 was decreased in the salivary glands, whereas that of sACE2 was increased in saliva, presumably by the up-regulated expression of ADAM17. The expression of TMPRSS2 in the salivary glands and sTMPRSS2 in saliva were both increased. Collectively, these results suggest that the protein expression patterns of ACE2 and TMPRSS2 in the salivary glands differ from those in other oral-related cells and tissues, and also that metformin and aging affect the salivary expression of ACE2 and TMPRSS2, which have the potential as targets for preventing the transmission of SARS-CoV-2.

Improving influenza forecast in the tropics and subtropics: a case study of Hong Kong.

Influenza forecasts could aid public health response as shown for temperate regions, but such efforts are more challenging in the tropics and subtropics due to more irregular influenza activities. Here, we built six forecast approaches for influenza in the (sub)tropics, with six model forms designed to model seasonal infection risk (i.e. seasonality) based on the dependence of virus survival on climate conditions and to flexibly account for immunity waning. We ran the models jointly with the ensemble adjustment Kalman filter to generate retrospective forecasts of influenza incidence in subtropical Hong Kong from January 1999 to December 2019 including the 2009 A(H1N1)pdm09 pandemic. In addition to short-term targets (one to four weeks ahead predictions), we also tested mid-range (one to three months) and long-range (four to six months) forecasts, which could be valuable for long-term planning. The largest improvement came from the inclusion of climate-modulated seasonality modelling, particularly for the mid- and long-range forecasts. The best-performing approach included a seasonal-trend-based climate modulation and assumed mixed immunity waning; the forecast accuracies, including peak week and intensity, were comparable to that reported for temperate regions including the USA. These findings demonstrate that incorporating mechanisms of climate modulation on influenza transmission can substantially improve forecast performance in the (sub)tropics.

Immunotherapy in gastrointestinal cancers: current strategies and future directions – a literature review

Introduction: The National Cancer Institute defines the disease of “cancer” as a group of disorders in which aberrant cells proliferate uncontrollably and have the potential to infiltrate neighboring tissues. It is well established that cancer remains a significant etiology contributing to worldwide mortality. Gastrointestinal (GI) neoplasms are a type of cancer that affects the digestive system and adds to the total cancer burden. Conventionally, several therapies have been employed, such as radiation and chemotherapy; nevertheless, their adverse effects have prompted the need for an improved therapeutic alternative. Immunotherapy thus became a notable medium of treatment for several malignancies, including tumors of the GI tract. Aim: This comprehensive review seeks to provide insight on future directions and prospective therapies under development, as well as information regarding the present strategies utilized to mitigate one of the primary forms of cancer, GI cancer. Methods: A detailed analysis of the existing literature on GI cancers has been conducted. Several databases were employed to gather this information, mainly PubMed/MEDLINE. Different aspects of the disease were considered when searching the databases to provide a comprehensive review of the current and future strategies being incorporated to mitigate the negative consequences of this disease. Results: Many strategies are being used currently, and some are still under development. These comprise the usage of immune checkpoint inhibitors (ICIs), cytokine therapy, cancer vaccines, oncolytic viruses, and adoptive cell therapy. For instance, various monoclonal antibodies have been developed to inhibit the immunomodulatory effects of programmed death-1 and programmed death-1 ligand. There are also results of several clinical trials showing significant benefits and many changes are introduced to make the best of these strategies and minimize the challenges to group sizes. These challenges include overcoming the tumor’s immunosuppressive environment, finding suitable predictive biomarkers, and reducing the adverse effects. Additionally, several novel immunotherapeutic approaches, such as chimeric antigen receptor T-cell (CAR-T) therapy, are being studied. In 2017, the US FDA approved the use of two CAR-T therapies, which marks a major milestone following extensive research and clinical trials. New approaches such as toll-like receptor-directed and helminth-based immunotherapies are being developed for the treatment of GI cancers as well. These therapies, along with targeted treatments, represent the future of immunotherapy in GI cancers. Conclusion: Immunotherapy plays a significant role in the different types of GI cancers. However, optimizing these treatments will require overcoming barriers such as immune resistance, minimizing side effects, and improving the selection of patients through biomarkers. Continued research into these novel therapies and the mechanisms of immune modulation will be key to maximizing the therapeutic benefits of immunotherapy in the future.

Multicolor solid-state fluorescence and multicolor afterglow carbon dots: preparation, luminescence regulation, and applications

We review multicolor solid-state fluorescence and multicolor afterglow carbon dots (CDs) in perspectives of synthesis methods, luminescence modulation mechanisms, and applications.

On latent dynamics learning in nonlinear reduced order modeling.

In this work, we present the novel mathematical framework of latent dynamics models (LDMs) for reduced order modeling of parameterized nonlinear time-dependent PDEs. Our framework casts this latter task as a nonlinear dimensionality reduction problem, while constraining the latent state to evolve accordingly to an unknown dynamical system. A time-continuous setting is employed to derive error and stability estimates for the LDM approximation of the full order model (FOM) solution. We analyze the impact of using an explicit Runge-Kutta scheme in the time-discrete setting, resulting in the ΔLDM formulation, and further explore the learnable setting, ΔLDMθ, where deep neural networks approximate the discrete LDM components, while providing a bounded approximation error with respect to the FOM. Moreover, we extend the concept of parameterized Neural ODE - a possible way to build data-driven dynamical systems with varying input parameters - to be a convolutional architecture, where the input parameters information is injected by means of an affine modulation mechanism, while designing a convolutional autoencoder neural network able to retain spatial-coherence, thus enhancing interpretability at the latent level. Numerical experiments, including the Burgers' and the advection-diffusion-reaction equations, demonstrate the framework's ability to obtain a time-continuous approximation of the FOM solution, thus being able to query the LDM approximation at any given time instance while retaining a prescribed level of accuracy. Our findings highlight the remarkable potential of the proposed LDMs, representing a mathematically rigorous framework to enhance the accuracy and approximation capabilities of reduced order modeling for time-dependent parameterized PDEs.

The effect of carrier concentration on the electronic structure and magnetothermal properties of a two-dimensional VTe2 monolayer with a high Curie temperature.

Two-dimensional (2D) magnetic transition metal dichalcogenides have unique electronic properties, ferromagnetism, and tunable properties in low-dimensional systems. In this paper, the structural, electronic, and magnetic properties of the VTe2 monolayer under different carrier concentrations were investigated using first-principles calculations and Monte Carlo (MC) simulations. It is found that by introducing a suitable number of electrons, the VTe2 monolayer can undergo a transition from a semiconductor to a half-metal state, with 100% spin polarization. The magnetocrystalline anisotropy energy is up to 1855.62 μeV in the z-axis direction, which is conducive to maintaining ferromagnetic order above room temperature. In particular, the easy magnetic axis can undergo an in-plane to out-of-plane transition when doped with a small number of holes. In addition, doping can sensitively enhance or weaken the ferromagnetic exchange coupling strength. The magnetothermal results show that the Curie temperature of the VTe2 monolayer is 547 K in the absence of a size effect, and can be further increased to 574 K when hole doping reaches 1.825 × 1013 cm-2 (0.02 holes per atom). Increasing magnetocrystalline anisotropy and magnetic field can also make the Curie temperature larger. Our results suggest the potential applications of VTe2 in spintronics and provide a deeper understanding of the modulation mechanism.