Chemical Modulation Research Articles

Electron localization induced by intrinsic anion disorder in a transition metal oxynitride

Anderson localization derived from randomness plays a crucial role in various kinds of phase transitions. Although treated as a free variable parameter in theory, randomness in electronic materials is hard to control experimentally owing to the coexisting Coulomb interaction. Here we demonstrate that the intrinsic anion disorder in a mixed-anion system of SrNbO2N induces a significant random potential that overwhelms the Coulomb potential while maintaining the lattice structure. A metal-to-insulator transition is triggered by a chemical modulation of the electron density where the critical electron density is more than three orders of magnitude greater than that predicted by the well-known Mott criterion. The localized electrons show characteristic electrical properties such as temperature-dependent multiple crossovers of conduction mechanisms and a positive magnetoresistance above 50% at low temperature. The large magnetoresistance is attributed to wave-function shrinkage of the localized states and clearly visualizes the anisotropy in the band structure, which indicates a compatibility of the periodicity and randomness.

Development of SETS (Science, Environment, Technology, And Society) Oriented Chemical Learning Module on Natural Oil Concept

The Indonesian government is trying to prepare the next generation of nations to deal with the globalization era; one of these is education. It was transformed in the application of Kurikulum 2013, in which the object of the learning process is more emphasis on phenomena or real events. But, the learning methods are still unvaried, and learning materials based on real-life problems are still not available, which creates a performance gap in the learning process. This research aims to cope with the performance gap by developing the saints, environment, technology, and society (SETS)-oriented module on petroleum topic and determine the students' response. The module developed in this research is done following a phase of the ADDIE developmental model. This developmental model consists of analyze, design, development, implementation, and evaluation. This SETS-oriented module has been trialed to 30 second-grade students of SMA Negeri 8 Kota Serang. According to validation and students' response, the SETS-oriented module developed is valid and got 87,37% of an average percentage of response, which includes great criteria

Exploration of Aberrant E3 Ligases Implicated in Alzheimer's Disease and Development of Chemical Tools to Modulate Their Function.

The Ubiquitin Proteasome System (UPS) is responsible for the degradation of misfolded or aggregated proteins via a multistep ATP-dependent proteolytic mechanism. This process involves a cascade of ubiquitin (Ub) transfer steps from E1 to E2 to E3 ligase. The E3 ligase transfers Ub to a targeted protein that is brought to the proteasome for degradation. The inability of the UPS to remove misfolded or aggregated proteins due to UPS dysfunction is commonly observed in neurodegenerative diseases, such as Alzheimer’s disease (AD). UPS dysfunction in AD drives disease pathology and is associated with the common hallmarks such as amyloid-β (Aβ) accumulation and tau hyperphosphorylation, among others. E3 ligases are key members of the UPS machinery and dysfunction or changes in their expression can propagate other aberrant processes that accelerate AD pathology. The upregulation or downregulation of expression or activity of E3 ligases responsible for these processes results in changes in protein levels of E3 ligase substrates, many of which represent key proteins that propagate AD. A powerful way to better characterize UPS dysfunction in AD and the role of individual E3 ligases is via the use of high-quality chemical tools that bind and modulate specific E3 ligases. Furthermore, through combining gene editing with recent advances in 3D cell culture, in vitro modeling of AD in a dish has become more relevant and possible. These cell-based models of AD allow for study of specific pathways and mechanisms as well as characterization of the role E3 ligases play in driving AD. In this review, we outline the key mechanisms of UPS dysregulation linked to E3 ligases in AD and highlight the currently available chemical modulators. We present several key approaches for E3 ligase ligand discovery being employed with respect to distinct classes of E3 ligases. Where possible, specific examples of the use of cultured neurons to delineate E3 ligase biology have been captured. Finally, utilizing the available ligands for E3 ligases in the design of proteolysis targeting chimeras (PROTACs) to degrade aberrant proteins is a novel strategy for AD, and we explore the prospects of PROTACs as AD therapeutics.

Metabolic resistance to the inhibition of mitochondrial transcription revealed by CRISPR‐Cas9 screen

Cancer cells depend on mitochondria to sustain their increased metabolic need and mitochondria therefore constitute possible targets for cancer treatment. We recently developed small‐molecule inhibitors of mitochondrial transcription (IMTs) that selectively impair mitochondrial gene expression. IMTs have potent antitumor properties in vitro and in vivo, without affecting normal tissues. Because therapy‐induced resistance is a major constraint to successful cancer therapy, we investigated mechanisms conferring resistance to IMTs. We employed a CRISPR‐Cas9 (clustered regularly interspaced short palindromic repeats)‐(CRISP‐associated protein 9) whole‐genome screen to determine pathways conferring resistance to acute IMT1 treatment. Loss of genes belonging to von Hippel–Lindau (VHL) and mammalian target of rapamycin complex 1 (mTORC1) pathways caused resistance to acute IMT1 treatment and the relevance of these pathways was confirmed by chemical modulation. We also generated cells resistant to chronic IMT treatment to understand responses to persistent mitochondrial gene expression impairment. We report that IMT1‐acquired resistance occurs through a compensatory increase of mitochondrial DNA (mtDNA) expression and cellular metabolites. We found that mitochondrial transcription factor A (TFAM) downregulation and inhibition of mitochondrial translation impaired survival of resistant cells. The identified susceptibility and resistance mechanisms to IMTs may be relevant for different types of mitochondria‐targeted therapies.

Treatment of HT29 Human Colorectal Cancer Cell Line with Nanocarrier-Encapsulated Camptothecin Reveals Histone Modifier Genes in the Wnt Signaling Pathway as Important Molecular Cues for Colon Cancer Targeting.

Cancer cells are able to proliferate in an unregulated manner. There are several mechanisms involved that propel such neoplastic transformations. One of these processes involves bypassing cell death through changes in gene expression and, consequently, cell growth. This involves a complex epigenetic interaction within the cell, which drives it towards oncogenic transformations. These epigenetic events augment cellular growth by potentially altering chromatin structures and influencing key gene expressions. Therapeutic mechanisms have been developed to combat this by taking advantage of the underlying oncogenic mechanisms through chemical modulation. Camptothecin (CPT) is an example of this type of drug. It is a selective topoisomerase I inhibitor that is effective against many cancers, such as colorectal cancer. Previously, we successfully formulated a magnetic nanocarrier-conjugated CPT with β-cyclodextrin and iron NPs (Fe3O4) cross-linked using EDTA (CPT-CEF). Compared to CPT alone, it boasts higher efficacy due to its selective targeting and increased solubility. In this study, we treated HT29 colon cancer cells with CPT-CEF and attempted to investigate the cytotoxic effects of the formulation through an epigenetic perspective. By using RNA-Seq, several differentially expressed genes were obtained (p < 0.05). Enrichr was then used for the over-representation analysis, and the genes were compared to the epigenetic roadmap and histone modification database. The results showed that the DEGs had a high correlation with epigenetic modifications involving histone H3 acetylation. Furthermore, a subset of these genes was shown to be associated with the Wnt/β-catenin signaling pathway, which is highly upregulated in a large number of cancer cells. These genes could be investigated as downstream therapeutic targets against the uncontrolled proliferation of cancer cells. Further interaction analysis of the identified genes with the key genes of the Wnt/β-catenin signaling pathway in colorectal cancer identified the direct interactors and a few transcription regulators. Further analysis in cBioPortal confirmed their genetic alterations and their distribution across patient samples. Thus, the findings of this study reveal that colorectal cancer could be reversed by treatment with the CPT-CEF nanoparticle-conjugated nanocarrier through an epigenetic mechanism.

Generation of heart-forming organoids from human pluripotent stem cells.

Heart-forming organoids (HFOs) derived from human pluripotent stem cells (hPSCs) are a complex, highly structured in vitro model of early heart, foregut and vasculature development. The model represents a potent tool for various applications, including teratogenicity studies, gene function analysis and drug discovery. Here, we provide a detailed protocol describing how to form HFOs within 14 d. In an initial 4 d preculture period, hPSC aggregates are individually formed in a 96-well format and then Matrigel-embedded. Subsequently, the chemical WNT pathway modulators CHIR99021 and IWP2 are applied, inducing directed differentiation. This highly robust protocol can be used on many different hPSC lines and be combined with manipulation technologies such as gene targeting and drug testing. HFO formation can be assessed by numerous complementary methods, ranging from various imaging approaches to gene expression studies. Here, we highlight the flow cytometry-based analysis of individual HFOs, enabling the quantitative monitoring of lineage formation.

Modulation of a defined community ofOenococcus oenistrains byTorulaspora delbrueckiiand its impact on malolactic fermentation

Background and Aims Torulaspora delbrueckii is being used increasingly as a starter for alcoholic fermentation (AF) because of its chemical modulation of wine. Previous studies on this yeast in a natural must have shown a different Oenococcus oeni population by the end of MLF. In this study we aim to evaluate this aspect in a defined O. oeni strain consortium in a sterile grape must during winemaking. Methods and Results Before commencing AF with either S. cerevisiae or both T. delbrueckii and S. cerevisiae, the must was inoculated with a defined population of O. oeni strains. The use of T. delbrueckii determined the bacterial population at the end of MLF. Also, the inoculation of a selected strain after AF produced wines with different chemical composition to those fermented with the initial bacterial community. Conclusions Different yeast inoculation strategies modulate the O. oeni population, and this has an impact on the chemical composition of the wines. Moreover, the inoculation of a small O. oeni population in must leads to a process similar to spontaneous MLF. Significance of the Study Torulaspora delbrueckii can be used as a tool to modulate the O. oeni population and enhance the aromas related to MLF.

Impact of Unmitigated HFC Emissions on Stratospheric Ozone at the End of the 21st Century as Simulated by Chemistry‐Climate Models

AbstractHydrofluorocarbons (HFCs) have been increasingly replacing chlorofluorocarbons and hydrochlorofluorocarbons. Although their direct chemical ozone‐depleting potential is negligible, as potent greenhouse gases they modify atmospheric temperature and circulation patterns, thereby indirectly influencing stratospheric ozone recovery. Measurements and model projections must continue to evaluate HFC limitation measures and assess the long‐term impact of HFCs on the atmospheric radiation budget and stratospheric ozone. In this study, we present multi‐member ensemble simulations designed to estimate the impact of HFCs on stratospheric temperature, ozone and circulation changes at the end of the century. We compared simulations with and without HFCs for two three‐dimensional chemistry‐climate models that use the same chemistry module but different physical schemes. At low and mid‐latitudes, temperature and ozone responses were comparable for both models and in general agreement with previous studies. HFCs induced a marked temperature increase up to about 10–20 hPa and vertically alternating positive and negative ozone anomalies. We explained this pattern by competing effects of vertical motion (low and middle stratosphere) and temperature (upper stratosphere) anomalies. At northern high latitudes, there were strong discrepancies with previous studies and between the models themselves, attributed to differences in ozone anomalies caused by wave activity during winter. Quantitatively, we found a net positive, but small, HFC impact on total ozone amounts. Largest anomalies were less than 1% in the winter polar stratosphere. Our results indicate that increasing HFC amounts will likely have a limited impact on stratospheric ozone recovery within this century, with large uncertainty in the polar regions.

\u03b22-adrenergic receptor regulates ER-mitochondria contacts

Interactions between the endoplasmic reticulum (ER) and mitochondria (Mito) are crucial for many cellular functions, and their interaction levels change dynamically depending on the cellular environment. Little is known about how the interactions between these organelles are regulated within the cell. Here we screened a compound library to identify chemical modulators for ER-Mito contacts in HEK293T cells. Multiple agonists of G-protein coupled receptors (GPCRs), beta-adrenergic receptors (β-ARs) in particular, scored in this screen. Analyses in multiple orthogonal assays validated that β2-AR activation promotes physical and functional interactions between the two organelles. Furthermore, we have elucidated potential downstream effectors mediating β2-AR-induced ER-Mito contacts. Together our study identifies β2-AR signaling as an important regulatory pathway for ER-Mito coupling and highlights the role of these contacts in responding to physiological demands or stresses.

Identification of novel positive allosteric modulators of GLP1R that stimulate its interaction with ligands and Gα subunits

Glucagon-like peptide-1 (GLP-1) is a major incretin hormone that enhances the release of insulin from pancreatic β-cells by activating the glucagon-like peptide-1 receptor (GLP1R), which belongs to secretin-like class B of G protein-coupled receptors (GPCRs). Owing to the absence of small molecule agonist drugs to GLP1R, focus has been placed on chemical modulators that bind to the allosteric site of GLP1R. In this study, we identified novel small-molecule positive allosteric modulators of GLP1R from a chemical library consisting of commercial drug compounds using an assay system that measures the direct interaction between a purified GLP1R and its ligand, exendin-4. Two newly identified compounds, benzethonium and tamoxifen, significantly enhanced the affinity of peptide ligands for GLP1R although they lacked agonist activity by themselves. In addition, benzethonium augmented the ligand-induced accumulation of cAMP in GLP1R-transfected HEK293T cells. These compounds significantly increased the affinity of GLP1R to the alpha-subunit of G proteins, suggesting that they stabilize GLP1R in a conformation with a higher affinity to peptide ligand as well as G proteins. These compounds may lead to the design of an orally active positive allosteric modulator for GLP1R.

Iodine chemistry in the chemistry–climate model SOCOL-AERv2-I

Abstract. In this paper, we present a new version of the chemistry–climate model SOCOL-AERv2 supplemented by an iodine chemistry module. We perform three 20-year ensemble experiments to assess the validity of the modeled iodine and to quantify the effects of iodine on ozone. The iodine distributions obtained with SOCOL-AERv2-I agree well with AMAX-DOAS observations and with CAM-chem model simulations. For the present-day atmosphere, the model suggests that the iodine-induced chemistry leads to a 3 %–4 % reduction in the ozone column, which is greatest at high latitudes. The model indicates the strongest influence of iodine in the lower stratosphere with 30 ppbv less ozone at low latitudes and up to 100 ppbv less at high latitudes. In the troposphere, the account of the iodine chemistry reduces the tropospheric ozone concentration by 5 %–10 % depending on geographical location. In the lower troposphere, 75 % of the modeled ozone reduction originates from inorganic sources of iodine, 25 % from organic sources of iodine. At 50 hPa, the results show that the impacts of iodine from both sources are comparable. Finally, we determine the sensitivity of ozone to iodine by applying a 2-fold increase in iodine emissions, as it might be representative for iodine by the end of this century. This reduces the ozone column globally by an additional 1.5 %–2.5 %. Our results demonstrate the sensitivity of atmospheric ozone to iodine chemistry for present and future conditions, but uncertainties remain high due to the paucity of observational data of iodine species.

The weighted set covering problem combined to computational fluid dynamics for optimisation of gas detectors

We propose a new approach to optimise the number and location of gas detectors employing the weighted set covering problem combined with computational fluid dynamics (CFD). The optimisation mesh that represents the nodes and the links of the Graph V{N,L} (N is the set of nodes and L is the set of links) of the set covering problem was calculated using computational fluid dynamics. The 0–1 integer programming model is solved using Balas algorithm. The developed model covered 100% of the area. We also tested the model in a typical chemical process module and the same coverage was attained. The optimal distribution of gas detectors was able to detect the ammonia release within 5 s. We also show that the procedure can be combined with the leak frequency for the determination of the weights of the subareas (nodes of the Graph V{N,L}). Numerical findings show that the weighted approach led to a shorter detection time when compared with the case where the subareas were not assigned a weight.

Seasonal simulations of summer aerosol optical depth over the Arabian Peninsula using WRF‐Chem: Validation, climatology, and variability

AbstractThis study investigates the climatology and variability of summer aerosol optical depth (AOD) over the Arabian Peninsula (AP) using a long‐term high‐resolution Weather Research and Forecasting model coupled with the chemistry module (WRF‐Chem) simulation, available ground‐based and satellite observations, and reanalysis products from 2008 to 2018. The simulated spatial distribution of the summer AOD agrees well with the satellite observations and reanalysis over the AP, with spatial correlation coefficients of 0.81/0.83/0.89 with MODIS‐A/MODIS‐T/MERRA‐2, respectively. Higher values of summertime AOD are broadly found over the eastern AP regions and the southern Red Sea and minima over the northern Red Sea and northwest AP, consistent with observational datasets. The WRF‐Chem simulation suggests that the two regions of high AOD are associated with dust advected from the Tigris–Euphrates by the northwesterly summer Shamal wind in the eastern AP and from the African Sahara via Sudan by westerly winds through the Tokar Gap for the southern AP. The high AOD over the south‐central east AP is due to locally generated dust by the action of northerly winds, modulated by variations in relative humidity, vertical motion, soil moisture, and soil temperature over the desert regions. The vertical extent of this dust is primarily driven by upward motion triggered by thermal convection over the local source region. In terms of interannual variability, summer AOD exhibits significant year‐to‐year variations over the AP region. In particular, enhanced (reduced) AOD over the southern AP (Persian Gulf) is observed during La Niña conditions, favoured by stronger (weaker) Tokar westerly (northwesterly summer Shamal) winds.HighlightsThis study evaluated the long‐term simulations of AOD using high resolution WRF‐Chem model over the AP.WRF‐Chem successfully simulated the summer AOD climatology and its variability.Potential driving factors of summer AOD loading over the AP is explored.Summer AOD variability in the AP is mainly driven by northern Shamal winds and westerly Tokar winds.Enhanced (reduced) AOD over the southern AP (Arabian Gulf) is observed during La Niña conditions.

Psychedelics and Other Psychoplastogens for Treating Mental Illness.

Psychedelics have inspired new hope for treating brain disorders, as they seem to be unlike any treatments currently available. Not only do they produce sustained therapeutic effects following a single administration, they also appear to have broad therapeutic potential, demonstrating efficacy for treating depression, post-traumatic stress disorder (PTSD), anxiety disorders, substance abuse disorder, and alcohol use disorder, among others. Psychedelics belong to a more general class of compounds known as psychoplastogens, which robustly promote structural and functional neural plasticity in key circuits relevant to brain health. Here we discuss the importance of structural plasticity in the treatment of neuropsychiatric diseases, as well as the evidence demonstrating that psychedelics are among the most effective chemical modulators of neural plasticity studied to date. Furthermore, we provide a theoretical framework with the potential to explain why psychedelic compounds produce long-lasting therapeutic effects across a wide range of brain disorders. Despite their promise as broadly efficacious neurotherapeutics, there are several issues associated with psychedelic-based medicines that drastically limit their clinical scalability. We discuss these challenges and how they might be overcome through the development of non-hallucinogenic psychoplastogens. The clinical use of psychedelics and other psychoplastogenic compounds marks a paradigm shift in neuropsychiatry toward therapeutic approaches relying on the selective modulation of neural circuits with small molecule drugs. Psychoplastogen research brings us one step closer to actually curing mental illness by rectifying the underlying pathophysiology of disorders like depression, moving beyond simply treating disease symptoms. However, determining how to most effectively deploy psychoplastogenic medicines at scale will be an important consideration as the field moves forward.

Lysophosphatidic acid (LPA) receptor modulators: Structural features and recent development.

Lysophosphatidic acid (LPA) activates six LPA receptors (LPAR1-6) and regulates various cellular activities such as cell proliferation, cytoprotection, and wound healing. Many studies elucidated the pathological outcomes of LPA are due to the alteration in signaling pathways, which include migration and invasion of cancer cells, fibrosis, atherosclerosis, and inflammation. Current pathophysiological research on LPA and its receptors provides a means that LPA receptors are new therapeutic targets for disorders associated with LPA. Various chemical modulators are developed and are under investigation to treat a wide range of pathological complications. This review summarizes the physiological and pathological roles of LPA signaling, development of various LPA modulators, their structural features, patents, and their clinical outcomes.

Discharge dynamics, plasma kinetics and gas flow effect in argon–acetylene discharges

We investigated capacitively coupled Ar/C2H2 RF plasmas with a 1D fluid model that couples a 13.56 MHz discharge module, a long timescale chemical module and a flow transport module. A new solution procedure was developed in order to accurately describe the coupling between the short timescale discharge dynamics and the long characteristic time processes that play a major role in the molecular growth of reactive species. The plasma was simulated for different inlet gas configurations and flowrates. We showed that for a showerhead configuration one may distinguish two situations. For short residence time the plasma was strongly electronegative in the very center of the discharge gap and dominated by large hydrocarbon positive and negative ions. In this situation the acetylene conversion, although moderate, lead to a significant molecular growth. For long residence time, although C2H2 underwent a total conversion, the products of the primary C2H2 dissociation process were consumed by surface deposition which reduced drastically the molecular growth in the short gap discharge considered here. Whatever the conditions, we confirmed the key-role of Ar* in the acetylene conversion, ionization kinetics as well as the subsequent molecular growth for neutral and charged species. We also showed that remote feed gas and showerhead configurations predicted similar results at low flowrate. At larger flowrate the two configurations presented some discrepancy. Especially H2 density was much larger for the remote feed gas configuration, which affected the overall plasma behavior. Our results highlight that realistic gas-flow models are essential for an accurate description of acetylene conversion in Ar/C2H2 plasma.

Spin-Dependent Transport at 2D Solids: From Nonmagnetic Layers to Ferromagnetic van der Waals Structures

Spintronics is a promising alternative to the conventional silicon transistor-based electronics that are gradually approaching their physical limitations. Ultrathin two-dimensional van der Waals (vdW) materials (2D materials) with controllable spin degrees of freedom are recognized as extremely promising spintronic materials in architectures for the post-Moore era. In this Perspective, we review recent progress on spin-dependent transport behaviors (SDTBs) confined at the 2D scale, which are the mainstream paradigms for spintronic devices. We first present the mechanism and the key factors of SDTBs in 2D nonmagnetic materials-based hybrid devices. Then, some chemical modulation strategies for inducing short-range magnetic order and magneto-electric performance into 2D nonmagnetic materials are discussed. Furthermore, we concentrate on introducing intriguing SDTBs in 2D long-range ferromagnetic materials-based vdW devices. Finally, we highlight the current challenges in the study of spin-dependent transport of 2D modified materials and 2D material-based spintronic devices, in the hope of accelerating their applications.

Modeling the time evolution of the dissociation fraction in low-pressure CO2 plasmas

The time evolution of the CO2 dissociation fraction in pulsed discharges is studied through kinetic modeling. The simulations are compared against experimental data obtained in pulsed DC glow and radio-frequency discharges, operated with currents of about 40 mA and powers of 40 W, sustained under low gas pressures (< 600 Pa). The model is used to analyse the experimental trends associated with different pulsed configurations, namely different combinations of pulse duration and delay between pulses. The results validate the chemical module used in this work and reveal the importance of electronically excited states, in particular CO(a3Π), to describe the evolution of CO2(X1Σ+) and CO(X1Σg+) densities. In particular, it is shown that CO(a3Π) can promote CO2 formation for increasing concentrations of O2 due to bimolecular reactions such as CO(a3Π) + O2(X3Σg−) → CO2(X1Σ+) + O(3P). At the same time, for low concentration of O2 the CO2 dissociation fraction can be stimulated through CO(a3Π) + CO2(X1Σ +) → 2CO(X1Σg+) + O(3P). It is also found that the pulse parameters influence the concentration of O2(X3Σg−) by favouring or limiting oxygen atomic recombination during the afterglow. Overall, this work addresses reaction mechanisms often overlooked in the CO2 plasma-based reforming literature, while confirming that electronically excited states play a key role in describing the dissociation fraction in CO2 plasmas operated under low pressure conditions.

Chemical Modulation of DNA Replication along G-Quadruplex Based on Topology-Dependent Ligand Binding.

Ligands that bind to and stabilize guanine-quadruplex (G4) structures to regulate DNA replication have therapeutic potential for cancer and neurodegenerative diseases. Because there are several G4 topologies, ligands that bind to their specific types may have the ability to preferentially regulate the replication of only certain genes. Here, we demonstrated that binding ligands stalled the replication of template DNA at G4, depending on different topologies. For example, naphthalene diimide derivatives bound to the G-quartet of G4 with an additional interaction between the ligand and the loop region of a hybrid G4 type from human telomeres, which efficiently repressed the replication of the G4. Thus, these inhibitory effects were not only stability-dependent but also topology-selective based on the manner in which G4 structures interacted with G4 ligands. Our original method, referred to as a quantitative study of topology-dependent replication (QSTR), was developed to evaluate correlations between replication rate and G4 stability. QSTR enabled the systematic categorization of ligands based on topology-dependent binding. It also demonstrated accuracy in determining quantitatively how G4 ligands control the intermediate state of replication and the kinetics of G4 unwinding. Hence, the QSTR index would facilitate the design of new drugs capable of controlling the topology-dependent regulation of gene expression.

Modulation of the nociceptive flexion reflex by conservative therapy in patients and healthy people: a systematic review and meta-analysis.

The nociceptive flexion reflex (NFR) is a spinally mediated withdrawal response and is used as an electrophysiological marker of descending modulation of spinal nociception. Chemical and pharmacological modulation of nociceptive neurotransmission at the spinal level has been evidenced by direct effects of neurotransmitters and pharmacological agents on the NFR. Largely unexplored are, however, the effects of nonpharmacological noninvasive conservative interventions on the NFR. Therefore, a systematic review and meta-analysis was performed and reported following the PRISMA guidelines to determine whether and to what extent spinal nociception measured through the assessment of the NFR is modulated by conservative therapy in patients and healthy individuals. Five electronic databases were searched to identify relevant articles. Retrieved articles were screened on eligibility using the predefined inclusion criteria. Risk of bias was investigated according to Version 2 of the Cochrane risk-of-bias assessment tool for randomized trials. The evidence synthesis for this review was conducted in accordance with the Grading of Recommendations Assessment, Development and Evaluation. Thirty-six articles were included. Meta-analyses provided low-quality evidence showing that conservative therapy decreases NFR area and NFR magnitude and moderate-quality evidence for increases in NFR latency. This suggests that conservative interventions can exert immediate central effects by activating descending inhibitory pathways to reduce spinal nociception. Such interventions may help prevent and treat chronic pain characterized by enhanced spinal nociception. Furthermore, given the responsiveness of the NFR to conservative interventions, the NFR assessment seems to be an appropriate tool in empirical evaluations of treatment strategies.PROSPERO registration number: CRD42020164495.