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Epigenetic regulation and mitochondrial dysfunction are essential to the progression of idiopathic pulmonary fibrosis (IPF). Curcumin (CCM) in inhibits the progression of pulmonary fibrosis by regulating the expression of specific miRNAs and pulmonary fibroblast mitochondrial function; however, the underlying mechanism is unclear. C57BL/6 mice were intratracheally injected with bleomycin (5â¯mg/kg) and treated with CCM (25â¯mg/kg body weight/3 times per week, intraperitoneal injection) for 28 days. Verhoeff-Van Gieson, Picro sirius red, and Masson's trichrome staining were used to examine the expression and distribution of collagen and elastic fibers in the lung tissue. Pulmonary fibrosis was determined using micro-computed tomography and transmission electron microscopy. Human pulmonary fibroblasts were transfected with miR-29a-3p, and RT-qPCR, immunostaining, and western blotting were performed to determine the expression of DNMT3A and extracellular matrix collagen-1 (COL1A1) and fibronectin-1 (FN1) levels. The expression of mitochondrial electron transport chain complex (MRC) and mitochondrial function were detected using western blotting and Seahorse XFp Technology. CCM in increased the expression of miR-29a-3p in the lung tissue and inhibited the DNMT3A to reduce the COL1A1 and FN1 levels leading to pulmonary extracellular matrix remodeling. In addition, CCM inhibited pulmonary fibroblasts MRC and mitochondrial function via the miR-29a-3p/DNMT3A pathway. CCM attenuates pulmonary fibrosis via the miR-29a-3p/DNMT3A axis to regulate extracellular matrix remodeling and mitochondrial function and may provide a new therapeutic intervention for preventing pulmonary fibrosis.
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Curcumina , ADN Metiltransferasa 3A , Matriz Extracelular , Fibroblastos , Ratones Endogámicos C57BL , MicroARNs , Mitocondrias , Animales , MicroARNs/genética , MicroARNs/metabolismo , Curcumina/farmacología , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , ADN Metiltransferasa 3A/metabolismo , Matriz Extracelular/metabolismo , Matriz Extracelular/efectos de los fármacos , Humanos , Ratones , Masculino , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Fibroblastos/patología , Bleomicina , Fibrosis Pulmonar/genética , Fibrosis Pulmonar/patología , Fibrosis Pulmonar/metabolismo , Fibrosis Pulmonar/tratamiento farmacológico , Pulmón/efectos de los fármacos , Pulmón/patología , Pulmón/metabolismo , ADN (Citosina-5-)-Metiltransferasas/metabolismo , ADN (Citosina-5-)-Metiltransferasas/genética , Fibrosis Pulmonar Idiopática/patología , Fibrosis Pulmonar Idiopática/genética , Fibrosis Pulmonar Idiopática/tratamiento farmacológico , Fibrosis Pulmonar Idiopática/metabolismo , Modelos Animales de EnfermedadRESUMEN
Spatial-spectral interferometry (SSI) is a technique used to reconstruct the electrical field of an ultrafast laser. By analyzing the spectral phase distribution, SSI provides valuable information about the optical dispersion affecting the spectral phase, which is related to the energy distribution of the laser pulses. SSI is a single-shot measurement process and has a low laser power requirement. However, the reconstruction algorithm involves numerous Fourier transform and filtering operations, which limits the applicability of SSI for real-time dispersion analysis. To address this issue, this Letter proposes a field-programmable gate array (FPGA)-based deep neural network to accelerate the spectral phase reconstruction and dispersion estimation process. The results show that the analysis time is improved from 124 to 9.27â ms, which represents a 13.4-fold improvement on the standard Fourier transform-based reconstruction algorithm.
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Doping sorted graphene quantum dots (GQDs) with heteroatoms and functionalizing them with amino acid could improve their radiative recombination and two-photon properties-including their excitation-wavelength-independent photoluminescence from the ultraviolet to the near-infrared-I (NIR-I) region, absorption, quantum yield, absolute cross section, lifetime, and radiative-to-nonradiative decay ratio-under two-photon excitation (TPE) at a low excitation energy and short photoexcitation duration, as determined using a self-made optical microscopy system with a femtosecond Ti-sapphire laser. Four types of sorted GQDs were investigated: undoped GQDs, nitrogen-doped GQDs (N-GQDs), amino-functionalized GQDs (amino-GQDs), and N-doped and amino-functionalized GQDs (amino-N-GQDs). Among them, the sorted amino-N-GQDs are effective as a two-photon photosensitizer and generate the highest quantity of reactive oxygen species for the elimination of multidrug-resistant cancer cells through two-photon photodynamic therapy (PDT). Larger amino-N-GQDs result in a greater number of C-N and N-functionalities, leading to a superior photochemical effect and more favorable intrinsic luminescence properties, making the dots effective contrast agents for tracking and localizing cancer cells during in-depth bioimaging in a three-dimensional biological environment under TPE in the NIR-II region. Overall, this study highlights the potential of large amino-N-GQDs as a material for future application to dual-modality two-photon PDT and biomedical imaging.
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Técnicas Biosensibles , Grafito , Fotoquimioterapia , Puntos Cuánticos , Grafito/química , Iluminación , Resistencia a Múltiples Medicamentos , Puntos Cuánticos/química , Resistencia a Antineoplásicos , Fotoquimioterapia/métodosRESUMEN
Adult neurogenesis is reduced during aging and impaired in disorders of stress, memory, and cognition though its normal function remains unclear. Moreover, a systems level understanding of how a small number of young hippocampal neurons could dramatically influence brain function is lacking. We examined whether adult neurogenesis sustains hippocampal connections cumulatively across the life span. Long-term suppression of neurogenesis as occurs during stress and aging resulted in an accelerated decline in hippocampal acetylcholine signaling and a slow and progressing emergence of profound working memory deficits. These deficits were accompanied by compensatory reorganization of cholinergic dentate gyrus inputs with increased cholinergic innervation to the ventral hippocampus and recruitment of ventrally projecting neurons by the dorsal projection. While increased cholinergic innervation was dysfunctional and corresponded to overall decreases in cholinergic levels and signaling, it could be recruited to correct the resulting memory dysfunction even in old animals. Our study demonstrates that hippocampal neurogenesis supports memory by maintaining the septohippocampal cholinergic circuit across the lifespan. It also provides a systems level explanation for the progressive nature of memory deterioration during normal and pathological aging and indicates that the brain connectome is malleable by experience.
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Ultrafast lasers concentrate the energy in a short pulse with a duration of several tens to hundreds of femtoseconds. The resulting high peak power induces various nonlinear optical phenomena that find use in many different fields. However, in practical applications, the optical dispersion broadens the laser pulse width and spreads the energy in time, thereby reducing the peak power. Accordingly, the present study develops a piezo bender-based pulse compressor to compensate for this dispersion effect and restore the laser pulse width. The piezo bender has a rapid response time and a large deformation capacity and thus provides a highly effective means of performing dispersion compensation. However, due to hysteresis and creep effects, the piezo bender is unable to maintain a stable shape over time and hence the compensation effect is gradually degraded. To address this problem, this study further proposes a single-shot modified laterally sampled laser interferometer to estimate the parabolic shape of the piezo bender. The curvature variation of the bender is then sent as a feedback signal to a closed-loop controller to restore the bender to the desired shape. It is shown that the steady-state error of the converged group delay dispersion is around 530 fs2. Moreover, the ultrashort laser pulse is compressed from 1620 fs in the original condition to 140 fs in the compressed condition, corresponding to a 12-fold improvement.
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BACKGROUND: Long-term consumption of an excessive fat and sucrose diet (Western diet, WD) has been considered a risk factor for metabolic syndrome (MS) and cardiovascular disease. Caveolae and caveolin-1 (CAV-1) proteins are involved in lipid transport and metabolism. However, studies investigating CAV-1 expression, cardiac remodeling, and dysfunction caused by MS, are limited. This study aimed to investigate the correlation between the expression of CAV-1 and abnormal lipid accumulation in the endothelium and myocardium in WD-induced MS, and the occurrence of myocardial microvascular endothelial cell dysfunction, myocardial mitochondrial remodeling, and damage effects on cardiac remodeling and cardiac function. METHODS: We employed a long-term (7 months) WD feeding mouse model to measure the effect of MS on caveolae/vesiculo-vacuolar organelle (VVO) formation, lipid deposition, and endothelial cell dysfunction in cardiac microvascular using a transmission electron microscopy (TEM) assay. CAV-1 and endothelial nitric oxide synthase (eNOS) expression and interaction were evaluated using real-time polymerase chain reaction, Western blot, and immunostaining. Cardiac mitochondrial shape transition and damage, mitochondria-associated endoplasmic reticulum membrane (MAM) disruption, cardiac function change, caspase-mediated apoptosis pathway activation, and cardiac remodeling were examined using TEM, echocardiography, immunohistochemistry, and Western blot assay. RESULTS: Our study demonstrated that long-term WD feeding caused obesity and MS in mice. In mice, MS increased caveolae and VVO formation in the microvascular system and enhanced CAV-1 and lipid droplet binding affinity. In addition, MS caused a significant decrease in eNOS expression, vascular endothelial cadherin, and ß-catenin interactions in cardiac microvascular endothelial cells, accompanied by impaired vascular integrity. MS-induced endothelial dysfunction caused massive lipid accumulation in the cardiomyocytes, leading to MAM disruption, mitochondrial shape transition, and damage. MS promoted brain natriuretic peptide expression and activated the caspase-dependent apoptosis pathway, leading to cardiac dysfunction in mice. CONCLUSION: MS resulted in cardiac dysfunction, remodeling by regulating caveolae and CAV-1 expression, and endothelial dysfunction. Lipid accumulation and lipotoxicity caused MAM disruption and mitochondrial remodeling in cardiomyocytes, leading to cardiomyocyte apoptosis and cardiac dysfunction and remodeling.
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Cardiopatías , Síndrome Metabólico , Animales , Ratones , Caveolas , Caveolina 1/genética , Miocitos Cardíacos , Síndrome Metabólico/etiología , Dieta Occidental , Células Endoteliales , Remodelación Ventricular , LípidosRESUMEN
BACKGROUND: Macrosomia, defined as a birth weight of ≥4000 g, is associated with a high risk of birth injury. Fetal growth is highly correlated with maternal conditions, and several maternal factors are associated with neonatal birth size. The current study aimed to assess maternal factors related to fetal macrosomia in a Taiwanese population. METHODS: The medical records of pregnant mothers and their newborns were retrospectively reviewed. All singleton pregnancies delivered at and after 37 weeks of gestation were included in the analysis. Maternal and neonatal conditions were evaluated according to different birth weights. RESULTS: A total of 4262 infants were enrolled in our study. The mean birth weight was 3156 ± 383 g, including 77 (1.8%) cases with birth weight ≥4000 g, and 154 (3.6%) infants with birth weight <2500 g. The mean maternal body weight before delivery was 67.6 ± 10.0 kg. The mean 6-month gestational weight gain (6mGWG) was 12.3 ± 4.2 kg, and the mean maternal body mass index (BMI) was 26.2 ± 3.6 kg/m 2 . The maternal weight, height, and 6mGWG, gestational age, and placental weight were significantly positively correlated with neonatal birth weight. The odds ratios of macrosomia were 3.1 in neonates born to mothers with a 6mGWG of ≥15 kg, 6.3 in those born to mothers with gestational diabetes mellitus, and 4.1 in those born to mothers with a BMI of ≥30 kg/m 2 . Newborn macrosomia was associated with adverse events in pregnant mothers and newborn infants. CONCLUSION: Gestational diabetes mellitus, 6mGWG, and maternal BMI are significantly correlated with neonatal macrosomia in full-term singleton births. Further, neonatal macrosomia is an important cause of maternal and neonatal morbidity. Hence, pregnant women should undergo maternal counseling for weight management before and during pregnancy, and the appropriate delivery method should be identified to prevent perinatal adverse events.
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Diabetes Gestacional , Macrosomía Fetal , Lactante , Femenino , Recién Nacido , Embarazo , Humanos , Macrosomía Fetal/etiología , Macrosomía Fetal/epidemiología , Peso al Nacer , Diabetes Gestacional/etiología , Diabetes Gestacional/epidemiología , Estudios Retrospectivos , Factores de Riesgo , Placenta , Índice de Masa CorporalRESUMEN
Adult neurogenesis is reduced during aging and impaired in disorders of stress, memory, and cognition though its normal function remains unclear. Moreover, a systems level understanding of how a small number of young hippocampal neurons could dramatically influence brain function is lacking. We examined whether adult neurogenesis sustains hippocampal connections cumulatively across the life span. Long-term suppression of neurogenesis as occurs during stress and aging resulted in an accelerated decline in hippocampal acetylcholine signaling and a slow and progressing emergence of profound working memory deficits. These deficits were accompanied by compensatory reorganization of cholinergic dentate gyrus inputs with increased cholinergic innervation to the ventral hippocampus and recruitment of ventrally projecting neurons by the dorsal projection. While increased cholinergic innervation was dysfunctional and corresponded to overall decreases in cholinergic levels and signaling, it could be recruited to correct the resulting memory dysfunction even in old animals. Our study demonstrates that hippocampal neurogenesis supports memory by maintaining the septohippocampal cholinergic circuit across the lifespan. It also provides a systems level explanation for the progressive nature of memory deterioration during normal and pathological aging and indicates that the brain connectome is malleable by experience.
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OBJECTIVE: Doctors, nowadays, primarily use auditory-perceptual evaluation, such as the grade, roughness, breathiness, asthenia, and strain scale, to evaluate voice quality and determine the treatment. However, the results predicted by individual physicians often differ, because of subjective perceptions, and diagnosis time interval, if the patient's symptoms are hard to judge. Therefore, an accurate computerized pathological voice quality assessment system will improve the quality of assessment. METHOD: This study proposes a self_attention-based system, with a deep learning technology, named self_attention-based bidirectional long-short term memory (SA BiLSTM). Different pitches [low, normal, high], and vowels [/a/, /i/, /u/], were added into the proposed model, to make it learn how professional doctors evaluate the grade, roughness, breathiness, asthenia, and strain scale, in a high dimension view. RESULTS: The experimental results showed that the proposed system provided higher performance than the baseline system. More specifically, the macro average of the F1 score, presented as decimal, was used to compare the accuracy of classification. The (G, R, and B) of the proposed system were (0.768±0.011, 0.820±0.009, and 0.815±0.009), which is higher than the baseline systems: deep neural network (0.395±0.010, 0.312±0.019, 0.321±0.014) and convolution neural network (0.421±0.052, 0.306±0.043, 0.3250±0.032) respectively. CONCLUSIONS: The proposed system, with SA BiLSTM, pitches, and vowels, provides a more accurate way to evaluate the voice. This will be helpful for clinical voice evaluations and will improve patients' benefits from voice therapy.
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Clinical trials are indispensable in developing new treatments, but they face obstacles in patient recruitment and retention, hindering the enrollment of necessary participants. To tackle these challenges, deep learning frameworks have been created to match patients to trials. These frameworks calculate the similarity between patients and clinical trial eligibility criteria, considering the discrepancy between inclusion and exclusion criteria. Recent studies have shown that these frameworks outperform earlier approaches. However, deep learning models may raise fairness issues in patient-trial matching when certain sensitive groups of individuals are underrepresented in clinical trials, leading to incomplete or inaccurate data and potential harm. To tackle the issue of fairness, this work proposes a fair patient-trial matching framework by generating a patient-criterion level fairness constraint. The proposed framework considers the inconsistency between the embedding of inclusion and exclusion criteria among patients of different sensitive groups. The experimental results on real-world patient-trial and patient-criterion matching tasks demonstrate that the proposed framework can successfully alleviate the predictions that tend to be biased.
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Ensayos Clínicos como Asunto , Selección de Paciente , HumanosRESUMEN
Organ transplant is the essential treatment method for some end-stage diseases, such as liver failure. Analyzing the post-transplant cause of death (CoD) after organ transplant provides a powerful tool for clinical decision making, including personalized treatment and organ allocation. However, traditional methods like Model for End-stage Liver Disease (MELD) score and conventional machine learning (ML) methods are limited in CoD analysis due to two major data and model-related challenges. To address this, we propose a novel framework called CoD-MTL leveraging multi-task learning to model the semantic relationships between various CoD prediction tasks jointly. Specifically, we develop a novel tree distillation strategy for multi-task learning, which combines the strength of both the tree model and multi-task learning. Experimental results are presented to show the precise and reliable CoD predictions of our framework. A case study is conducted to demonstrate the clinical importance of our method in the liver transplant.
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Enfermedad Hepática en Estado Terminal , Trasplante de Hígado , Obtención de Tejidos y Órganos , Humanos , Trasplante de Hígado/métodos , Causas de Muerte , Índice de Severidad de la EnfermedadRESUMEN
The exponential growth in scholarly publications necessitates advanced tools for efficient article retrieval, especially in interdisciplinary fields where diverse terminologies are used to describe similar research. Traditional keyword-based search engines often fall short in assisting users who may not be familiar with specific terminologies. To address this, we present a knowledge graph based paper search engine for biomedical research to enhance the user experience in discovering relevant queries and articles. The system, dubbed DiscoverPath, employs Named Entity Recognition (NER) and part-of-speech (POS) tagging to extract terminologies and relationships from article abstracts to create a KG. To reduce information overload, DiscoverPath presents users with a focused subgraph containing the queried entity and its neighboring nodes and incorporates a query recommendation system enabling users to iteratively refine their queries. The system is equipped with an accessible Graphical User Interface that provides an intuitive visualization of the KG, query recommendations, and detailed article information, enabling efficient article retrieval, thus fostering interdisciplinary knowledge exploration. DiscoverPath is open-sourced at https://github.com/ynchuang/DiscoverPath with a demo video at Youtube.
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The optical dispersion effect in ultrafast pulse laser systems broadens the laser pulse duration and reduces the theoretical peak power. The present study proposes an adaptive ultrashort pulse compressor for compensating the optical dispersion using a direct optical-dispersion estimation by spectrogram (DOES) method. The DOES has fast and accurate computation time which is suitable for real time controller design. In the proposed approach, the group delay dispersion (GDD) and its polarity are estimated directly from the delay marginal of the trace obtained from a single-shot frequency-resolved optical gating (FROG). The estimated GDD is then processed by a closed-loop controller, which generates a command signal to drive a linear deformable mirror as required to achieve the desired laser pulse compression. The dispersion analysis, control computation, and deformable mirror control processes are implemented on a single field programmable gate array (FPGA). It is shown that the DOES dispersion computation process requires just 0.5â ms to complete. Moreover, the proposed pulse compressor compensates for both static dispersion and dynamic dispersion within five time steps when closed-loop controller is performed at a frequency of 100â Hz. The experimental results show that the proposed pulse compressor yields an effective fluorescence intensity improvement in a multiphoton excited fluorescence microscope (MPEFM).
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Temporal focusing-based multiphoton excitation microscopy (TFMPEM) just provides the advantage of widefield optical sectioning ability with axial resolution of several micrometers. However, under the plane excitation, the photons emitted from the molecules in turbid tissues undergo scattering, resulting in complicated background noise and an impaired widefield image quality. Accordingly, this study constructs a general and comprehensive numerical model of TFMPEM utilizing Fourier optics and performs simulations to determine the superior spatial frequency and orientation of the structured pattern which maximize the axial excitation confinement. It is shown experimentally that the optimized pattern minimizes the intensity of the out-of-focus signal, and hence improves the quality of the image reconstructed using the Hilbert transform (HT). However, the square-like reflection components on digital micromirror device leads to pattern residuals in the demodulated image when applying high spatial frequency of structured pattern. Accordingly, the HT is replaced with Hilbert-Huang transform (HHT) in order to sift out the low-frequency background noise and pattern residuals in the demodulation process. The experimental results obtained using a kidney tissue sample show that the HHT yields a significant improvement in the TFMPEM image quality.
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Microscopía de Fluorescencia por Excitación Multifotónica , Fotones , Técnicas Histológicas , Microscopía Fluorescente , Microscopía de Fluorescencia por Excitación Multifotónica/métodosRESUMEN
Coronavirus disease-2019 (COVID-19) causes severe pneumonia and acute respiratory distress syndrome. According to the current consensus, immunosuppressants, such as dexamethasone and anti-interleukin-6 receptor monoclonal antibodies, are therapeutic medications in the early stages of infection. However, in critically ill patients, viral, fungal, and bacterial coinfection results in higher mortality. We conducted a single-center, retrospective analysis of 29 mechanically ventilated patients with artificial airways. Patients were adults with confirmed COVID-19 infection and severe pneumonia. Acute respiratory distress syndrome was diagnosed according to the Kigali modification of the Berlin definition. Six patients had invasive pulmonary aspergillosis coinfection based on elevated serum galactomannan levels and/or bronchoalveolar lavage fluid. We present two cases with brief histories and available clinical data. We also conducted a literature review to determine whether immunosuppressants, such as tocilizumab, increase infection risk or invasive aspergillosis in patients with COVID-19. There is no conclusive evidence to suggest that tocilizumab increases coinfection risk. However, further studies are needed to determine the optimal dose, between-dose interval, and timing of tocilizumab administration in patients with COVID-19.
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Nitrogen doping and amino group functionalization through chemical modification lead to strong electron donation. Applying these processes to a large π-conjugated system of graphene quantum dot (GQD)-based materials as electron donors increases the charge transfer efficiency of nitrogen-doped amino acid-functionalized GQDs (amino-N-GQDs), resulting in enhanced two-photon absorption, post-two-photon excitation (TPE) stability, TPE cross-sections, and two-photon luminescence through the radiative pathway when the lifetime decreases and the quantum yield increases. Additionally, it leads to the generation of reactive oxygen species through two-photon photodynamic therapy (PDT). The sorted amino-N-GQDs prepared in this study exhibited excitation-wavelength-independent two-photon luminescence in the near-infrared region through TPE in the near-infrared-II region. The increase in size resulted in size-dependent photochemical and electrochemical efficacy, increased photoluminescence quantum yield, and efficient two-photon PDT. Therefore, the sorted amino-N-GQDs can be applicable as two-photon contrast probes to track and localize analytes in in-depth two-photon imaging executed in a biological environment along with two-photon PDT to eliminate infectious or multidrug-resistant microbes.
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Antiinfecciosos , Grafito , Puntos Cuánticos , Antibacterianos , Grafito/farmacología , Nitrógeno , FotonesRESUMEN
In ultrashort pulse laser applications, optical dispersion seriously affects the energy concentration in the laser pulse duration and lowers the peak power. Accordingly, this study proposes a rapid dispersion estimation mechanism to facilitate the compensation of optical dispersion using a closed-loop control system. In the proposed approach, the optical dispersion information of the laser pulse is estimated directly from a frequency-resolved optical gating trace without the need for an iterative pulse-retrieval algorithm. In particular, the group delay dispersion (GDD) is determined from frequency and delay marginals, which are related to the laser spectrum and intensity autocorrelation, respectively, using a simple lookup table approach. The accuracy of the estimated GDD results is confirmed via a comparison with the spectral phase distribution of the electric field reconstructed using the principal component generalized projections algorithm. It is shown that the computation time of the proposed direct estimation method is around 13 times faster than that of the traditional iterative algorithm. It thus provides a feasible approach for enabling the real-time compensation of ultrafast laser pulse compression. Moreover, in a multiphoton-excited fluorescence imaging application, the proposed pulse compression mechanism yields an effective improvement in the intensity and contrast of the reconstructed image due to the increased nonlinear optical excitation efficiency of the optimized laser pulses.
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A reconfigurable differential-to-single-ended autonomous current adaptation buffer amplifier (ACABA) is proposed. The ACABA, based on floating-gate technologies, is a capacitive circuit, of which output DC level and bandwidth can be adjusted by programming charges on floating nodes. The gain is variable by switching different amounts of capacitors without altering the output DC level. Without extra sensing and control circuitries, the current consumption of the proposed ACABA increases spontaneously when the input signal is fast or large, achieving a high slew rate. The supply current dwindles back to the low quiescent level autonomously when the output voltage reaches equilibrium. Therefore, the proposed ACABA is power-efficient and suitable for processing physiological signals. A prototype ACABA has been designed and fabricated in a [Formula: see text] CMOS process occupying an area of [Formula: see text]. When loaded by a [Formula: see text] capacitor, it consumes [Formula: see text] to achieve a unity-gain bandwidth of [Formula: see text] with a measured IIP2 value of [Formula: see text] and a slew rate of [Formula: see text].
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Amplificadores Electrónicos , ElectrodosRESUMEN
Schizophrenia is a severe mental illness that affects ~1% of the world's population. It is clinically characterized by positive, negative, and cognitive symptoms. Currently available antipsychotic medications are relatively ineffective in improving negative and cognitive deficits, which are related to a patient's functional outcomes and quality of life. Negative symptoms and cognitive deficits are unmet by the antipsychotic medications developed to date. In recent decades, compelling animal and clinical studies have supported the NMDA receptor (NMDAR) hypofunction hypothesis of schizophrenia and have suggested some promising therapeutic agents. Notably, several NMDAR-enhancing agents, especially those that function through the glycine modulatory site (GMS) of NMDAR, cause significant reduction in psychotic and cognitive symptoms in patients with schizophrenia. Given that the NMDAR-mediated signaling pathway has been implicated in cognitive/social functions and that GMS is a potential therapeutic target for enhancing the activation of NMDARs, there is great interest in investigating the effects of direct and indirect GMS modulators and their therapeutic potential. In this review, we focus on describing preclinical and clinical studies of direct and indirect GMS modulators in the treatment of schizophrenia, including glycine, D-cycloserine, D-serine, glycine transporter 1 (GlyT1) inhibitors, and D-amino acid oxidase (DAO or DAAO) inhibitors. We highlight some of the most promising recently developed pharmacological compounds designed to either directly or indirectly target GMS and thus augment NMDAR function to treat the cognitive and negative symptoms of schizophrenia. Overall, the current findings suggest that indirectly targeting of GMS appears to be more beneficial and leads to less adverse effects than direct targeting of GMS to modulate NMDAR functions. Indirect GMS modulators, especially GlyT1 inhibitors and DAO inhibitors, open new avenues for the treatment of unmet medical needs for patients with schizophrenia.