Identification of diagnostic markers related to inflammatory response and cellular senescence in endometriosis using machine learning and in vitro experiment.

OBJECTIVE: To understand the association between chronic inflammation, cellular senescence, and immunological infiltration in endometriosis. METHODS: Datasets from GEO comprising 108 endometriosis and 97 healthy human samples and the human endometrial stromal cell. Differentially expressed genes were identified using Limma and WGCNA. Inflammatory response-related subtypes were constructed using consensus clustering analysis. The CIBERSORT algorithm and correlation analyses assessed immune cell infiltration. LASSO, SVM-RFE, and RF identified diagnostic genes. Functional enrichment analysis and multifactor regulatory networks established functional effects. Nomograms, internal and external validations, and in vitro experiments validated the diagnostic genes. RESULTS: Inflammatory response subtypes were highly correlated with the immune activities of B and NK cells. Sixteen genes were associated with inflammatory response and cellular senescence and six diagnostic genes (NLK, RAD51, TIMELESS, TBX3, MET, and BTG3) were identified. The six diagnostic gene models had an area under the curve of 0.828 and their expression was significantly downregulated in endometriosis samples. Low expression of NLK and BTG3 promoted the proliferation, migration, and invasion of endometriotic cells. CONCLUSIONS: Inflammatory response subtypes were successfully constructed for endometriosis. Six diagnostic genes related to inflammatory response and cellular senescence were identified and validated. Our study provides novel insights for inflammatory response in endometriosis and markers for endometriosis diagnosis and treatment.

Biogenic Selenium Nanoparticles Synthesized by L. brevis 23017 Enhance Aluminum Adjuvanticity and Make Up for its Disadvantage in Mice.

The most popular vaccine adjuvants are aluminum ones, which have significantly reduced the incidence and mortality of many diseases. However, aluminum-adjuvanted vaccines are constrained by their limited capacity to elicit cellular and mucosal immune responses, thus constraining their broader utilization. Biogenic selenium nanoparticles are a low-cost, environmentally friendly, low-toxicity, and highly bioactive form of selenium supplementation. Here, we purified selenium nanoparticles synthesized by Levilactobacillus brevis 23017 (L-SeNP) and characterized them using Fourier-transform infrared spectroscopy, energy-dispersive X-ray spectroscopy, scanning electron microscopy, and transmission electron microscopy. The results indicate that the L-SeNP has a particle size ranging from 30 to 200 nm and is coated with proteins and polysaccharides. Subsequently, we assessed the immune-enhancing properties of L-SeNP in combination with an adjuvant-inactivated Clostridium perfringens type A vaccine using a mouse model. The findings demonstrate that L-SeNP can elevate the IgG and SIgA titers in immunized mice and modulate the Th1/Th2 immune response, thereby enhancing the protective effect of aluminum-adjuvanted vaccines. Furthermore, we observed that L-SeNP increases selenoprotein expression and regulates oxidative stress in immunized mice, which may be how L-SeNP regulates immunity. In conclusion, L-SeNP has the potential to augment the immune response of aluminum adjuvant vaccines and compensate for their limitations in eliciting Th1 and mucosal immune responses.

An Overview of miRNAs Involved in PASMC Phenotypic Switching in Pulmonary Hypertension.

Pulmonary hypertension (PH) is occult, with no distinctive clinical manifestations and a poor prognosis. Pulmonary vascular remodelling is an important pathological feature in which pulmonary artery smooth muscle cells (PASMCs) phenotypic switching plays a crucial role. MicroRNAs (miRNAs) are a class of evolutionarily highly conserved single-stranded small noncoding RNAs. An increasing number of studies have shown that miRNAs play an important role in the occurrence and development of PH by regulating PASMCs phenotypic switching, which is expected to be a potential target for the prevention and treatment of PH. miRNAs such as miR-221, miR-15b, miR-96, miR-24, miR-23a, miR-9, miR-214, and miR-20a can promote PASMCs phenotypic switching, while such as miR-21, miR-132, miR-449, miR-206, miR-124, miR-30c, miR-140, and the miR-17~92 cluster can inhibit it. The article reviews the research progress on growth factor-related miRNAs and hypoxia-related miRNAs that mediate PASMCs phenotypic switching in PH.

Adenosine A2A receptor modulates microglia-mediated synaptic pruning of the retinogeniculate pathway during postnatal development.

Synapse pruning is essential not only for the developmental establishment of synaptic connections in the brain but also for the pathogenesis of neurodevelopmental and neurodegenerative disorders. However, there are no effective pharmacological means to regulate synaptic pruning during early development. Using the eye-specific segregation of the dorsal lateral geniculate nucleus (dLGN) as a model of synaptic pruning coupled with adenosine A2A receptor (A2AR) antagonism and knockout, we demonstrated while genetic deletion of the A2AR throughout the development attenuated eye-specific segregation with the attenuated microglial phagocytosis at postnatal day 5 (P5), selective treatment with the A2AR antagonist KW6002 at P2-P4 facilitated synaptic pruning of visual pathway with microglial activation, increased lysosomal activity in microglia and increased microglial engulfment of retinal ganglion cell (RGC) inputs in the dLGN at P5 (but not P10). Furthermore, KW6002-mediated facilitation of synaptic pruning was activity-dependent since tetrodotoxin (TTX) treatment abolished the KW6002 facilitation. Moreover, the A2AR antagonist also modulated postsynaptic proteins and synaptic density at early postnatal stages as revealed by the reduced immunoreactivity of postsynaptic proteins (Homer1 and metabotropic glutamate receptor 5) and colocalization of presynaptic VGlut2 and postsynaptic Homer1 puncta in the dLGN. These findings suggest that A2AR can control pruning by multiple actions involving the retinal wave, microglia engulfment, and postsynaptic stability. Thus, A2AR antagonists may represent a novel pharmacological strategy to modulate microglia-mediated synaptic pruning and treatment of neurodevelopmental disorders associated with dysfunctional pruning.

Dual-responsive doxorubicin-loaded nanomicelles for enhanced cancer therapy.

BACKGROUND: The enhancement of tumor retention and cellular uptake of drugs are important factors in maximizing anticancer therapy and minimizing side effects of encapsulated drugs. Herein, a delivery nanoplatform, armed with a pH-triggered charge-reversal capability and self-amplifiable reactive oxygen species (ROS)-induced drug release, is constructed by encapsulating doxorubicin (DOX) in pH/ROS-responsive polymeric micelle. RESULTS: The surface charge of this system was converted from negative to positive from pH 7.4 to pH 6.8, which facilitated the cellular uptake. In addition, methionine-based system was dissociated in a ROS-rich and acidic intracellular environment, resulting in the release of DOX and α-tocopheryl succinate (TOS). Then, the exposed TOS segments further induced the generation of ROS, leading to self-amplifiable disassembly of the micelles and drug release. CONCLUSIONS: We confirms efficient DOX delivery into cancer cells, upregulation of tumoral ROS level and induction of the apoptotic capability in vitro. The system exhibits outstanding tumor inhibition capability in vivo, indicating that dual stimuli nano-system has great potential to function as an anticancer drug delivery platform.

Comparison of Multicolored Spot Reflection Topographer and Scheimpflug-Placido System in Corneal Power and Astigmatism Measurements With Normal and Post-refractive Patients.

PURPOSE: To evaluate the repeatability of corneal power and astigmatism derived by a novel multicolored spot reflection topographer system (Cassini; i-Optics, Hague, Netherlands) and compare its agreement with a Placido-Scheimpflug system (Sirius; Costruzione Strumenti Oftalmici, Florence, Italy) in normal and post-refractive patients. METHODS: This prospective study comprised patients who underwent myopic excimer laser refractive surgery (96 eyes) and normal patients (102 eyes). Each patient was measured three times with the Cassini and Sirius. The simulated keratometry (SimK), total corneal power (TCP), and astigmatism were recorded. The repeatability was assessed by one-way analysis of variance. The paired t test was used to compare the differences, whereas the agreement was evaluated by Bland-Altman analysis. RESULTS: All parameters obtained by the Cassini demonstrated high repeatability, except for total corneal astigmatism (TCA) in the post-refractive group. The intraclass correlation coefficients of all parameters were greater than 0.85, the correlation of variation values was less than 0.55%, and the test-retest repeatability was less than 0.85 diopters (D). The paired t test showed significant differences in steep keratometry, astigmatism, TCP, and TCA in the normal group and in J0, TCP, and TCA in the post-refractive group. The 95% limits of agreement (LoA) in the normal group demonstrated good agreement, except for TCP. Only J0 and J45 of astigmatism and TCA remained narrow for 95% LoA in the post-refractive group. CONCLUSIONS: These results suggested that the Cassini provided high repeatable measurements in corneal power and astigmatism, except the TCA of post-refractive patients. The parameters could be used interchangeably in normal patients, except for TCP, whereas only J0 of astigmatism and J0, J45 of TCA showed good agreement in post-refractive patients. [J Refract Surg. 2019;35(6):370-376.].

Precision of a new ocular biometer in eyes with cataract using swept source optical coherence tomography combined with Placido-disk corneal topography.

The present study was to assess the precision (repeatability and reproducibility) of a new optical biometer (OA-2000, Tomey, Japan) based on swept-source optical coherence tomography (SS-OCT) and Placido disk topography in eyes with cataracts. Seventy-eight eyes from seventy-eight patients with cataracts were evaluated. Axial length (AL), anterior chamber depth (ACD), keratometry (K) over a 2.5 mm and 3.0 mm diameter, lens thickness (LT), central corneal thickness (CCT) and white-to-white (WTW) distance were measured by 2 skilled operators. OA-2000 measurements were highly repeatable and reproducible for all parameters (intraclass correlation, 0.925 to 1.000). OA-2000 derived K-values with a diameter of 3.0mm showed narrower 95% limits of agreement (LoA) (SRK/T: -0.18 to 0.16D; Holladay 1: -0.20 to 0.19D; Hoffer Q: -0.22 to 0.20D) than those with a diameter of 2.5 mm for IOL power calculations (SRK/T: -0.20 to 0.20D; Holladay 1: -0.23 to 0.23D; Hoffer Q: -0.25 to 0.25D). The precision (repeatability and reproducibility) of the OA-2000 was excellent for all parameters. The 3.0mm diameter K-readings appear to be the most reliable choice for calculation of IOL power with the OA-2000. In addition, the average values determined from each operator's 3 consecutive readings were more reproducible.

Comparison of ocular biometric measurements between a new swept-source optical coherence tomography and a common optical low coherence reflectometry.

The purpose of the current study was to compare the measurements between a new optical biometer based on swept-source optical coherence tomography (SS-OCT), the OA-2000 (Tomey, Japan), and an optical biometer based on optical low coherence reflectometry (OLCR), the Lenstar (Haag-Streit, Switzerland). Ninety-nine eyes of 99 healthy subjects were included. The axial length (AL), central corneal thickness (CCT), anterior chamber depth (ACD), aqueous depth (AD), lens thickness (LT), keratometry (K) readings, including flat K (Kf), steep K (Ks), mean K (Km), astigmatism vectors J0, J45 at diameters of 2.5 and 3.0 mm, and white-to-white diameter (WTW) were measured three times each using both biometer in normal eyes by random sequence. Bland-Altman analysis showed good agreement between the SS-OCT and OLCR devices for AL, AD, ACD, LT, with narrow 95% LoA (-0.05 to 0.07 mm, -0.09 to 0.10 mm, -0.10 to 0.09 mm, and -0.06 to 0.22 mm, respectively), and the P values of ACD were both >0.05. The CCT, Kf, Ks, Km, J0, J45 and WTW values provided by the OA-2000 were in good agreement with the Lenstar, and statistically significant differences were detected for some of them but not clinical differences. The agreement was excellent especially for AL.