A phase I, randomized study to evaluate the safety, tolerability, and pharmacokinetics of mefunidone in healthy subjects.

Background: Mefunidone is a novel synthetic compound and is better when compared to pirfenidone for the anti-fibrotic treatment of renal fibrosis in end-stage renal disease. We conducted this first-in-human, phase I clinical trial to determine the safety, tolerability, and pharmacokinetic (PK) (including food effect) profiles of mefunidone administered orally as single and multiple ascending doses in healthy subjects. Methods: Part A assessed single ascending doses of mefunidone from 25 mg to 800 mg or placebo once daily in the fasting state. Part A also assessed the effect of food on tolerability and PK in the 100 mg cohort. Part B consisted of three treatment groups who received 100 mg, 200 mg, or 400 mg of mefunidone or placebo twice daily (BID, bis in die) on days 1-6 and once in the morning on day 7. Results: Single oral doses of mefunidone up to 800 mg and multiple doses of mefunidone up to 400 mg BID were all well-tolerated. Mefunidone behaved with ideal dose proportionality within the single-dose range of 50 mg-600 mg and the multiple-dose range of 100 mg BID to 400 mg BID by day 7. High-fat fed conditions led to a delay in Tmax by approximately 1 h and a slight reduction of approximately 20% in Cmax compared to that in fasting conditions, but it did not significantly affect systemic exposure. Conclusion: Mefunidone exhibited favorable pharmacokinetics and safety profiles. The present study informed and supported further developmental clinical studies of mefunidone. Clinical Trial Registration: clinicaltrials.gov, identifier CXHL1900206.

Electrophysiological Analysis of Retinal Organoid Development Using 3D Microelectrodes of Liquid Metals.

Despite of the substantial potential of human-derived retinal organoids, the degeneration of retinal ganglion cells (RGCs) during maturation limits their utility in assessing the functionality of later-born retinal cell subtypes. Additionally, conventional analyses primarily rely on fluorescent emissions, which limits the detection of actual cell functionality while risking damage to the 3D cytoarchitecture of organoids. Here, an electrophysiological analysis is presented to monitor RGC development in early to mid-stage retinal organoids, and compare distinct features with fully-mature mouse retina. This approach utilizes high-resolution 3D printing of liquid-metal microelectrodes, enabling precise targeting of specific inner retinal layers within organoids. The adaptable distribution and softness of these microelectrodes facilitate the spatiotemporal recording of inner retinal signals. This study not only demonstrates the functional properties of RGCs in retinal organoid development but also provides insights into their synaptic connectivity, reminiscent of fetal native retinas. Further comparison with fully-mature mouse retina in vivo verifies the organoid features, highlighting the potential of early-stage retinal organoids in biomedical research.

The relationship between serum coagulation parameters and the recurrence of chronic subdural hematoma.

The aim is to investigate the relationship between serum coagulation parameters (PT, APTT, D-D and FDP) before hospitalization and recurrence of chronic subdural hematoma (CSDH). 236 patients with CSDH who were diagnosed for the first time and had complete medical records were followed up for at least 90 days. Fifty patients (21.2%) had relapsed. Univariate analysis was conducted including general data, imaging data and test results. Serum coagulation parameters (PT, APTT, D-D and FDP) were detected for all CSDH patients. The study identified several factors that exhibited a significant correlation with chronic subdural hematoma (CSDH) recurrence. These factors included advanced age (p = 0.01), hypertension (p = 0.04), liver disease (p = 0.01), anticoagulant drug use (p = 0.01), antiplatelet drug use (p = 0.02), bilateral hematoma (p = 0.02), and single-layer hematoma (p = 0.01). In addition, the presence of fibrin/fibrinogen degradation products (FDP) exceeding 5 mg/L demonstrated a significant relationship with CSDH recurrence (P < 0.05). Notably, the combined assessment of D-dimer (D-D) and FDP exhibited a significant difference, particularly regarding recurrence within 30 days after surgery (P < 0.05). The simultaneous elevation of serum FDP and D-D levels upon admission represents a potentially novel predictor for CSDH recurrence. This finding is particularly relevant for patients who experience recurrence within 30 days following surgical intervention. Older individuals with CSDH who undergo trepanation and drainage should be closely monitored due to their relatively higher recurrence rate.

A scoping review of utilization of the verbal fluency task in Chinese and Japanese clinical settings with near-infrared spectroscopy.

This review targets the application of the Verbal Fluency Task (VFT) in conjunction with functional near-infrared spectroscopy (fNIRS) for diagnosing psychiatric disorders, specifically in the contexts of China and Japan. These two countries are at the forefront of integrating fNIRS with VFT in clinical psychiatry, often employing this combination as a complementary tool alongside traditional psychiatric examinations. Our study aims to synthesize research findings on the hemodynamic responses elicited by VFT task in clinical settings of the two countries, analyzing variations in task design (phonological versus semantic), stimulus modality (auditory versus visual), and the impact of language typology. The focus on China and Japan is crucial, as it provides insights into the unique applications and adaptations of VFT in these linguistically and culturally distinct environments. By exploring these specific cases, our review underscores the importance of tailoring VFT to fit the linguistic and cultural context, thereby enhancing its validity and utility in cross-cultural psychiatric assessments.

Liquid-metal-based three-dimensional microelectrode arrays integrated with implantable ultrathin retinal prosthesis for vision restoration.

Electronic retinal prostheses for stimulating retinal neurons are promising for vision restoration. However, the rigid electrodes of conventional retinal implants can inflict damage on the soft retina tissue. They also have limited selectivity due to their poor proximity to target cells in the degenerative retina. Here we present a soft artificial retina (thickness, 10 µm) where flexible ultrathin photosensitive transistors are integrated with three-dimensional stimulation electrodes of eutectic gallium-indium alloy. Platinum nanoclusters locally coated only on the tip of these three-dimensional liquid-metal electrodes show advantages in reducing the impedance of the stimulation electrodes. These microelectrodes can enhance the proximity to the target retinal ganglion cells and provide effective charge injections (72.84 mC cm-2) to elicit neural responses in the retina. Their low Young's modulus (234 kPa), owing to their liquid form, can minimize damage to the retina. Furthermore, we used an unsupervised machine learning approach to effectively identify the evoked spikes to grade neural activities within the retinal ganglion cells. Results from in vivo experiments on a retinal degeneration mouse model reveal that the spatiotemporal distribution of neural responses on their retina can be mapped under selective localized illumination areas of light, suggesting the restoration of their vision.

Facts in counterfactuals-cognitive representations of Chinese counterfactuals.

How do people represent counterfactuals? As languages differ in expressibility of counterfactuals-some languages employ explicit grammatical marking for counterfactuals while others do not-are some speakers' representations of counterfactuals less explicit? Prior studies examining this question with Chinese speakers-a language devoid of explicit counterfactual markings-found mixed results. Here we re-examined the issue by using a more sensitive test: people's sensitivity to detect anomalies in sentences. We asked Chinese speakers to rate the acceptability of sentences employing "ruguo (if)…jiu (then)" configuration-the typical but non-unique, non-explicit marking of counterfactuals. Critically, we varied the semantic adherence to real-world facts [factuality], with some sentences containing made-up conditions [-fact as in "If fish had legs, then…"] versus real facts [+ fact: "If dogs had legs, then…"]. If speakers represent counterfactuals clearly, they should give higher acceptability ratings to [- facts] than to [+ facts] sentences, because the ostensible point of counterfactuals is to express non-factual situations. That is, expressing a true fact under a syntactic counterfactual construction makes the sentence anomalous. Instead, we found that Chinese speakers gave the opposite ratings: factual "if…then" sentences were rated as more acceptable than non-factual ones. This suggests that Chinese speakers find the processing of counterfactuals to be more challenging than processing facts, and that their representation of counterfactuals may be less explicit. Overall, this research contributes to our understanding of the link between linguistic markings and cognitive representations.

Transradial versus transfemoral access for posterior circulation endovascular intervention: A systematic review and meta-analysis.

OBJECTIVE: Transradial access (TRA) provides a more direct entry to posterior circulation system for endovascular therapy compared to transfemoral access (TFA). This meta-analysis aims to evaluate the safety and feasibility of TRA in neurointervention of posterior circulation. MATERIALS AND METHODS: A systematic search was conducted in the Wanfang Data, CBM, PubMed, Embase, Cochrane Library, Web of Science databases. The primary outcomes included total complications and access site complications. Secondary outcomes were single puncture success, procedural success, access cross-over, catheter retention time and fluoroscopy time. RESULTS: Six studies encompassing 297 patients were included in the meta-analysis. Compared to the TFA group, the TRA group showed significantly decreased total complications (odds ratio [OR] = 0.29, 95% confidence interval [CI] [0.12, 0.73], p < 0.01) and access site complications (OR = 0.19, 95%CI [0.06, 0.62], p < 0.01), yet it had a longer catheter retention time (mean difference [MD] = 0.80, 95%CI [0.60, 1.00], p < 0.01). There were no significant differences in single puncture success (OR = 3.68, 95%CI[0.38, 35.86], p = 0.26), procedural success (OR = 0.30，95%CI [0.05, 1.73], p = 0.18), access cross-over (OR = 2.29, 95%CI [0.19, 28.26], p = 0.52), fluoroscopy time (MD = 0.97, 95%CI [- 0.91, 2.84], p = 0.31) between the TRA and TFA groups. CONCLUSION: This meta-analysis demonstrated that TRA is a safe and feasible alternative to TFA for neurointervention in the posterior circulation. TRA showed significantly decreased total complications and access site complications, yet it had a longer catheter retention time than TFA.

Restoring System xc- activity by xCT overexpression inhibited neuronal ferroptosis and improved neurological deficits after experimental subarachnoid hemorrhage.

BACKGROUND: Ferroptosis is an important therapeutic target to alleviate early brain injury (EBI) after subarachnoid hemorrhage (SAH), yet the mechanism of neuronal ferroptosis after SAH remains unclear. System xc- dysfunction is one of the key pathways to induce ferroptosis. System xc- activity is mainly regulated by the expression of xCT. This study was designed to investigate the effect of xCT expression and System xc- activity on ferroptosis and EBI in an experimental SAH model both in vitro and in vivo. METHODS: SAH was induced in adult male Sprague-Dawley rats by injecting autologous blood into the prechiasmatic cistern. Primary neurons treated with oxyhemoglobin (10 µM) were used to mimic SAH in vitro. Plasmid transfection was used to induce xCT overexpression. Western blotting, immunofluorescence staining, measurement of cystine uptake, enzyme-linked immunosorbent assay, transmission electron microscopy, Nissl staining, and a series of neurobehavioral tests were conducted to explore the role of xCT and System xc- activity in ferroptosis and EBI after SAH. RESULTS: We found that System xc- dysfunction induced ferroptosis and exacerbated EBI after SAH in rats. xCT deficiency after SAH resulted in System xc- dysfunction, weakened neuronal antioxidant capacity and activated neuronal ferroptosis. xCT overexpression improved neuronal antioxidant capacity and inhibited neuronal ferroptosis by restoring System xc- activity. Rats with xCT overexpression after SAH presented with attenuated brain edema and inflammation, increased neuronal survival, and ameliorated neurological deficits. CONCLUSIONS: Our study revealed that restoring System xc- activity by xCT overexpression inhibited neuronal ferroptosis and EBI and improved neurological deficits after SAH.

Gentiopicroside Ameliorates Cerebrovascular Angiogenesis, Neuronal Injury and Immune Disorder in Rats with Cerebral Ischemia/Reperfusion Injury via VEGF and Phosphorylated Nrf2 Elevation.

BACKGROUND: Cerebral ischemia-reperfusion (CI/R) injury is induction of blood flow restoration after an ischemic stroke. Gentiopicroside (GPC) is the principal active secoiridoid glycoside of Gentiana Manshurica Kitagawa. This research aimed to illuminate the function of GPC and its mechanism in CI/R injury. METHODS: After CI/R injury models were constructed, GPC (25, 50 or 100 mg/kg) was then administered by gavage to rats. Rats were grouped into Sham, CI/R, CI/R+25 mg/kg GPC, CI/R+50 mg/kg GPC, and CI/R+100 mg/kg GPC. Neuronal cells were exposed to oxygen-glucose deprivation and reperfusion (OGD/R) injury to establish ischemic-like conditions in vitro, and cells were further treated with 25, 50, or 100 µM GPC. Cells were grouped into control, OGD/R, OGD/R+25 µM GPC, OGD/R+50 µM GPC, and OGD/R+100 µM GPC. GPC's function on rat cerebral injury, angiogenesis, oxidative stress, neuronal injury and immune dysfunction in vivo was estimated using hematoxylin-eosin staining, Western blot, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) staining, commercial kits and enzyme linked-immunosorbent assay. Meanwhile, GPC's mechanism in CI/R injury was examined via Western blot. GPC's function in vitro was estimated via Cell Counting Kit-8 assay, 5-ethynyl-2'-deoxyuridine (EdU) staining, flow cytometry. RESULTS: GPC alleviated cerebral injury through decreasing cerebral infarction volume, cerebral indexes, brain water contents (p < 0.05). GPC reduced oxidative stress and boosted cerebral angiogenesis in CI/R rats (p < 0.05). Meanwhile, GPC weakened neuronal cell apoptosis, and decreased neuron-specific enolase and S100beta protein levels in CI/R rats. GPC reduced inflammatory cytokines contents in serum and brain tissues of CI/R rats (p < 0.05). Moreover, GPC increased the viability and proliferation in OGD/R-treated neuronal cells, but decreased cell apoptosis (p < 0.05). Mechanistically, GPC upregulated vascular endothelial growth factor (VEGF) and phosphorylated nuclear factor E2-related factor 2 (p-Nrf2) levels in CI/R rat brain tissues (p < 0.05). CONCLUSIONS: GPC reduced cerebrovascular angiogenesis, neuronal injury and immune disorder in CI/R injury through elevating VEGF and p-Nrf2.

Vitamin D3 suppresses the cholesterol homeostasis pathway in patient-derived glioma cell lines.

Glioblastoma is one of the most common malignant brain tumors. Vitamin D, primarily its hormonally active form calcitriol, has been reported to have anti-cancer activity. In the present study, we used patient-derived glioma cell lines to examine the effect of vitamin D3 and calcitriol on glioblastoma. Surprisingly, vitamin D3 showed a more significant inhibitory effect than calcitriol on cell viability and proliferation. Vitamin D receptor (VDR) mediates most of the cellular effects of vitamin D, and thus we examined the expression level and function of VDR via gene silencing and gene knockout experiments. We observed that VDR does not affect the sensitivity of patient-derived glioma cell lines to vitamin D3, and the gene encoding VDR is not essential for growth of patient-derived glioma cell lines. RNA sequencing data analysis and sterolomics analysis revealed that vitamin D3 inhibits cholesterol synthesis and cholesterol homeostasis by inhibiting the expression level of 7-dehydrocholesterol reductase, which leads to the accumulation of 7-dehydrocholesterol and other sterol intermediates. In conclusion, our results suggest that vitamin D3, rather than calcitriol, inhibits growth of patient-derived glioma cell lines via inhibition of the cholesterol homeostasis pathway.

Safety, pharmacokinetics, and pharmacodynamics of TG103, a novel long-acting GLP-1/Fc fusion protein after a single ascending dose in Chinese healthy subjects.

BACKGROUND AND OBJECTIVE: TG103 is a novel GLP-1/Fc fusion protein, developed for the treatment of type 2 diabetes and obesity. This trial was designed to assess the safety and tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) profiles after single ascending dose of TG103 in healthy Chinese subjects. METHOD: In this double-blind, randomized, placebo-controlled phase I study, Chinese healthy subjects were admitted consecutively to TG103 3 mg, 7.5 mg, 15 mg, and 22.5 mg group with 8 subjects per group and randomized in a 3:1 ratio to receive TG103 treatment or placebo. Following a single subcutaneous(s.c.) injections of TG103, safety and tolerability were evaluated and blood samples were collected for PK and PD analysis at the specified time-points. RESULT: Overall, 32 healthy subjects were enrolled and completed the study. During the study, a total of 84 adverse effects (AEs) were reported in 25 subjects, all were mild or moderate and resolved spontaneously without intervention. The most common treatment related AEs in TG103 group were decreased appetite (41.7%), nausea, flatulence, elevated urinary ß2-microglobulin, increased serum total bile acid (20.8% each), decreased high-density lipoprotein (16.7%), abdominal distension (12.5%). After a single s.c. administration of TG103 3-22.5 mg, the median Tmax was 36∼48 h, and mean t1/2 was about 147.16∼184.72 h. The mean Cmax for each group was 94.35±52.19, 337.67±56.71, 757.67±206.99, 1236.33±666.25 ng/mL, with AUC0-t of 14.93±7.67, 59.15±7.39, 91.79±20.41, 163.61±55.99 µg·h/mL, respectively. It showed a linear pharmacokinetic profile in the single dose of TG103 3 mg to 22.5 mg. Compared with placebo, fasting blood glucose decreased in all dose groups, most notably in the 15 mg group, which was consistent with the changes in blood glucose during OGTT, while 2-hour postprandial glucose decreased in all dose groups except 3 mg group. CONCLUSION: TG103 offers a potential option for hypoglycemic therapy with good tolerability and safety. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT03990090; registered 18 June 2019.

CRISPR/Cas9 mediated specific ablation of vegfa in retinal pigment epithelium efficiently regresses choroidal neovascularization.

The CRISPR/Cas9 system easily edits target genes in various organisms and is used to treat human diseases. In most therapeutic CRISPR studies, ubiquitously expressed promoters, such as CMV, CAG, and EF1α, are used; however, gene editing is sometimes necessary only in specific cell types relevant to the disease. Therefore, we aimed to develop a retinal pigment epithelium (RPE)-specific CRISPR/Cas9 system. We developed a CRISPR/Cas9 system that operates only in retinal pigment epithelium (RPE) by expressing Cas9 under the RPE-specific vitelliform macular dystrophy 2 promoter (pVMD2). This RPE-specific CRISPR/pVMD2-Cas9 system was tested in human retinal organoid and mouse model. We confirmed that this system works specifically in the RPE of human retinal organoids and mouse retina. In addition, the RPE-specific Vegfa ablation using the novel CRISPR-pVMD2-Cas9 system caused regression of choroidal neovascularization (CNV) without unwanted knock-out in the neural retina in laser-induced CNV mice, which is a widely used animal model of neovascular age-related macular degeneration. RPE-specific Vegfa knock-out (KO) and ubiquitous Vegfa KO were comparable in the efficient regression of CNV. The promoter substituted, cell type-specific CRISPR/Cas9 systems can be used in specific 'target cell' therapy, which edits genes while reducing unwanted off- 'target cell' effects.

Astragaloside IV alleviates stroke-triggered early brain injury by modulating neuroinflammation and ferroptosis via the Nrf2/HO-1 signaling pathway.

PURPOSE: Stroke is an acute cerebrovascular disease. Astragaloside IV (AS-IV) is an active ingredient extracted from Astragalus membranaceus with an established therapeutic effect on central nervous system diseases. This study examined the neuroprotective properties and possible mechanisms of AS-IV in stroke-triggered early brain injury (EBI) in a rat transient middle cerebral artery occlusion (MCAO) model. METHODS: The neurological scores and brain water content were analyzed. 2,3,5-triphenyl tetrazolium chloride (TTC) staining was utilized to determine the infarct volume, neuroinflammatory cytokine levels, and ferroptosis-related genes and proteins, and neuronal damage and molecular mechanisms were evaluated by terminal deoxynucleotidyl transferase dutp nick-end labeling (TUNEL) staining, western blotting, and real-time polymerase chain reaction. RESULTS: AS-IV administration decreased the infarct volume, brain edema, neurological deficits, and inflammatory cytokines TNF-α, interleukin-1ß (IL-1ß), IL-6, and NF-κB, increased the levels of SLC7A11 and glutathione peroxidase 4 (GPX4), decreased lipid reactive oxygen species (ROS) levels, and prevented neuronal ferroptosis. Meanwhile, AS-IV triggered the Nrf2/HO-1 signaling pathway and alleviated ferroptosis due to the induction of stroke. CONCLUSIONS: Hence, the findings of this research illustrate that AS-IV administration can improve delayed ischemic neurological deficits and decrease neuronal death by modulating nuroinflammation and ferroptosis via the Nrf2/HO-1 signaling pathway.

Extru-seq: a method for predicting genome-wide Cas9 off-target sites with advantages of both cell-based and in vitro approaches.

We present a novel genome-wide off-target prediction method named Extru-seq and compare it with cell-based (GUIDE-seq), in vitro (Digenome-seq), and in silico methods using promiscuous guide RNAs with large numbers of valid off-target sites. Extru-seq demonstrates a high validation rate and retention of information about the intracellular environment, both beneficial characteristics of cell-based methods. Extru-seq also shows a low miss rate and could easily be performed in clinically relevant cell types with little optimization, which are major positive features of the in vitro methods. In summary, Extru-seq shows beneficial features of cell-based and in vitro methods.

A Single-center, Open-label, Parallel Control Study Comparing the Pharmacokinetics and Safety of a Single Oral Dose of Roflumilast and Its Active Metabolite Roflumilast N-oxide in Healthy Chinese and Caucasian Volunteers.

Roflumilast is a phosphodiesterase-4 inhibitor which treats chronic obstructive pulmonary disease (COPD). Roflumilast N-oxide is the major metabolite of roflumilast with a similar mechanism of action to roflumilast. Although racial differences in roflumilast drug disposition have been observed, the necessity of dose adjustment is subject to debate. This study compares the pharmacokinetics of a single 500 µg dose of roflumilast in healthy Chinese and Caucasian subjects under uniform conditions. Chinese subjects were found to have longer t1/2 and higher AUC0-t and Cmax than Caucasian subjects. The point estimates on the geometric mean of AUC0-t in Chinese subjects were 22% higher for roflumilast and 46% higher for roflumilast N-oxide. Point estimates on the geometric mean of Cmax were 9% and 24% higher for roflumilast and roflumilast N-oxide, respectively. Total phosphodiesterase-4 (PDE4) inhibitory (tPDE4i) activity, a theoretical parameter that describes the combined contribution to PDE4 inhibitory activity of roflumilast and roflumilast N-oxide, was 44% higher in Chinese subjects than in Caucasian subjects. With about a 10-fold higher plasma AUC compared to the parent roflumilast and a much longer observed half-life, roflumilast N-oxide has been estimated to contribute about 90% of tPDE4i, with 10% attributed to the parent compound roflumilast. Following body weight normalization, these figures were lower but remained significant. Safety analysis showed signs of reduced tolerance or different pharmacodynamic response to roflumilast in Chinese recipients than in Caucasians. Our results suggest that Chinese patients should receive a dose of roflumilast lower than 500 µg daily during future clinical trials.

Astragaloside IV alleviates stroke-triggered early brain injury by modulating neuroinflammation and ferroptosis via the Nrf2/HO-1 signaling pathway

Purpose: Stroke is an acute cerebrovascular disease. Astragaloside IV (AS-IV) is an active ingredient extracted from Astragalus membranaceus with an established therapeutic effect on central nervous system diseases. This study examined the neuroprotective properties and possible mechanisms of AS-IV in stroke-triggered early brain injury (EBI) in a rat transient middle cerebral artery occlusion (MCAO) model. Methods: The neurological scores and brain water content were analyzed. 2,3,5-triphenyl tetrazolium chloride (TTC) staining was utilized to determine the infarct volume, neuroinflammatory cytokine levels, and ferroptosis-related genes and proteins, and neuronal damage and molecular mechanisms were evaluated by terminal deoxynucleotidyl transferase dutp nickend labeling (TUNEL) staining, western blotting, and real-time polymerase chain reaction. Results: AS-IV administration decreased the infarct volume, brain edema, neurological deficits, and inflammatory cytokines TNF-α, interleukin-1ß (IL-1ß), IL-6, and NF-κB, increased the levels of SLC7A11 and glutathione peroxidase 4 (GPX4), decreased lipid reactive oxygen species (ROS) levels, and prevented neuronal ferroptosis. Meanwhile, AS-IV triggered the Nrf2/HO-1 signaling pathway and alleviated ferroptosis due to the induction of stroke. Conclusion: Hence, the findings of this research illustrate that AS-IV administration can improve delayed ischemic neurological deficits and decrease neuronal death by modulating nuroinflammation and ferroptosis via the Nrf2/HO-1 signaling pathway.

The promising fNIRS: Uncovering the function of prefrontal working memory networks based on multi-cognitive tasks.

The diversity of cognitive task paradigms using functional near-infrared spectroscopy (fNIRS) and the lack of theoretical explanations for these functional imaging atlases have greatly hindered the application of fNIRS in psychiatry. The fNIRS brain imaging based on multiple cognitive tasks could generally reflect the working patterns and neurovascular coupling changes in the prefrontal working memory network. By alternating the stimulation patterns of resting and task states, six typical symptom-related functional brain imaging waveforms related to psychiatric disorders are identified and three joint networks of the prefrontal working memory, namely, the attentional working memory primary coordination network, the perceptual content working memory secondary network, and the emotional-behavioral working memory executive network, are initially represented. This is the first attempt to characterize the cognitive, emotional, and behavioral regulation of the prefrontal working memory network using fNIRS, which may promote the application of fNIRS in clinical settings.

PTBP3 promotes tumorigenesis of glioblastoma by stabilizing Twist1.

OBJECTIVE: Glioblastoma (GBM) is the most common malignancy tumor of central nervous system. PTBP3 was closely associated with the development of tumor. However, the function and molecular mechanism of PTBP3 in GBM is little known. METHODS: qPCR and immunoblotting were used to detect PTBP3 expression levels in glioma tissues and cells. CCK8, Edu, flow cytometry, wound healing, and transwell assays were used to examined the function of PTBP3 in GBM. qPCR, Immunoblotting, and ubiquitination assays were performed to identify the mechanism of PTBP3. RESULTS: We found that PTBP3 was upregulated in GBM, and high expression of PTBP3 correlated with the poor survival of GBM patients. PTBP3 knockdown reduced proliferation, invasion, and migration of GBM. Conversely, overexpressing PTBP3 has an opposite effect. Moreover, PTBP3 had an effect on the EMT of GBM. More importantly, we found that PTBP3 stabilized Twist1 by decreasing its ubiquitination and degradation. Furthermore, orthotopic xenograft models were used to demonstrate the PTBP3 on the development of GBM in vivo. CONCLUSION: This study proved that PTBP3 promoted tumorigenesis of GBM by stabilizing Twist1, which provided a new therapeutic target for GBM.

TREM2 modulates neuroinflammation with elevated IRAK3 expression and plays a neuroprotective role after experimental SAH in rats.

BACKGROUND: The modulation of neuroinflammation is a new direction that may alleviate the early brain injury after subarachnoid hemorrhage (SAH). Brain resident microglia/macrophages (Mi/MΦ) are the key drivers of neuroinflammation. Triggering receptor expressed on myeloid cells 2 (TREM2) has been reported to play a neuroprotective role by activating phagocytosis and suspending inflammatory response in experimental ischemic stroke and intracerebral hemorrhage. This study was designed to investigate the role of TREM2 on neuroinflammation and neuroprotective effects in a rat SAH model. METHODS: Adult male Sprague-Dawley rats were induced SAH through endovascular perforation. Lentivirus vectors were administered by i.c.v. to induce TREM2 overexpression or knockdown 7 days before SAH induction. Short- and long-term neurobehavioral tests, western blotting, immunofluorescence, enzyme-linked immunosorbent assay, terminal deoxynucleotidyl transferase dUTP nick end labeling and Nissl staining were performed to explore the neuroprotective role of TREM2 after SAH. RESULTS: The expression of TREM2 elevated in a rat SAH model with a peak at 48 h after SAH and mainly expressed in Mi/MΦ in brain. TREM2 overexpression improved short- and long-term neurological deficits induced by SAH in rats, while TREM2 knockdown worsened neurological dysfunction. The rats with TREM2 overexpressed presented less neuronal apoptosis and more neuronal survival at 48 h after SAH, while the rats with TREM2 knockdown presented on the contrary. TREM2 overexpression manifested activated phagocytosis and suppressed inflammatory response, with the increase of CD206+/CD11b+ cells and IL-10 expression as well as the decrease of the infiltration of MPO+ cells and the expression of TNF-α, IL-1ß. While TREM2 knockdown abolished these effects. The protein level of IRAK3, a negative regulatory factor of inflammation, was significantly elevated after TREM2 overexpression and declined after TREM2 knockdown. CONCLUSIONS: Our research suggested TREM2 played a neuroprotective role and improved the short- and long-term neurological deficits by modulating neuroinflammation after SAH. The modulation on neuroinflammation of TREM2 after SAH was related with the elevated protein level of IRAK3.