Circuit-specific gene therapy reverses core symptoms in a primate Parkinson's disease model.

Parkinson's disease (PD) is a debilitating neurodegenerative disorder. Its symptoms are typically treated with levodopa or dopamine receptor agonists, but its action lacks specificity due to the wide distribution of dopamine receptors in the central nervous system and periphery. Here, we report the development of a gene therapy strategy to selectively manipulate PD-affected circuitry. Targeting striatal D1 medium spiny neurons (MSNs), whose activity is chronically suppressed in PD, we engineered a therapeutic strategy comprised of a highly efficient retrograde adeno-associated virus (AAV), promoter elements with strong D1-MSN activity, and a chemogenetic effector to enable precise D1-MSN activation after systemic ligand administration. Application of this therapeutic approach rescues locomotion, tremor, and motor skill defects in both mouse and primate models of PD, supporting the feasibility of targeted circuit modulation tools for the treatment of PD in humans.

OsEIN2-OsEIL1/2 pathway negatively regulates chilling tolerance by attenuating OsICE1 function in rice.

Low temperature severely affects rice development and yield. Ethylene signal is essential for plant development and stress response. Here, we reported that the OsEIN2-OsEIL1/2 pathway reduced OsICE1-dependent chilling tolerance in rice. The overexpressing plants of OsEIN2, OsEIL1 and OsEIL2 exhibited severe stress symptoms with excessive reactive oxygen species (ROS) accumulation under chilling, while the mutants (osein2 and oseil1) and OsEIL2-RNA interference plants (OsEIL2-Ri) showed the enhanced chilling tolerance. We validated that OsEIL1 and OsEIL2 could form a heterxodimer and synergistically repressed OsICE1 expression by binding to its promoter. The expression of OsICE1 target genes, ROS scavenging- and photosynthesis-related genes were downregulated by OsEIN2 and OsEIL1/2, which were activated by OsICE1, suggesting that OsEIN2-OsEIL1/2 pathway might mediate ROS accumulation and photosynthetic capacity under chilling by attenuating OsICE1 function. Moreover, the association analysis of the seedling chilling tolerance with the haplotype showed that the lower expression of OsEIL1 and OsEIL2 caused by natural variation might confer chilling tolerance on rice seedlings. Finally, we generated OsEIL2-edited rice with an enhanced chilling tolerance. Taken together, our findings reveal a possible mechanism integrating OsEIN2-OsEIL1/2 pathway with OsICE1-dependent cascade in regulating chilling tolerance, providing a practical strategy for breeding chilling-tolerant rice.

Extracellular vesicles derived from bone marrow mesenchymal stem cells ameliorate chronic liver damage via microRNA-136-5p.

Chronic liver damage (CLD) encompasses a spectrum of conditions and poses a significant global health challenge, affecting millions of individuals. Currently, there is a deficiency of clinically validated therapeutics with minimal side effects. Emerging evidence underscores the significant potential of extracellular vesicles derived from bone marrow mesenchymal stem cells (BMSC-EVs) as a promising therapeutic method for CLD. This study aimed to evaluate the influence of BMSC-EVs containing microRNA-136-5p (BMSC-EVs-miR-136-5p) on macrophage polarization during chronic liver injury and elucidate the mechanisms associated with the GNAS/PI3K/ERK/STAT3 axis. Surface markers of BMSCs were detected via Immunofluorescent Staining. Subsequently, EVs were harvested from the BMSC culture medium. In vivo fluorescence imaging was employed to locate the BMSC-EVs. Additionally, fluorescence microscopy was used to visualize the uptake of DIR-labeled BMSC-EVs by RAW264.7 cells. Various methods were employed to assess the impact of BMSC-EVs on the expression levels of inflammatory factors (IL-1ß, IL-6, IL-10, and TNF-α), M1/M2 macrophage markers (iNOS and Arg-1), and members of inflammation-related signaling pathways (GNAS, PI3K, ERK, and STAT3) in RAW264.7 cells co-cultured with BMSC-EVs. Loss-of-function approaches targeting miR-136-5p in RAW264.7 cells were subsequently utilized to validate the role of BMSC-EVs-miR-136-5p. The Luciferase Reporter Assay indicates that GNAS was identified to be a target of miR-136-5p, and miR-136-5p demonstrating increased within BMSC-EVs compared to Raw264.7-EVs. BMSC-EVs-miR-136-5p mitigated CCl4-induced liver inflammation and improved liver function by Suppressing the GNAS/STAT3 Signaling. Notably, miR-136-5p suppressed lipopolysaccharide (LPS)-induced inflammation in RAW264.7 cells. BMSC-EVs-miR-136-5p alleviates CLD by activating M2 polarization through the GNAS-mediated PI3K/ERK/STAT3 axis. Accordingly, the members of this axis may serve as therapeutic targets.

Lactococcus garvieae exerts a critical role in inducing inflammation in dairy mastitis by triggering NLRP3 inflammasome-mediated pyroptosis in MAC-T cells.

Lactococcus garvieae (L. garvieae) is a pathogenic bacterium that is Gram-positive and catalase-negative (GPCN), and it is capable of growing in a wide range of environmental conditions. This bacterium is associated with significant mortality and losses in fisheries, and there are concerns regarding its potential as a zoonotic pathogen, given its presence in cattle and dairy products. While we have identified and characterized virulent strains of L. garvieae through phenotyping and molecular typing studies, their impact on mammary tissue remains unknown. This study aims to investigate the pathogenicity of strong and weak virulent strains of L. garvieae using in vivo mouse models. We aim to establish MAC-T cell model to examine potential injury caused by the strong virulent strain LG41 through the TLR2/NLRP3/NF-kB pathway. Furthermore, we assess the involvement of NLRP3 inflammasome-mediated pyroptosis in dairy mastitis by silencing NLRP3. The outcomes of this study will yield crucial theoretical insights into the potential mechanisms involved in mastitis in cows caused by the L. garvieae-induced inflammatory response in MAC-T cells.

Coexistence of MRCS syndrome, extremely long axis and exfoliation syndrome: a case report and literature review.

BACKGROUND: The coexistence of MRCS (microcornea, retinal dystrophy, cataract, and posterior staphyloma) syndrome and extremely long axis is rare since microcornea frequently accompanies with diminution of entire anterior segment and occasionally the whole globe. In the case presented here, combination of these two elements were identified, together with XFS (exfoliation syndrome). CASE PRESENTATION: A 66-year-old Han Chinese woman presented for consultation due to impaired vision which accompanied throughout her entire life span and worsened during the last 2 years. Combination of MRCS syndrome and extremely long axial length was evidently diagnosed in both eyes, with XFS confirmed in her right eye, but mutation screening failed to identify disease-causing sequence variants in some specific genes reported previously, including BEST1 and ARL2. However, likely pathogenic mutations in FBN2 gene were identified. Bilateral cataract phacoemulsification without intraocular lens implantation was performed using scleral tunnel incision and under general anesthesia. At 3-month follow-up, ocular recovery of the patient was satisfactory. CONCLUSIONS: The case presented here exhibited rare coexistence of MRCS syndrome, extremely long axis and XFS. The complexity of her ocular abnormalities brought challenges to surgical management, in which multidisciplinary collaboration is often required. Furthermore, the genetic analysis in this case yielded a possible novel candidate gene for MRCS syndrome and provided evidence in support of genetic heterogeneity in this phenotype.

Multi-Target Tracking Based on a Combined Attention Mechanism and Occlusion Sensing in a Behavior-Analysis System.

Multi-object tracking (MOT) is a topic of great interest in the field of computer vision, which is essential in smart behavior-analysis systems for healthcare, such as human-flow monitoring, crime analysis, and behavior warnings. Most MOT methods achieve stability by combining object-detection and re-identification networks. However, MOT requires high efficiency and accuracy in complex environments with occlusions and interference. This often increases the algorithm's complexity, affects the speed of tracking calculations, and reduces real-time performance. In this paper, we present an improved MOT method combining an attention mechanism and occlusion sensing as a solution. A convolutional block attention module (CBAM) calculates the weights of space and channel attention from the feature map. The attention weights are used to fuse the feature maps to extract adaptively robust object representations. An occlusion-sensing module detects an object's occlusion, and the appearance characteristics of an occluded object are not updated. This can enhance the model's ability to extract object features and improve appearance feature pollution caused by the short-term occlusion of an object. Experiments on public datasets demonstrate the competitive performance of the proposed method compared with the state-of-the-art MOT methods. The experimental results show that our method has powerful data association capability, e.g., 73.2% MOTA and 73.9% IDF1 on the MOT17 dataset.

Lactococcus lactis, a bacterium with probiotic functions and pathogenicity.

Lactococcus lactis (L. lactis) is the primary organism for lactic acid bacteria (LAB) and is a globally recognized safe microorganism for the regulation of the intestinal micro-ecological balance of animals and improving the immune performance of the host. L. lactis is known to play a commercially important role in feed fortification, milk fermentation, and vaccine production, but pathogenic L. lactis has been isolated from many clinical cases in recent years, such as the brain of silver carp with Lactococcosis, the liver and spleen of diseased waterfowl, milk samples and padding materials with cow mastitis, and blood and urine from human patients with endocarditis. In dairy farming, where L. lactis has been used as a probiotic in the past, however, some studies have found that L. lactis can cause mastitis in cows, but the lack of understanding of the pathogenesis of mastitis in cows caused by L. lactis has become a new problem. The main objective of this review is to analyze the increasingly serious clinical mastitis caused by L. lactis and combined with the wide application of L. lactis as probiotics, to comprehensively discuss the characteristics and diversity of L. lactis.

Allergen-specific IgE in the tear fluid of Chinese patients with common allergic conjunctivitis in autumn and winter.

PURPOSE: In this study, we determined the positive rates of allergen-specific immunoglobulin E (IgE) in the tear fluid of Chinese patients with common allergic conjunctivitis (AC) in autumn and winter, compared systemic and ocular allergen tests, and explored the correlation between the numbers and categories of allergens and clinical AC features. METHODS: This cross-sectional study recruited 44 patients with AC (86 eyes). Specific IgEs for allergens common in China (house dust mite, cat/dog dander, mugwort/ragweed pollen, cottonwood/willow/elm pollen, milk, egg whites, soybeans) were measured in collected tears using kits for allergen-specific IgE antibodies. AC signs and symptoms were graded according to severity. RESULTS: Specific IgE in tears was positive in 87.2% of eyes. House dust mite was the most common allergen (86.0%), followed by cat (24.4%) and dog (7.0%) dander; tree and grass pollen accounted for only 4.7% and 2.3%, respectively. Food allergens were not detected. The positive rates of the systemic allergen tests were lower than in tear fluid tests in both eyes, especially for house dust mites (P = 0.000). In patients with more allergens, itching was more severe (P = 0.035), while conjunctival hyperemia was milder (P = 0.002). CONCLUSION: In autumn and winter, the most common AC allergen in Chinese patients was house dust mites. Compared with systemic allergen tests, measuring specific IgE in tears may be a non-invasive method to diagnose and evaluate AC severity, which may be more suitable to reflect the local conditions of ocular surface inflammation due to its high positive rate and convenience.

Change patterns in the corneal sub-basal nerve and corneal aberrations in patients with dry eye disease: An artificial intelligence analysis.

We aimed to investigate the change patterns in corneal sub-basal nerve morphology and corneal intrinsic aberrations in dry eye disease (DED). Our study included 229 eyes of 155 patients with DED and 40 eyes of 20 healthy control. We used the Oculus keratograph and the ocular surface disease index questionnaire to assess their signs and symptoms. In vivo confocal microscopy was used to observe the corneal sub-basal nerves, corneal endothelial cells, and Langerhans cells (LCs). An artificial intelligence (AI) technique run by the deep learning model generated the sub-basal nerve fibre parameters. Furthermore, we used the Pentacam HR system to measure the corneal intrinsic aberrations and corneal surface regularity indices. DED patients more frequently had increased anterior and total corneal aberrations than controls (P < 0.05). In addition, DED had decreased average density and maximum length of corneal nerve. (Both P < 0.01) The LC number was significantly correlated with maximum length (CC = -0.19, P = 0.01) of the sub-basal nerve fibre. Furthermore, the corneal nerve average density was negatively correlated with IHD, and anterior, posterior, and total corneal aberrations (All P < 0.05) especially the higher-order aberrations. Significant correlations were seen between corneal nerve morphology changes, analysed by AI and corneal intrinsic aberrations, particularly higher-order aberrations.

Mesenchymal stem cells protect against TBI-induced pyroptosis in vivo and in vitro through TSG-6.

BACKGROUND: Pyroptosis, especially microglial pyroptosis, may play an important role in central nervous system pathologies, including traumatic brain injury (TBI). Transplantation of mesenchymal stem cells (MSCs), such as human umbilical cord MSCs (hUMSCs), has been a focus of brain injury treatment. Recently, MSCs have been found to play a role in many diseases by regulating the pyroptosis pathway. However, the effect of MSC transplantation on pyroptosis following TBI remains unknown. Tumor necrosis factor α stimulated gene 6/protein (TSG-6), a potent anti-inflammatory factor expressed in many cell types including MSCs, plays an anti-inflammatory role in many diseases; however, the effect of TSG-6 secreted by MSCs on pyroptosis remains unclear. METHODS: Mice were subjected to controlled cortical impact injury in vivo. To assess the time course of pyroptosis after TBI, brains of TBI mice were collected at different time points. To study the effect of TSG-6 secreted by hUMSCs in regulating pyroptosis, normal hUMSCs, sh-TSG-6 hUMSCs, or different concentrations of rmTSG-6 were injected intracerebroventricularly into mice 4 h after TBI. Neurological deficits, double immunofluorescence staining, presence of inflammatory factors, cell apoptosis, and pyroptosis were assessed. In vitro, we investigated the anti-pyroptosis effects of hUMSCs and TSG-6 in a lipopolysaccharide/ATP-induced BV2 microglial pyroptosis model. RESULTS: In TBI mice, the co-localization of Iba-1 (marking microglia/macrophages) with NLRP3/Caspase-1 p20/GSDMD was distinctly observed at 48 h. In vivo, hUMSC transplantation or treatment with rmTSG-6 in TBI mice significantly improved neurological deficits, reduced inflammatory cytokine expression, and inhibited both NLRP3/Caspase-1 p20/GSDMD expression and microglial pyroptosis in the cerebral cortices of TBI mice. However, the therapeutic effect of hUMSCs on TBI mice was reduced by the inhibition of TSG-6 expression in hUMSCs. In vitro, lipopolysaccharide/ATP-induced BV2 microglial pyroptosis was inhibited by co-culture with hUMSCs or with rmTSG-6. However, the inhibitory effect of hUMSCs on BV2 microglial pyroptosis was significantly reduced by TSG-6-shRNA transfection. CONCLUSION: In TBI mice, microglial pyroptosis was observed. Both in vivo and in vitro, hUMSCs inhibited pyroptosis, particularly microglial pyroptosis, by regulating the NLRP3/Caspase-1/GSDMD signaling pathway via TSG-6. Video Abstract.

High expression of HHLA2 predicts poor prognosis in medullary thyroid carcinoma.

BACKGROUND: Human endogenous retrovirus-H long terminal repeat-associating protein 2 is a newly identified immune checkpoint molecule that was aberrantly expressed in many malignant tumors. However, its expression in medullary thyroid carcinoma is still unclear. This study aimed to investigate the human endogenous retrovirus-H long terminal repeat-associating protein 2 expression in medullary thyroid carcinoma tissues and to evaluate the relationships between its expression and clinicopathologic together with prognostic relevance. METHODS: Using 51 surgical specimens obtained from medullary thyroid carcinoma patients, the expression levels of the human endogenous retrovirus-H long terminal repeat-associating protein 2 protein in medullary thyroid carcinoma tumor tissues and adjacent noncancerous tissues were measured by immunohistochemistry, and its correlations with clinicopathologic and prognostic features were analyzed. Status of CD8+ tumor infiltrating lymphocytes was also investigated. RESULTS: The results showed that human endogenous retrovirus-H long terminal repeat-associating protein 2 was only detected in tumor tissues, and 31.4% of the medullary thyroid carcinoma patients had high expression of human endogenous retrovirus-H long terminal repeat-associating protein 2. High human endogenous retrovirus-H long terminal repeat-associating protein 2 expression was significantly associated with lymph node metastasis and advanced American Joint Committee on Cancer stages (P = 0.005). There existed an inverse trend between human endogenous retrovirus-H long terminal repeat-associating protein 2 expression and CD8+ tumor infiltrating lymphocytes infiltration in medullary thyroid carcinoma tumor samples (P = 0.042). The log-rank test showed a shorter disease-free survival in patients with high human endogenous retrovirus-H long terminal repeat-associating protein 2 expression (P = 0.002). The disease-free survival rates were also significantly low in cases of medullary thyroid carcinoma with lymph node metastasis, American Joint Committee on Cancer stages III-IV and multifocality. Multivariate Cox analysis confirmed that human endogenous retrovirus-H long terminal repeat-associating protein 2 acted as an independent predictive factor in the disease-free survival of medullary thyroid carcinoma patients (hazard ratio = 4.138, 95% confidence interval: 1.027-16.667, P = 0.046). CONCLUSIONS: Taken together, human endogenous retrovirus-H long terminal repeat-associating protein 2 is highly expressed in medullary thyroid carcinoma patients and is a poor prognostic biomarker of disease-free survival of medullary thyroid carcinoma patients.

A Three-Dimensional-reconstruction-based study on the ocular volume of Chinese children with high myopia.

BACKGROUND: Highly myopic eyes differ in morphology from emmetropic eyes, and the correct estimation of the vitreous volume is difficult. To explore an effective method to estimate ocular volume using refractive factors in children. METHODS: This is a retrospective study of children with high myopia who visited the Shenzhen Shekou People's Hospital (July-December 2018) before undergoing posterior scleral reinforcement surgery. Data on refractive factors and ocular 3D reconstruction imaging based on high-end CT were collected for linear correlation and linear regression analyses. RESULTS: Ten patients (20 eyes) were included. There are nine males and one female. They were 4 to 12 years of age. The spherical equivalent ranges from + 0.25 to -20.00 D. The cylindrical equivalent ranges from - 0.50 to -6.25 D. The AL(axial length, AL) ranges from 21.78 to 33.90 mm. The corneal curvature (mean) ranges from 42.44 to 46.75. The 3D reconstruction of the CT images shows that the ocular volume ranges from 4.591 to 10.988 ml. The ocular volume of the 20 eyes decreases with the increase of diopter and total curvature, both presenting a linear trend, with the Pearson correlation coefficients being - 0.776 (P < 0.001) and - 0.633 (P = 0.003), respectively. The ocular volume of the 20 eyes increases with the increasing AL, also presenting a linear trend, with the Pearson correlation coefficient being 0.939 (P < 0.001). CONCLUSIONS: In children, the ocular volume is negatively and linearly correlated with the diopter and curvature, and positively and linearly correlated with the AL.

Case Series: Ocular Trauma Secondary to Masks during the COVID-19 Pandemic.

SIGNIFICANCE: Previously, people had only recognized the discomfort of masks, and no one had ever realized the risk of ocular trauma associated with masks. We classify the causes of injuries into two categories and emphasize the importance of using masks properly. PURPOSE: This study aimed to characterize and classify ocular injuries caused by masks. CASE REPORTS: With the increase in the number of masks used during the coronavirus disease 2019 pandemic, we have seen a rise in mask-related ocular injuries. This is a single-center retrospective case series of patients presenting to the Peking University Third Hospital Ophthalmology Department emergency department with ocular injuries secondary to masks from February to August 2020. Nine patients (six males, three females) were reviewed. All patients had a unilateral injury (four right eyes, five left eyes). The most frequently injured site was the cornea, which was seen in five patients. Some patients were injured in more than one area. Seven patients were injured by metal nose wires or other rigid, sharp parts of masks. The other two patients were injured by elastic mask straps. CONCLUSIONS: Masks can cause two types of ocular injuries that may require surgical intervention. One kind is metal nose wires or other rigid, sharp parts of masks causing lacerations or abrasions. The other is recoiling elastic mask straps snapping into the eyes and causing contusions. Our report emphasizes the importance of using masks properly.

Analysis of lens epithelium telomere length in age-related cataract.

We aimed to investigate the associations among lens epithelium telomere length (LETL), cataract types, and systemic pro-senescence factors in patients with age-related cataract. In this prospective study, the general demographic factors, body mass index, smoking history, depression, hypertension, diabetes, various psychological measures, and uncorrected distant visual acuity of patients with age-related cataract were recorded. Lens Opacities Classification System III (LOCS III) scores and lens density measured by Scheimpflug imaging were used to evaluate the cataracts. LETL was measured by real-time polymerase chain reaction. Correlations among these parameters were analyzed. The LOCS III nuclear opalescence (NO) score was associated with age (ß = 0.053, P < 0.001) and Patient Health Questionnaire-9 score (ß = -0.042, P = 0.004). Smoking was identified as a risk factor affecting LOCS III NO score (odds ratio = 1.546, 95% confidence interval, 1.128-2.119), but not the LOCS III cortical or posterior subcapsular scores. LETLs showed a weak association with systemic factors and LOCS III scores, and a significantly moderate correlation with the average objective lens densities of different regions measured by Scheimpflug imaging (r values ranged from -0.278 to -0.523, P < 0.05). However, there was no correlation between the LETLs and the maximum lens densities. The groups with a relatively low lens density had longer LETLs. In Conclusion, being an age-related disease, cortical cataract was also associated with "aging of the lens epithelium." Notably, lens epithelium activity rarely showed systemic effects. Thus, future studies should emphasize the importance of the telomeric system in cataractous process and aging.

Lysobacter oculi sp. nov., isolated from human Meibomian gland secretions.

A Gram-stain negative, rod-shaped bacterial, catalase and oxidase positive strain (83-4T) that formed yellow colonies was isolated from human Meibomian gland secretions. Strain 83-4T belongs to the genus Lysobacter according to phylogenetic analysis based on 16S rRNA gene sequences. The DNA G+C content was 67.1 mol%. The circular genome was 2.6 Mb, which contained 2431 protein-coding sequences, 75 pseudogenes, 46 tRNAs, 3 rRNAs and 4 ncRNAs. A bacteriocin cluster and aryl polyene cluster were also found in the genome. The average nucleotide identity value was 79.6% between isolate 83-4T and the closely related type strain Lysobacter tolerans UM1T. The estimated DNA-DNA hybridization value between strain 83-4T and L. tolerans UM1T was 41.6%. Diphosphatidylglycerol, phosphatidylethanolamine and phosphatidylglycerol were the major polar lipids. Iso-C15:0, iso-C11:0 3-OH, iso-C11:0 and summed feature 9 (iso-C17:1ω9c) were the major fatty acids. Ubiquinone (Q-8) was the only respiratory quinone. Therefore, based on the data of phylogenetic analysis, chemotaxonomical and biochemical analyses, it is concluded that strain 83-4T represents a novel species of the genus Lysobacter with the name of Lysobacter oculi sp. nov. The type strain is 83-4T (= CGMCC 1.13464T = NRBC 113451T).

Evaluation of objective visual quality in dry eye disease and corneal nerve changes.

PURPOSE: To explore objective visual quality in dry eye diseases (DED) and the correlation between corneal nerves and objective visual quality. METHODS: Ninety-eight eyes of 49 patients with DED were included. Each patient was evaluated with the ocular surface disease index (OSDI), eyelid margin signs and meibomian gland assessments; corneal staining; tear film breakup time (TBUT); tear meniscus height (TMH); in vivo confocal microscopic (IVCM); objective visual quality including the objective scatter index (OSI), mean objective scattering index (mOSI), modulation transfer function (MTF) cutoff value and Strehl ratio. RESULTS: A significant correlation was found between the OSDI and mOSI (r = 0.422, p = 0.005), MTF cutoff value (r = - 0.355, p = 0.020), and Strehl ratio (r = - 0.446, p = 0.003). The OSI was significantly correlated with TBUTf (r = - 0.213, p = 0.042). The mOSI, MTF cutoff value, Strehl ratio were correlated with eyelid margin signs and meibomian assessments. Additionally, there was a statistically significant correlation between corneal nerve length and the mOSI (r = - 0.239, p = 0.037), OSI (r = - 0.294, p = 0.028), MTF cutoff value(r = 0.282, p = 0.012), and Strehl ratio (r = 0.299, p = 0.008). CONCLUSIONS: Our study explored that objective visual quality was correlated with clinical symptoms and signs in DED patients. Furthermore, for the first time, our study explored the relationship between corneal nerves and objective visual quality and discovered that longer and wider corneal nerves were associated with better objective visual quality, which suggested that nerve changes may be a factor that related to poor visual quality in DED patients.

Sprouty1 regulates neuritogenesis and survival of cortical neurons.

In multicellular organisms, receptor tyrosine kinases (RTKs) control a variety of cellular processes, including cell proliferation, differentiation, migration, and survival. Sprouty (SPRY) proteins represent an important class of ligand-inducible inhibitors of RTK-dependent signaling pathways. Here, we investigated the role of SPRY1 in cells of the central nervous system (CNS). Expression of SPRY1 was substantially higher in neural stem cells than in cortical neurons and was increased during neuronal differentiation of cortical neurons. We found that SPRY1 was a direct target gene of the CNS-specific microRNA, miR-124 and miR-132. In primary cultures of cortical neurons, the neurotrophic factors brain-derived neurotrophic factor (BDNF) and Basic fibroblast growth factor (FGF2) downregulated SPRY1 expression to positively regulate their own functions. In immature cortical neurons and mouse N2 A cells, we found that overexpression of SPRY1 inhibited neurite development, whereas knockdown of SPRY1 expression promoted neurite development. In mature neurons, overexpression of SPRY1 inhibited the prosurvival effects of both BDNF and FGF2 on glutamate-mediated neuronal cell death. SPRY1 was also upregulated upon glutamate treatment in mature neurons and partially contributed to the cytotoxic effect of glutamate. Together, our results indicate that SPRY1 contributes to the regulation of CNS functions by influencing both neuronal differentiation under normal physiological processes and neuronal survival under pathological conditions.

NUF2 is a valuable prognostic biomarker to predict early recurrence of hepatocellular carcinoma after surgical resection.

Early tumor recurrence after curative surgical resection poses a great challenge to the clinical management of hepatocellular carcinoma (HCC). We conducted whole genome expression microarrays on 64 primary HCC tumors with clinically defined recurrence status and cross-referenced with RNA-seq data from 18 HCC tumors in the Cancer Genome Atlas project. We identified a 77-gene signature, which is significantly associated with early recurrent (ER) HCC tumors. This ER-associated signature shows significant enrichment in genes involved in cell cycle pathway. We performed receiver operating characteristic (ROC) analysis to evaluate the prognostic biomarker potential of these 77 genes and Pearson correlation analysis to identify 11 close clusters. The one gene with the best area under the ROC curve in each of the 11 clusters was selected for validation using reverse-transcription quantitative PCR in an independent cohort of 24 HCC tumors. NUF2 was identified to be the minimal biomarker sufficient to discriminate ER tumors from LR tumors. NUF2 in combination with liver cirrhosis could significantly improve the detection of ER tumors with an AUROC of 0.82 and 0.85 in the test and validation cohort, respectively. In conclusion, NUF2 in combination with liver cirrhosis is a promising prognostic biomarker for early HCC recurrence.

Intranasal endoscopic prelacrimal recess approach for maxillary sinus inverted papilloma.

PURPOSE: This study aims to determine the indications and effectiveness of transnasal endoscopic prelacrimal recess approach (PLRA) in patients with maxillary sinus inverted papilloma (IP). METHODS: We retrospectively analyzed 71 patients treated in our institution for maxillary sinus IP between August 2008 and April 2015. 20 patients underwent endoscopic surgery via PLRA. All the patients who had postoperative follow-up for 3 years were enrolled. Demographic data, surgical technique, location of IP attachment, intra- and postoperative complications, follow-up duration and recurrence were recorded. RESULTS: The outpatient follow-up period was 3-10 years after surgery. Recurrence of IP was seen in 6 (8.5%) of 71 patients, including 1 patient in the PLRA group. The recurrence rate was 5% in the PLRA group. Six of 71 patients experienced postoperative complications, but none was observed in the PLRA group. CONCLUSION: Transnasal endoscopic PLRA is a minimally invasive, safe and effective method for maxillary sinus IP. The indication for PLRA is tumor pedicle located on the antero-inferior or infero-lateral wall or at multiple attachment sites of the maxillary sinus.

α-adrenergic agonist brimonidine control of experimentally induced myopia in guinea pigs: A pilot study.

Purpose: To investigate the efficacy of α-adrenergic agonist brimonidine either alone or combined with pirenzepine for inhibiting progressing myopia in guinea pig lens-myopia-induced models. Methods: Thirty-six guinea pigs were randomly divided into six groups: Group A received 2% pirenzepine, Group B received 0.2% brimonidine, Group C received 0.1% brimonidine, Group D received 2% pirenzepine + 0.2% brimonidine, Group E received 2% pirenzepine + 0.1% brimonidine, and Group F received the medium. Myopia was induced in the right eyes of all guinea pigs using polymethyl methacrylate (PMMA) lenses for 3 weeks. Eye drops were administered accordingly. Intraocular pressure was measured every day. Refractive error and axial length measurements were performed once a week. The enucleated eyeballs were removed for hematoxylin and eosin (H&E) and Van Gieson (VG) staining at the end of the study. Results: The lens-induced myopia model was established after 3 weeks. Treatment with 0.1% brimonidine alone and 0.2% brimonidine alone was capable of inhibiting progressing myopia, as shown by the better refractive error (p=0.024; p=0.006) and shorter axial length (p=0.005; p=0.0017). Treatment with 0.1% brimonidine and 0.2% brimonidine combined with 2% pirenzepine was also effective in suppressing progressing refractive error (p=0.016; p=0.0006) and axial length (p=0.017; p=0.0004). The thickness of the sclera was kept stable in all groups except group F; the sclera was much thinner in the lens-induced myopia eyes compared to the control eyes. Conclusions: Treatment with 0.1% brimonidine alone and 0.2% brimonidine alone, as well as combined with 2% pirenzepine, was effective in inhibiting progressing myopia. The result indicates that intraocular pressure elevation is possibly a promising mechanism and potential treatment for progressing myopia.