Neurokinin-1 Receptor Antagonism Reduces Nonallergic Ocular Redness in a Rabbit Model.

Purpose: To evaluate the therapeutic efficacy of topical application of a neurokinin-1 receptor (NK1R) antagonist in a rabbit model of nonallergic ocular redness. Methods: Nonallergic ocular redness was induced in rabbits by a single, topical application of dapiparzole hydrochloride eye drops (0.5%, 1%, 2%, or 5%). The NK1R antagonist L-703,606 was topically applied to the eye at the same time of induction or 20 min after induction, and phosphate buffered saline (PBS) treatment served as the control. Superior bulbar conjunctival images were taken every 30 s for the first 2 min, followed by every 4 min for 8 min, and then every 10 min until 1 h. The severity of ocular redness was evaluated on the images using ImageJ-based ocular redness index (ORI) calculations. Results: The ORI scores were significantly increased after the application of 0.5%, 1%, 2%, or 5% dapiparzole at each time point evaluated, with the most severe redness induced by the 5% dapiprazole that led to a maximal mean increase in ORI score of 14 at 20 min post-induction and thus used for subsequent evaluation of therapeutic efficacy of NK1R antagonism. Topical L-703,606, when applied at the same time as dapiprazole induction, significantly suppressed the increase of ORI scores at all time points (∼40% decrease). Furthermore, when applied at 20 min after dapiprazole induction, L-703,606 rapidly and effectively suppressed the increase of ORI scores at 30, 40, 50, and 60 min (∼30% decrease). Conclusions: Topical blockade of NK1R effectively prevents and alleviates nonallergic ocular redness in a novel animal model.

Understanding the association between adverse childhood experiences and subsequent attention deficit hyperactivity disorder: A systematic review and meta-analysis of observational studies.

OBJECTIVES: Attention deficit hyperactivity disorder (ADHD) is a common neurodevelopmental disorder in childhood, which may be related to adverse childhood experiences (ACEs). Our study aims to explore the association between ACEs and subsequent ADHD, and analyze the potential moderators. METHODS: Literature search was conducted by a combined computer-assisted and manual method. Studies were included if they had reported the association between ACEs and subsequent ADHD. Overall estimates of odds ratios (ORs) were obtained using random-effects meta-analyses, meta-regressions and further stratified analyses were conducted to examine potential moderator variables. RESULTS: Totals of 70 studies involving nearly 4 million participants from among 6,452 unique articles were included. In the primary analyses, ACEs were found to be associated with subsequent ADHD (OR = 1.68, 95% CI: 1.54-1.83), and the negative effects of different forms of ACEs for ADHD were nonequivalent. Such as lived in the stepfamily, been adopted or fostered, and experienced sexual abuse were more deleterious than others. It was found that individuals who had experienced multiple ACEs or who are female were more vulnerable to ADHD. CONCLUSIONS: The findings provide critical evidence for understanding the association between ACEs and ADHD. ACEs could increase the susceptibility of ADHD, especially for individuals who ever experienced multiple ACEs and females.

Therapeutic efficacy of topical blockade of substance P in experimental allergic red eye.

PURPOSE: Allergic conjunctivitis is the most common cause leading to ocular redness (OR). Herein, using an animal model of allergic OR, we evaluated the therapeutic efficacy of topical blockade of substance P (SP) in treating red eye. METHODS: Allergic OR was induced in guinea pigs with topical histamine. Ocular SP was blocked using a specific SP receptor (neurokinin-1 receptor, NK1R) antagonist, L-703,606, via topical application 10 min before or 10 min after histamine instillation. Animal eyes were examined and a series of images were taken for up to 60 min post-OR induction. The severity of redness was analyzed using the quantitative ocular redness index (ORI). At the end of clinical examination, conjunctival tissues were collected for histological examination of conjunctival blood vessels and infiltrating eosinophils and neutrophils. In addition, SP concentration was quantified in the tear fluid and expression levels of inflammatory cytokines were assessed in the conjunctival tissues. RESULTS: Topical histamine application successfully induced red eye, evidenced by the significantly increased ORI during the observation period, with peak values at 10 min, along with significantly increased levels of SP in the tears. Topical treatment with L-703,606, either before histamine application or at the time of peak ORI, effectively reduced ORI and suppressed conjunctival blood vessel dilation, along with decreased eosinophil and neutrophil infiltration, and inflammatory cytokine expression in the conjunctiva, as well as reduced SP levels in the tears. CONCLUSIONS: Topical blockade of SP effectively prevents and treats allergy-related ocular redness by suppressing blood vessel dilation and allergic inflammation.

Robust, accurate, and improved measurement of structural deformation based on off-axis digital image correlation.

We propose a noncontact method for measuring structural deformation using off-axis digital image correlation. An efficient and high-precision algorithm that is insensitive to the accuracy of the initial guess is proposed and validated through numerical simulation. Image displacements in pixels are converted to physical displacements in millimeters using a calibration model based on a new method of measuring the objective distance. A new image-based structural deformation measurement system is proposed and validated using laboratory test results. The proposed method is easy to implement and accurate for structural deformation measurements.

Deep Echo State Q-Network (DEQN) and Its Application in Dynamic Spectrum Sharing for 5G and Beyond.

Deep reinforcement learning (DRL) has been shown to be successful in many application domains. Combining recurrent neural networks (RNNs) and DRL further enables DRL to be applicable in non-Markovian environments by capturing temporal information. However, training of both DRL and RNNs is known to be challenging requiring a large amount of training data to achieve convergence. In many targeted applications, such as those used in the fifth-generation (5G) cellular communication, the environment is highly dynamic, while the available training data is very limited. Therefore, it is extremely important to develop DRL strategies that are capable of capturing the temporal correlation of the dynamic environment requiring limited training overhead. In this article, we introduce the deep echo state Q-network (DEQN) that can adapt to the highly dynamic environment in a short period of time with limited training data. We evaluate the performance of the introduced DEQN method under the dynamic spectrum sharing (DSS) scenario, which is a promising technology in 5G and future 6G networks to increase the spectrum utilization. Compared with conventional spectrum management policy that grants a fixed spectrum band to a single system for exclusive access, DSS allows the secondary system to share the spectrum with the primary system. Our work sheds light on the application of an efficient DRL framework in highly dynamic environments with limited available training data.

Ocular redness - I: Etiology, pathogenesis, and assessment of conjunctival hyperemia.

The translucent appearance of the conjunctiva allows for immediate visualization of changes in the circulation of the conjunctival microvasculature consisting of extensive branching of superficial and deep arterial systems and corresponding drainage pathways, and the translucent appearance of the conjunctiva allows for immediate visualization of changes in the circulation. Conjunctival hyperemia is caused by a pathological vasodilatory response of the microvasculature in response to inflammation due to a myriad of infectious and non-infectious etiologies. It is one of the most common contributors of ocular complaints that prompts visits to medical centers. Our understanding of these neurogenic and immune-mediated pathways has progressed over time and has played a critical role in developing targeted novel therapies. Due to a multitude of underlying etiologies, patients must be accurately diagnosed for efficacious management of conjunctival hyperemia. The diagnostic techniques used for the grading of conjunctival hyperemia have also evolved from descriptive and subjective grading scales to more reliable computer-based objective grading scales.

Ocular redness - II: Progress in development of therapeutics for the management of conjunctival hyperemia.

Conjunctival hyperemia is one of the most common causes for visits to primary care physicians, optometrists, ophthalmologists, and emergency rooms. Despite its high incidence, the treatment options for patients with conjunctival hyperemia are restricted to over-the-counter drugs that provide symptomatic relief due to short duration of action, tachyphylaxis and rebound redness. As our understanding of the immunopathological pathways causing conjunctival hyperemia expands, newer therapeutic targets are being discovered. These insights have also contributed to the development of animal models for mimicking the pathogenic changes in microvasculature causing hyperemia. Furthermore, this progress has catalyzed the development of novel therapeutics that provide efficacious, long-term relief from conjunctival hyperemia with minimal adverse effects.

Can probiotic supplements improve the symptoms of autism spectrum disorder in children?: A protocol for systematic review and meta analysis.

INTRODUCTION: Autism spectrum disorder (ASD) is a neurodevelopmental disorder with increasing incidence. The externalizing and internalizing problems among children with ASD often persistent and highly impair functioning of both the child and the family. Children with ASD often develop gut-related comorbidities and dysbiosis can have negative effects on not only the gastrointestinal (GI) tract, but also psychological symptoms. Dietary exclusions and probiotic supplements also have been investigated in the management of ASD symptoms. Especially, there is some anecdotal evidence that probiotics supplements are able to alleviate GI symptoms as well as improve behaviors in children with ASD. METHOD AND ANALYSIS: This review will report on overall studies that include randomized control trials, randomized cross-over studies and cluster-randomized trials designs that consider curative effect in children with ASD by probiotic supplements. We will search 6 databases: MEDLINE, Embase, Scopus, PubMed, The Cochrane Library, and Web of Science and we will perform a manual search the journal Autism and information of ongoing or unpublished studies. The Mixed Methods Appraisal Tool (MMAT) will be used to assess quality of articles and the Jadad scale will be used to assess for bias. Assessment of publication bias will be performed using funnel plots generated by Comprehensive Meta-Analysis (CMA) 3.0 software. Clarifying the evidence in this area will be important for future research directions when reformulating and promoting the therapeutic regime in the field. ETHICS AND DISSEMINATION: There are no human participants, data, or tissue being directly studied for the purposes of the review; therefore, ethics approval and consent to participate are not applicable. The results of this study will be presented at conferences and published in peer-reviewed journals. REGISTRATION AND STATUS: PROSPERO 2019 CRD42019132754.

The Differential Expression of Cytokines and Growth Factors After SMILE Compared With FS-LASIK in Rabbits.

Purpose: To investigate the differential expression of cytokines and growth factors in the cornea and aqueous humor after small incision lenticule extraction (SMILE) compared with femtosecond LASIK (FS-LASIK) using rabbit model. Methods: Sixteen eyes of 16 rabbits in each group underwent SMILE or FS-LASIK with refractive correction of -6.00 DS/-1.00 DC. Eight additional rabbits served as controls. Pre- and 24 hours, 1 week, 1 month, and 3 months postoperatively, slit-lamp and anterior segment optical coherence tomography were performed, followed by cornea and aqueous humor collection. Apoptosis and proliferation were evaluated with TUNEL assay and Ki-67 immunostaining, respectively. The mRNA and protein expression of cytokines and growth factors was determined by RT-qPCR and Western blotting, respectively. Cytokine levels in the aqueous humor were detected with ELISA. Results: Compared with FS-LASIK, SMILE induced less apoptosis and proliferation in the cornea within 1 week postoperatively. Levels of IL-1ß, TNF-α, and EGFR in the cornea were significantly increased after FS-LASIK compared with SMILE within 24 hours. Levels of IL-8 in the aqueous humor remained elevated until 1 week after FS-LASIK but not SMILE. TGF-ß1 level was elevated up to 1 month after both procedures, while BFGF level was kept high within 1 month after SMILE but not FS-LASIK. Conclusions: SMILE could induce significantly less acute inflammation than FS-LASIK in the cornea and aqueous humor. The differential expression of TGF-ß1 and BFGF between two procedures until 1 month might contribute to the post-SMILE delayed recovery and underline the importance of continued treatment postoperatively.

Sensory neurons directly promote angiogenesis in response to inflammation via substance P signaling.

Blood vessels and nerves travel together to supply most tissues in the body. However, there is a knowledge gap in the mechanisms underlying the direct regulation of angiogenesis by nerves. In the current study, we examined the regulation of angiogenesis by sensory nerves in response to inflammation using the cornea, a normally avascular and densely innervated ocular tissue, as a model. We used desiccating stress as an inflammatory stimulus in vivo and found that sub-basal and epithelial nerve densities in the cornea were reduced in dry eye disease (DED). We established a co-culture system of trigeminal ganglion sensory neurons and vascular endothelial cells (VEC) and found that neurons isolated from mice with DED directly promoted VEC proliferation and tube formation compared with normal controls. In addition, these neurons expressed and secreted higher levels of substance P (SP), a proinflammatory neuropeptide. SP potently promoted VEC activation in vitro and blockade of SP signaling with spantide I, an antagonist of SP receptor Neurokinin-1, significantly reduced corneal neovascularization in vivo. Spantide I and siRNA knockdown of SP abolished the promotion of VEC activation by DED neurons in vitro. Taken together, our data suggested that sensory neurons directly promote angiogenesis via SP signaling in response to inflammation in the cornea.

Brain-Inspired Wireless Communications: Where Reservoir Computing Meets MIMO-OFDM.

Reservoir computing (RC) is a class of neuromorphic computing approaches that deals particularly well with time-series prediction tasks. It significantly reduces the training complexity of recurrent neural networks and is also suitable for hardware implementation whereby device physics are utilized in performing data processing. In this paper, the RC concept is applied to detecting a transmitted symbol in multiple-input multiple-output orthogonal frequency division multiplexing (MIMO-OFDM) systems. Due to wireless propagation, the transmitted signal may undergo severe distortion before reaching the receiver. The nonlinear distortion introduced by the power amplifier at the transmitter may further complicate this process. Therefore, an efficient symbol detection strategy becomes critical. The conventional approach for symbol detection at the receiver requires accurate channel estimation of the underlying MIMO-OFDM system. However, in this paper, we introduce a novel symbol detection scheme where the estimation of the MIMO-OFDM channel becomes unnecessary. The introduced scheme utilizes an echo state network (ESN), which is a special class of RC. The ESN acts as a black box for system modeling purposes and can predict nonlinear dynamic systems in an efficient way. Simulation results for the uncoded bit error rate of nonlinear MIMO-OFDM systems show that the introduced scheme outperforms conventional symbol detection methods.

Real-Time Intraocular Pressure Measurements in the Vitreous Chamber of Rabbit Eyes During Small Incision Lenticule Extraction (SMILE).

PURPOSE: To investigate real-time intraocular pressure (IOP) during small incision lenticule extraction (SMILE) in rabbit eyes for myopia correction. METHODS: During SMILE, real-time IOP was measured in the vitreous cavity of rabbit eyes with an optic fiber pressure sensor (OFPS). Two groups (n = 6 for each) underwent surgery, one group for a -2.00 diopter (D) refractive spherical correction and the other for a -6.00 D correction. RESULTS: During surgery, the IOP increased once the glass contact attached to the cornea (Pre-suction), and peaked 83.94 mmHg (SD ± 23.87 mmHg) for the -2.00 D group and 89.17 mmHg (SD ± 22.66 mmHg) for the -6.00 D group, both average values were less than 110 mmHg when suction was initiated to fix the glass contact onto the cornea (Suction on). It then fell to 74.81 mmHg (SD ± 20.64 mmHg) and 76.94 mmHg (SD ± 27.43 mmHg), respectively, and remained stable during lenticule creation (Cutting). After suction stopped (Suction off), IOP fell steeply. During lenticule separation/extraction, the change in IOP was 32.26 mmHg (SD ± 2.91 mmHg). Notably, the average duration of elevated IOP during the surgery was 166.05 s (no longer than 3 min). CONCLUSIONS: The IOP fluctuations in the vitreous cavity using an OFPS in a rabbit model during SMILE showed that real-time IOP significantly was increased during Pre-suction, Suction on, Cutting, Suction off, and lenticule separation/extraction compared to baseline IOP, although, peaked at Suction on. Neither the degree of myopic correction nor central corneal thickness significantly affected these changes in IOP.

Hypoxia with Wharton's jelly mesenchymal stem cell coculture maintains stemness of umbilical cord blood-derived CD34+ cells.

BACKGROUND: The physiological approach suggests that an environment associating mesenchymal stromal cells with low O2 concentration would be most favorable for the maintenance of hematopoietic stem/progenitor cells (HSPCs). To test this hypothesis, we performed a coculture of cord blood CD34+ cells with Wharton's jelly mesenchymal stem cells (WJ-MSCs) under different O2 concentration to simulate the growth of HSPCs in vivo, and assessed the impacts on stemness maintenance and proliferation of cord blood HSPCs in vitro. METHODS: CD34+ cells derived from cord blood were isolated and cocultured under 1%, 3%, or 20% O2 concentrations with irradiated WJ-MSCs without adding exogenous cytokines for 7 days. The cultured cells were harvested and analyzed for phenotype and functionality, including total nuclear cells (TNC), CD34+Lin- cells, colony forming unit (CFU) for committed progenitors, and long-term culture initiating cells (LTC-ICs) for HSPCs. The cytokine levels in the medium were detected with Luminex liquid chips, and the mRNA expression of hypoxia inducible factor (HIF) genes and stem cell signal pathway (Notch, Hedgehog, and Wnt/ß-catenin) downstream genes in cord blood HSPCs were confirmed by quantitative real-time polymerase chain reaction (qRT-PCR). RESULTS: Our results showed that the number of TNC cells, CD34+Lin- cells, and CFU were higher or similar with 20% O2 (normoxia) in coculture and compared with 1% O2 (hypoxia). Interestingly, a 1% O2 concentration ensured better percentages of CD34+Lin- cells and LTC-IC cells. The hypoxia tension (1% O2) significantly increased vascular endothelial growth factor (VEGF) secretion and decreased interleukin (IL)-6, IL-7, stem cell factor (SCF), and thrombopoietin (TPO) secretion of WJ-MSCs, and selectively activated the Notch, Wnt/ß-catenin, and Hedgehog signaling pathway of cord blood HSPCs by HIF-related factors, which may play an important role in stemness preservation and for sustaining HSPC quiescence. CONCLUSIONS: Our data demonstrate that cord blood HSPCs maintain stemness better under hypoxia than normoxia with WJ-MSC coculture, partially due to the increased secretion of VEGF, decreased secretion of IL-6 by WJ-MSCs, and selective activation of stem cell signal pathways in HSPCs. This suggests that the oxygenation may not only be a physiological regulatory factor but also a cell engineering tool in HSPC research, and this may have important translational and clinical implications.

Dynamic RACH Partition for Massive Access of Differentiated M2M Services.

In machine-to-machine (M2M) networks, a key challenge is to overcome the overload problem caused by random access requests from massive machine-type communication (MTC) devices. When differentiated services coexist, such as delay-sensitive and delay-tolerant services, the problem becomes more complicated and challenging. This is because delay-sensitive services often use more aggressive policies, and thus, delay-tolerant services get much fewer chances to access the network. To conquer the problem, we propose an efficient mechanism for massive access control over differentiated M2M services, including delay-sensitive and delay-tolerant services. Specifically, based on the traffic loads of the two types of services, the proposed scheme dynamically partitions and allocates the random access channel (RACH) resource to each type of services. The RACH partition strategy is thoroughly optimized to increase the access performances of M2M networks. Analyses and simulation demonstrate the effectiveness of our design. The proposed scheme can outperform the baseline access class barring (ACB) scheme, which ignores service types in access control, in terms of access success probability and the average access delay.

ZEB1 Upregulates VEGF Expression and Stimulates Angiogenesis in Breast Cancer.

Although zinc finger E-box binding homeobox 1 (ZEB1) has been identified as a key factor in the regulation of breast cancer differentiation and metastasis, its potential role in modulating tumor angiogenesis has not been fully examined. Here, we present the novel finding that conditioned medium derived from ZEB1-expressing MDA-MB-231 cells significantly increased the capillary tube formation of human umbilical vein endothelial cells (HUVECs), whereas ZEB1 knockdown by RNA interference had the opposite effect. ZEB1 caused marked upregulation of the expression of vascular endothelial growth factor A (VEGFA) at both mRNA and protein levels. Pre-incubation of HUVECs with anti-VEGFA neutralized antibody attenuated ZEB1-mediated tube formation of HUVECs. In breast cancer tissues, expression of ZEB1 was positively correlated with those of VEGFA and CD31. At the molecular level, ZEB1 activated VEGFA transcription by increasing SP1 recruitment to its promoter, which was mediated via the activation of PI3K and p38 pathways. Using a nude mouse xenograft model, we demonstrated that elevated expression of ZEB1 promotes in vivo tumorigenesis and angiogenesis in breast cancer. Collectively, we found that ZEB1-expressing breast cancer cells increase VEGFA production and thus stimulate tumor growth and angiogenesis via a paracrine mechanism.

MKL1 inhibits cell cycle progression through p21 in podocytes.

BACKGROUND: The glomerular podocyte is a highly specialized cell type with the ability to ultrafilter blood and support glomerular capillary pressure. However, little is known about the genetic programs leading to this functionality or the final phenotype. RESULTS: In the current study, we found that the expression of a myocardin/MKL family member, MKL1, was significantly upregulated during cell cycle arrest induced by a temperature switch in murine podocyte clone 5 (MPC5) cells. Further investigation demonstrated that overexpression of MKL1 led to inhibition of cell proliferation by decreasing the number of cells in S phase of the cell cycle. In contrast, MKL1 knockdown by RNA interference had the opposite effect, highlighting a potential role of MKL1 in blocking G1/S transition of the cell cycle in MPC5 cells. Additionally, using an RT(2) Profiler PCR Array, p21 was identified as a direct target of MKL1. We further revealed that MKL1 activated p21 transcription by recruitment to the CArG element in its promoter, thus resulting in cell cycle arrest. In addition, the expression of MKL1 is positively correlated with that of p21 in podocytes in postnatal mouse kidney and significantly upregulated during the morphological switch of podocytes from proliferation to differentiation. CONCLUSIONS: Our observations demonstrate that MKL1 has physiological roles in the maturation and development of podocytes, and thus its misregulation might lead to glomerular and renal dysfunction.

[Isolation, amplification and identification of human natural CD4⁺CD25⁺ regulatory T cells in vitro].

OBJECTIVE: To establish a method for in vitro expansion of human natural CD4⁺CD25⁺ T regulatory cell (Treg) cells for clinical study and immunotherapy. METHODS: Human natural CD4⁺CD25⁺ Treg were isolated from peripheral blood monocyte cells (PBMCs) by magnetic activated cell sorting (MACS) and expanded by CD3/CD28 expansion beads, IL-2 and rapamycin. The number and the viability of the freshly isolated and expanded Treg were detemined by trypan blue staining. The phenotype and the purity of the freshly isolated and expanded Treg were analyzed by FACS. Treg suppression activity was assessed by mixed lymphocyte reaction (MLR) assay. RESULTS: Human natural Treg were expanded up to 2 000 folds after 3 weeks in culture, and the activity was more than 97%. The expanded Treg retained Treg phenotype as shown by their freshly isolated counterparts, and the purity of CD4⁺CD25⁺FoxP3⁺ Treg was (94.22 ± 2.12)%. The expanded Treg demonstrated a similar potent suppression of both proliferating auto- and allo- CD4⁺CD25⁻ effector T cells in vitro in a cell number-dependent manner. CONCLUSION: An in vitro expansion of human natural Treg was established to obtain large numbers of human Treg with highly suppressive phenotype and function, thereby providing a solution to the availability of sufficient human natural Treg in clinical study and immunotherapy.

[Serum vitamin D levels in postmenopausal women with type 2 diabetes mellitus].

OBJECTIVE: To investigate the correlation between serum vitamin D levels and index of glucose and lipid metabolism in postmenopausal women with type 2 diabetes mellitus (T2DM). METHODS: A total of 44 postmenopausal women with T2DM and 41 healthy postmenopausal women were matched with age, body mass index and menopausal duration. The serum vitamin D was detected by enzyme-linked immuno-sorbent assay (ELISA). RESULTS: Compared with the control group, the level of 25(OH)D3 in postmenopausal women with T2DM was lower, with no statistical significance. Multiple regression analysis revealed that only BMI(bj'=-0.372, P<0.05) was independently related to 25(OH)D3 with statistical significance. The percentages of 25(OH)D3 deficiency in all subjects in the control group and in the T2DM group were 84.7%, 80.5%, and 88.6%, respectively. The 25(OH)D3 deficiency in the T2DM group was more prevalent than that in the control group, with no statistical difference (P=0.372). The binary logistic regression analysis showed the serum 25(OH)D3 level was not related to the risk of diabetes. CONCLUSION: Compared with the control group, a lower 25(OH)D3 level and a higher rate of 25(OH)D3 deficiency is found in T2DM subjects. When rectified by BMI, these is no significant difference. In postmenopausal women, hypovitaminosis D is associated with obesity and dyslipidemia, but not with the risk of T2DM.