Neurons in Primate Area MSTd Signal Eye Movement Direction Inferred from Dynamic Perspective Cues in Optic Flow.

Smooth eye movements are common during natural viewing; we frequently rotate our eyes to track moving objects or to maintain fixation on an object during self-movement. Reliable information about smooth eye movements is crucial to various neural computations, such as estimating heading from optic flow or judging depth from motion parallax. While it is well established that extraretinal signals (e.g., efference copies of motor commands) carry critical information about eye velocity, the rotational optic flow field produced by eye rotations also carries valuable information. Although previous work has shown that dynamic perspective cues in optic flow can be used in computations that require estimates of eye velocity, it has remained unclear where and how the brain processes these visual cues and how they are integrated with extraretinal signals regarding eye rotation. We examined how neurons in the dorsal region of the medial superior temporal area (MSTd) of two male rhesus monkeys represent the direction of smooth pursuit eye movements based on both visual cues (dynamic perspective) and extraretinal signals. We find that most MSTd neurons have matched preferences for the direction of eye rotation based on visual and extraretinal signals. Moreover, neural responses to combinations of these signals are well predicted by a weighted linear summation model. These findings demonstrate a neural substrate for representing the velocity of smooth eye movements based on rotational optic flow and establish area MSTd as a key node for integrating visual and extraretinal signals into a more generalized representation of smooth eye movements.SIGNIFICANCE STATEMENT We frequently rotate our eyes to smoothly track objects of interest during self-motion. Information about eye velocity is crucial for a variety of computations performed by the brain, including depth perception and heading perception. Traditionally, information about eye rotation has been thought to arise mainly from extraretinal signals, such as efference copies of motor commands. Previous work shows that eye velocity can also be inferred from rotational optic flow that accompanies smooth eye movements, but the neural origins of these visual signals about eye rotation have remained unknown. We demonstrate that macaque neurons signal the direction of smooth eye rotation based on visual signals, and that they integrate both visual and extraretinal signals regarding eye rotation in a congruent fashion.

Combined amplification-based single-molecule fluorescence in situ hybridization with immunofluorescence for simultaneous in situ detection of RNAs and proteins.

We present a combined amplification-based single-molecule fluorescence in situ hybridization and immunofluorescence (asmFISH-IF) method for the detection of multiple RNAs and proteins simultaneously in cells and formaldehyde-fixed and paraffin-embedded tissue sections. We showed that performing asmFISH before immunofluorescence gives a better IF signal than the opposite. Our asmFISH-IF method could help study the interplay of RNA and protein, helping to understand their functions.

Predictors of meaningful improvement in quality of life after selective amygdalohippocampectomy in Chinese patients with refractory temporal lobe epilepsy: A prospective study.

PURPOSE: Our aim was to determine the independent predictors of minimum clinically important difference (MCID) in quality of life (QOL) after selective amygdalohippocampectomy (SAH) among Chinese patients with refractory mesial temporal lobe epilepsy (MTLE). METHODS: We conducted a prospective study and enrolled 50 consecutive patients with refractory MTLE who underwent SAH after their presurgical evaluations. The variables independently associated with MCID in the Quality of Life in Epilepsy Inventory-31 (QOLIE-31) overall score 1 year after SAH were analyzed by multiple binary logistic regression analysis. RESULTS: Significant improvements in the QOLIE-31 overall score and all subscale scores were observed after SAH (p < 0.001). Among 50 patients with refractory MTLE, 78% reached the criteria for MCID of QOL overall score after SAH. In the multiple binary logistic regression model, the presurgical independent predictors of significant improvement by MCID in QOL were absence of depression diagnosis (adjusted odds ratio [OR] = 8.391, 95% confidence interval [CI] = 1.240-56.776, p = 0.029) and good cognitive function (adjusted OR = 8.427, 95% CI = 1.115-63.670, p = 0.039); the postoperative independent predictor was seizure freedom (adjusted OR = 8.477, 95% CI = 1.195-60.122, p = 0.032). The sensitivity and specificity for significant improvement in the QOL were 97.4% and 45.5% respectively, with an overall model accuracy of 86.0%. CONCLUSIONS: Presurgical depression, cognitive function, and postsurgical seizure freedom are independent predictors for meaningful improvement in QOL after SAH among the Chinese patients with refractory MTLE. Preoperative evaluation of patients with refractory MTLE should consider the cognitive dysfunction and psychological disorders.

Suppression of hepatocellular carcinoma by Ulva lactuca ulvan via gut microbiota and metabolite interactions.

INTRODUCTION: Ulva lactuca polysaccharide (ULP) is green algae extract with numerous biological activities, including anticoagulant, anti-inflammatory, and antiviral effects. However, the inhibitory ability of ULP in the development of hepatocellular carcinoma warrants further studies. OBJECTIVES: To elucidate the anti-tumor mechanism of ULP action and evaluate its regulatory effect on gut microbiota and metabolism in H22 hepatocellular carcinoma tumor-bearing mice. METHODS: An H22 tumor-bearing mouse model was established by subcutaneously injecting H22 hepatoma cells. The gut microbiota composition in cecal feces was assessed and subjected to untargeted metabolomic sequencing. The antitumor activity of ULP was verified further by western blot, RT-qPCR, and reactive oxygen species (ROS) assays. RESULTS: Administration of ULP alleviated tumor growth by modulating the compositions of the gut microbial communities (Tenericutes, Agathobacter, Ruminiclostridium, Parabacteroides, Lactobacillus, and Holdemania) and metabolites (docosahexaenoic acid, uric acid, N-Oleoyl Dopamine, and L-Kynurenine). Mechanistically, ULP promoted ROS production by inhibiting the protein levels of JNK, c-JUN, PI3K, Akt, and Bcl-6, thereby delaying the growth of HepG2 cells. CONCLUSION: ULP attenuates tumor growth in H22 tumor-bearing mice by modulating gut microbial composition and metabolism. ULP inhibits tumor growth mainly by promoting ROS generation.

Relationship Between FERMT2, CELF1, COPI, CHRNA2, and ABCA7 Genetic Polymorphisms and Alzheimer's Disease Risk in the Southern Chinese Population.

Background: Alzheimer's disease (AD) is a multi-gene inherited disease, and apolipoprotein E (APOE) ɛ4 is a strong risk factor. Other genetic factors are important but limited. Objective: This study aimed to investigate the relationship between 17 single-nucleotide polymorphisms (SNPs) and AD in the Southern Chinese populations. Methods: We recruited 242 AD patients and 208 controls. The SNaPshot technique was used to detect the SNPs. Results: Adjusted for sex and age, we found rs6572869 (FERMT2), rs11604680 (CELF1), and rs1317149 (CELF1) were associated with AD risk in the dominant (rs6572869: p = 0.022, OR = 1.55; rs11604680: p = 0.007, OR = 1.68; rs1317149: p = 0.033, OR = 1.50) and overdominant models (rs6572869: p = 0.001, OR = 1.96; rs11604680: p = 0.002, OR = 1.82; rs1317149: p = 0.003, OR = 1.80). rs9898218 (COPI) was associated with AD risk in the overdominant model (p = 0.004, OR = 1.81). Further, rs2741342 (CHRNA2) was associated with AD protection in the dominant (p = 0.002, OR = 0.5) and additive models (p = 0.002, OR = 0.64). Mutations in rs10742814 (CELF1), rs11039280 (CELF1), and rs3752242 (ABCA7) contributed to AD protection. Among them, rs10742814 (CELF1), rs3752242 (ABCA7), and rs11039280 (CELF1) were more significantly associated with AD carrying APOE ɛ4, whereas rs1317149 (CELF1) showed an opposite trend. Interestingly, rs4147912 (ABCA7) and rs2516049 (HLA-DRB1) were identified to be relevant with AD carrying APOE ɛ4. Using expression quantitative trait locus analysis, we found polymorphisms in CELF1 (rs10742814 and rs11039280), ABCA7 (rs4147912), HLA-DRB1 (rs2516049), and ADGRF4 (rs1109581) correlated with their corresponding gene expression in the brain. Conclusions: We identified four risk and four protective SNPs associated with AD in the Southern Chinese population, with different correlations between APOE ɛ4 carriers and non-carriers. rs4147912 (ABCA7) and rs2516049 (HLA-DRB1) were associated with AD carrying APOE ɛ4.

Regulatory mechanisms of the edible alga Ulva lactuca polysaccharide via modulation of gut microbiota in diabetic mice.

In this study, Ulva lactuca polysaccharide (ULP) antihyperglycemic effect was assessed by monitoring changes in the gut microbiota of aging diabetic mice. The results showed that ULP alleviated type 2 diabetes by improving insulin tolerance, increasing SOD and CAT activities, and thus lowering blood glucose level. Moreover, ULP regulated the expressions of INSR and AMPK concurrent with inhibition the expression of JNK, JAK, STAT3, p16 and p38 to improve glucose metabolism dysfunction. Interestingly, the abundance of Alloprevotella and Pediococcus change might the key factor for ULP antihyperglycemic effectiveness in aging-related diabetes. These results suggest that ULP can exert a mechanism of blood glucose regulation by improving intestinal diversity composition asides from direct insulin mimetic actions.

Fucosylated oligosaccharide Lacto-N-fucopentaose I ameliorates enterovirus 71 infection by inhibiting apoptosis.

Enterovirus 71 (EV71) is the main cause of hand, foot and mouth disease that results in high rates of severe diseases in small children. Lacto-N-fucopentaose I (LNFPI) can inhibit pathogen invasion and regulate intestinal flora. However, whether LNFPI inhibits EV71 infection remains unknown. In this study, we examined the effect and mechanism of LNFPI against EV71. LNFPI reduced capsid protein VP1 to block virus adsorption, inhibited cyclin E transcription and promoted CDK2 expression in EV71-induced human rhabdomyosarcoma cells, thereby causing virus-induced S phase arrest and inhibiting death receptor and mitochondria-induced apoptosis. The effects of LNFPI on apoptosis were further confirmed in Caenorhabditis elegans. The correlation analysis revealed that LNFPI inhibited cell apoptosis by reducing the abundance of Sphingomonas, Stenotrophomonas and Achromatic, which are associated with pro-apoptotic genes in C. elegans, and by increasing the abundance of Micromonospora, which is related to apoptotic inhibition. These findings lead to further recommendations for LNFPI supplementation in infant formula, as it could offer antiviral benefits to formula-fed infants.

Metabolomics and biochemical insights on the regulation of aging-related diabetes by a low-molecular-weight polysaccharide from green microalga Chlorella pyrenoidosa.

Globally, aging and diabetes are considered prevalent threats to human health. Chlorella pyrenoidosa polysaccharide (CPP) is a natural active ingredient with multiple health benefits including antioxidant and hypolipidemic activities. In this study, the aging-related diabetic (AD) mice model was established to investigate the underlying hypoglycemic and antioxidant mechanisms of CPP. It improved superoxide dismutase, catalase (CAT), glutathione peroxidase (GSH-px), and malondialdehyde activities in liver and insulin secretion. CAT and GSH-px activity in the brain increased after CPP administration. In addition, through histopathological examinations, it was evident that injuries in the liver, brain, jejunum, and pancreas were restored by CPP. This restoration was likely mediated via the activation of glucagon-like peptide-1 receptor/FOXO-1 (forkhead box O1) pathway concurrent with the inhibition of interleukin-6 receptor/FOXO-1 pathway. Furthermore, metabolomics and correlation analysis revealed that CPP possibly relived AD through changes in insulin levels and declined oxidative stress as regulated by phenylpyruvic acid. These findings suggested that CPP exerted antioxidant and hypoglycemic roles in an AD mice model, thereby providing a sound scientific foundation for further development and utilization of CPP.

Functional Connectivity Alterations Based on the Weighted Phase Lag Index: An Exploratory Electroencephalography Study on Alzheimer's Disease.

OBJECTIVE: Numerous electroencephalography (EEG) studies focus on the alteration of electrical activity in patients with Alzheimer's Disease (AD), but there are no consistent results especially regarding functional connectivity. We supposed that the weighted Phase Lag Index (w- PLI), as phase-based measures of functional connectivity, may be used as an auxiliary diagnostic method for AD. METHODS: We enrolled 30 patients with AD, 30 patients with Mild Cognitive Impairment (MCI), and 30 Healthy Controls (HC). EEGs were recorded in all participants at baseline during relaxed wakefulness. Following EEG preprocessing, Power Spectral Density (PSD) and wPLI parameters were determined to further analyze whether they were correlated to cognitive scores. RESULTS: In the patients with AD, the increased PSD in theta band was presented compared with MCI and HC groups, which was associated with disturbances of the directional, computational, and delayed memory capacity. Furthermore, the wPLI revealed a distinctly lower connection strength between frontal and distant areas in the delta band and a higher connection strength of the central and temporo-occipital region in the theta band for AD patients. Moreover,we found a significant negative correlation between theta functional connectivity and cognitive scores. CONCLUSION: Increased theta PSD and decreased delta wPLI may be one of the earliest changes in AD and associated with disease severity. The parameter wPLI is a novel measurement of phase synchronization and has potentials in understanding underlying functional connectivity and aiding in the diagnostics of AD.

Cancer-fighting potentials of algal polysaccharides as nutraceuticals.

Cancer has been listed as one of the world's five incurable diseases by the World Health Organization and causes tens of thousands of deaths every year. Unfortunately, anticancer agents either show limited efficacy or show serious side effects. The algae possess high nutritional value and their polysaccharides have a variety of biological activities, especially anti-cancer and immunomodulatory properties. Algal polysaccharides exert anti-cancer effects by inducing apoptosis, cell cycle arrest, anti-angiogenesis, and regulating intestinal flora and immune function. Algal polysaccharides can be combined with nanoparticles and other drugs to reduce the side effects caused by chemotherapy and increase the anticancer effects. This review shows the signal pathways related to the anti-cancer mechanisms of algal polysaccharides, including their influence on intestinal flora and immune regulation, the application of nanoparticles, and the effects on combination therapy and clinical trials of cancer treatments.

Establishment of SIAISi002-A, an induced pluripotent stem cell (iPSC) line from 39-year old healthy female donor with a family history of Alzheimer's disease (AD) and two copies of APOE4 gene.

A 39-year old healthy female with a family history of Alzheimer's disease (AD) and two copies of apolipoprotein E(APOE) ε4 allele donated her Peripheral blood mononuclear cells (PBMC). The non-integrative Sendai viral vectors used to reprogram PBMCs with the human OKSM transcription factors. The pluripotency of iPSCs was confirmed by immunocytochemistry and ability of differentiation spontaneously into 3 germ layers. Furthermore, the iPSC line displayed a normal karyotype. The APOE gene is currently considered to be the most relevant gene for sporadic AD. Our model might offer a platform to study the pathological mechanisms and drug testing studies in AD.

Establishment of SIAISi001-A, an induced pluripotent stem cell (iPSC) line from 66-year old mild cognitive impairment (MCI) with two copies of APOE4 gene.

A 66-year old mild cognitive impairment (MCI) female patient donated her Peripheral blood mononuclear cells (PBMC). PBMC was reprogrammed using non-integrative Sendai viral vectors containing reprogramming factors OCT4, KLF4, SOX2 and C-MYC. The pluripotency of transgene-free iPSCs was confirmed by immunocytochemistry and ability of differentiation spontaneously into 3 germ layers in vitro. Moreover, the iPSC line displayed a normal karyotype. The apolipoprotein E (APOE) ε4 allele, is considered to be the strongest genetic risk factor for Sporadic Alzheimer's disease (AD). Our model might offer a good platform to study the pathological mechanisms and drug testing studies in AD and MCI.

Increased prediction value of biomarker combinations for the conversion of mild cognitive impairment to Alzheimer's dementia.

BACKGROUND: Progression of mild cognitive impairment (MCI) to Alzheimer's disease (AD) dementia can be predicted by clinical features and a combination of biomarkers may increase the predictive power. In the present study, we investigated whether the combination of olfactory function and plasma neuronal-derived exosome (NDE) Aß1-42 can best predict progression to AD dementia. METHODS: 87 MCI patients were enrolled and received the cognitive assessment at 2-year and 3-year follow-up to reevaluate cognition. In the meanwhile, 80 healthy controls and 88 AD dementia patients were enrolled at baseline as well to evaluate the diagnose value in cross-section. Olfactory function was evaluated with the sniffin sticks (SS-16) and Aß1-42 levels in NDEs were determined by ELISA. Logistic regression was performed to evaluate the risk factors for cognitive decline in MCI at 2-year and 3-year revisits. RESULTS: In the cross cohort, lower SS-16 scores and higher Aß1-42 levels in NDEs were found in MCI and AD dementia compared to healthy controls. For the longitudinal set, 8 MCI individuals developed AD dementia within 2 years, and 16 MCI individuals developed AD dementia within 3 years. The two parameter-combination of SS-16 scores and Aß1-42 level in NDEs showed better prediction in the conversion of MCI to AD dementia at 2-year and 3-year revisit. Moreover, after a 3-year follow-up, SS-16 scores also significantly predicted the conversion to AD dementia, where lower scores were associated with a 10-fold increased risk of developing AD dementia (p = 0.006). Similarly, higher Aß1-42 levels in NDEs in patients with MCI increased the risk of developing AD dementia by 8.5-fold (p = 0.002). CONCLUSION: A combination of two biomarkers of NDEs (Aß1-42) and SS-16 predicted the conversion of MCI to AD dementia more accurately in combination. These findings have critical implications for understanding the pathophysiology of AD dementia and for developing preventative treatments for cognitive decline.

Visual Abnormalities Associate With Hippocampus in Mild Cognitive Impairment and Early Alzheimer's Disease.

Background and Objective: Alzheimer's disease (AD) has been shown to affect vision in human patients and animal models. This study was conducted to explore ocular abnormalities in the primary visual pathway and their relationship with hippocampal atrophy in patients with AD and mild cognitive impairment (MCI). The aim of this study was to investigate the potential value of ocular examinations as a biomarker during the AD progression. Methods: Patients with MCI (n = 23) or AD (n = 17) and age-matched cognitively normal controls (NC; n = 19) were enrolled. Pattern visual-evoked potentials (PVEP), flash electroretinogram (FERG) recordings and optical coherence tomography (OCT) were performed for all participants. Hippocampal volumes were measured by 3T magnetic resonance imaging. Cognitive function was assessed by Mini Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA) and Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog). Pearson correlation was employed to analyze the potential associations between ocular abnormalities and hippocampal volumes. Hierarchical regression models were conducted to determine associations between cognitive performances and ocular abnormalities as well as hippocampal volumes after adjusting for confounding factors including age, sex, cognitive reserve, and APOE4 status. Results: PVEP amplitude of P100 waveform was significantly decreased in AD patients compared to MCI and normal individuals. In FERG test, delayed latencies of rod response, rod cone response and 3.0 flicker time were found in cognitively impaired groups, indicating dysfunctions of both the rod and cone systems in the disease progression. OCT test revealed reduced macular retinal nerve fiber layer (m-RNFL) thickness in MCI and AD patients, which significantly correlated with brain structure of hippocampus particularly vulnerable during the progression of AD. Interestingly, P100 amplitude showed a significant association with hippocampal volumes even after adjusting confounding factors including age, sex, and cognitive reserve. Hierarchical regression analysis further demonstrated that m-RNFL thickness, as well as hippocampal volumes, significantly associated with ADAS-cog scores. Conclusion: P100 amplitude and m-RNFL thickness showed significant correlations with brain structure involved in AD-related neurodegeneration, and therefore proved to be potential indicators of brain imaging pathologies.

Association between HLA-A*3201 allele and oxcarbazepine-induced cutaneous adverse reactions in Eastern Han Chinese population.

PURPOSE: To determine genetic associations between oxcarbazepine (OXC)-induced cutaneous adverse drug reactions (cADRs) and human leukocyte antigen (HLA) variants in the Eastern Han Chinese population. METHODS: A total of 120 patients were enrolled in this study, including 30 subjects with OXC-induced cADRs (case group) and 90 OXC-tolerant patients (control group). High-resolution HLA genotyping was conducted for HLA-A, HLA-B, HLA-C, and HLA-DRB1, and allele frequencies were compared. RESULTS: No patient carried the HLA-B *1502 allele in the case group, the frequency of HLA-B *1502 allele in the control group was 6.1%. HLA-A*3201 allele was detected in 13.3% of 30 patients with OXC-induced cADRs (4/30) and 0% of 90 OXC-tolerant patients (0/90). The difference in HLA-A*3201 frequency between the two groups was statistically significant [P = 0.004, odds ratio (OR) = 15.877, 95% confidence interval (CI) = 1.817-138.720]. CONCLUSIONS: Eastern Han Chinese patients with the HLA-A*3201 allele may be more susceptible to OXC-induced cADRs, while the HLA-B*1502 allele is not correlated with it. The precise association between HLA alleles and OXC-induced cADRs warrants further study.