Dual-task turn velocity - a novel digital biomarker for mild cognitive impairment and dementia.

Background: Disorders associated with cognitive impairment impose a significant burden on both families and society. Previous studies have indicated that gait characteristics under dual-task as reliable markers of early cognitive impairment. Therefore, digital gait detection has great potential for future cognitive screening. However, research on digital biomarkers based on smart devices to identify cognitive impairment remains limited. The aim of this study is to explore digital gait biomarkers by utilizing intelligent wearable devices for discriminating mild cognitive impairment and dementia. Methods: This study included 122 subjects (age: 74.7 ± 7.7 years) diagnosed with normal cognition (NC, n = 38), mild cognitive impairment (MCI, n = 42), or dementia (n = 42). All subjects underwent comprehensive neuropsychological assessments and cranial Magnetic Resonance Imaging (MRI). Gait parameters were collected using validated wearable devices in both single-task and dual-task (DT). We analyzed the ability of gait variables to predict MCI and dementia, and examined the correlations between specific DT-gait parameters and sub-cognitive functions as well as hippocampal atrophy. Results: Our results demonstrated that dual-task could significantly improve the ability to predict cognitive impairment based on gait parameters such as gait speed (GS) and stride length (SL). Additionally, we discovered that turn velocity (TV and DT-TV) can be a valuable novel digital marker for predicting MCI and dementia, for identifying MCI (DT-TV: AUC = 0.801, sensitivity 0.738, specificity 0.842), and dementia (DT-TV: AUC = 0.923, sensitivity 0.857, specificity 0.842). The correlation analysis and linear regression analysis revealed a robust association between DT-TV and memory function, as well as the hippocampus atrophy. Conclusion: This study presents a novel finding that DT-TV could accurately identify varying degrees of cognitive impairment. DT-TV is strongly correlated with memory function and hippocampus shrinkage, suggests that it can accurately reflect changes in cognitive function. Therefore, DT-TV could serve as a novel and effective digital biomarker for discriminating cognitive impairment.

Linear brain measurement: a new screening method for cognitive impairment in elderly patients with cerebral small vessel disease.

Background: The old adults have high incidence of cognitive impairment, especially in patients with cerebral small vessel disease (CSVD). Cognitive impairment is not easy to be detected in such populations. We aimed to develop clinical prediction models for different degrees of cognitive impairments in elderly CSVD patients based on conventional imaging and clinical data to determine the better indicators for assessing cognitive function in the CSVD elderly. Methods: 210 CSVD patients were screened out by the evaluation of Magnetic Resonance Imaging (MRI). Then, participants were divided into the following three groups according to the cognitive assessment results: control, mild cognitive impairment (MCI), and dementia groups. Clinical data were collected from all patients, including demographic data, biochemical indicators, carotid ultrasound, transcranial Doppler (TCD) indicators, and linear measurement parameters based on MRI. Results: Our results showed that the brain atrophy and vascular lesions developed progressive worsening with increased degree of cognitive impairment. Crouse score and Interuncal distance/Bitemporal distance (IUD/BTD) were independent risk factors for MCI in CSVD patients, and independent risk factors for dementia in CSVD were Crouse Score, the pulsatility index of the middle cerebral artery (MCAPI), IUD/BTD, and Sylvian fissure ratio (SFR). Overall, the parameters with high performance were the IUD/BTD (OR 2.28; 95% CI 1.26-4.10) and SFR (OR 3.28; 95% CI 1.54-6.91), and the AUC (area under the curve) in distinguishing between CSVD older adults with MCI and with dementia was 0.675 and 0.724, respectively. Linear brain measurement parameters had larger observed effect than other indexes to identify cognitive impairments in CSVD patients. Conclusion: This study shows that IUD/BTD and SFR are good predictors of cognitive impairments in CSVD elderly. Linear brain measurement showed a good predictive power for identifying MCI and dementia in elderly subjects with CSVD. Linear brain measurement could be a more suitable and novel method for screening cognitive impairment in aged CSVD patients in primary healthcare facilities, and worth further promotion among the rural population.

Increased cysteinyl-tRNA synthetase drives neuroinflammation in Alzheimer's disease.

BACKGROUND: Microglia-mediated neuroinflammation in Alzheimer's disease (AD) is not only a response to pathophysiological events, but also plays a causative role in neurodegeneration. Cytoplasmic cysteinyl-tRNA synthetase (CARS) is considered to be a stimulant for immune responses to diseases; however, it remains unknown whether CARS is involved in the pathogenesis of AD. METHODS: Postmortem human temporal cortical tissues at different Braak stages and AD patient-derived serum samples were used to investigate the changes of CARS levels in AD by immunocytochemical staining, real-time PCR, western blotting and ELISA. After that, C57BL/6J and APP/PS1 transgenic mice and BV-2 cell line were used to explore the role of CARS protein in memory and neuroinflammation, as well as the underlying mechanisms. Finally, the associations of morphological features among CARS protein, microglia and dense-core plaques were examined by immunocytochemical staining. RESULTS: A positive correlation was found between aging and the intensity of CARS immunoreactivity in the temporal cortex. Both protein and mRNA levels of CARS were increased in the temporal cortex of AD patients. Immunocytochemical staining revealed increased CARS immunoreactivity in neurons of the temporal cortex in AD patients. Moreover, overexpression of CARS in hippocampal neurons induced and aggravated cognitive dysfunction in C57BL/6J and APP/PS1 mice, respectively, accompanied by activation of microglia and the TLR2/MyD88 signaling pathway as well as upregulation of proinflammatory cytokines. In vitro experiments showed that CARS treatment facilitated the production of proinflammatory cytokines and the activation of the TLR2/MyD88 signaling pathway of BV-2 cells. The accumulation of CARS protein occurred within dense-core Aß plaques accompanied by recruitment of ameboid microglia. Significant upregulation of TLR2/MyD88 proteins was also observed in the temporal cortex of AD. CONCLUSIONS: The findings suggest that the neuronal CARS drives neuroinflammation and induces memory deficits, which might be involved in the pathogenesis of AD.

Development of a P-tau217 Electrochemiluminescent Immunosensor Reinforced with Au-Cu Nanoparticles for Alzheimer's Disease Precaution.

To simply and rapidly detect the highly phosphorylated tau protein at threonine 217 (p-tau217) as a precautionary measure against Alzheimer's disease and distinguish it from other neurodegenerative diseases, a novel immunosensor was prepared using luminol as the electrochemiluminescent (ECL) sensing probe reinforced by Au-Cu nanoparticles (Au-Cu NPs). The Au-Cu alloy NPs were prepared via a co-reduction reaction, exhibiting excellent conductivity and catalytic activity. These properties remarkably enhanced the ECL of luminol, providing a suitable background for the sensing response. After the Au-Cu NPs were decorated on the surface of indium tin oxide glass using 3-amino-propyl trimethoxysilane, the antibody of p-tau217 was immobilized via dominant Au-N bonding to enable the biological specificity of the immunosensor. When p-tau217 specifically interacted with an antibody to form an immune complex on the sensing interface, the ECL signal of the sensor was considerably inhibited by the resulting giant biomolecular complex. This complex prevented luminol diffusion to the electrode surface and electron transfer. The resulting immunosensor showed remarkable sensitivity to p-tau217, with a wide linear detection range from 5 to 600 pg/mL. A detection limit of 0.56 pg/mL was achieved, with recoveries in human serum ranging from 92.3 to 109%. This ECL immunosensor demonstrated high sensitivity and specificity toward p-tau217, along with good reproducibility and stability, providing a new approach for clinical research on Alzheimer's disease.

Alzheimer's disease knowledge of nursing staff in East China: A latent profile analysis.

AIM: The dementia population is expanding fast globally, posing a huge challenge to the healthcare system. Improving the level of Alzheimer's disease knowledge (ADK) in nursing staff is the key to providing quality dementia care and improving the patients' quality of life. This study aimed to investigate and classify the ADK level of nursing staff in East China and to identify the factors influencing the nursing staff's ADK level. DESIGN: A cross-sectional study. METHODS: A cross-sectional survey was conducted among 1896 nursing staff in East China from September 2022 to December 2022, using a self-designed general information questionnaire and the Chinese version of the Alzheimer's Disease Knowledge Scale. Latent profile analysis (LPA) was used to classify the nursing staff according to their ADK level, and multinomial logistic regression was used to identify the factors influencing the nursing staff's ADK level. RESULTS: Nursing staff could be classified into four latent profiles according to their ADK level (p < 0.05), namely, the 'Low ADK group', 'Medium ADK group', 'Medium-high ADK group', and 'High ADK group'. Age, education, experience in AD care and training in ADK were the main factors influencing the classification of the nursing staff's ADK level. Therefore, upgrading education, participating in ADK training, and increasing AD care experience will be conducive to improving the ADK of nursing staff. No Patient or Public Contribution.

Direct deamidation analysis of intact adeno-associated virus serotype 9 capsid proteins using reversed-phase liquid chromatography.

Recombinant adeno-associated viral (AAV) vectors have taken center stage as gene delivery vehicles for gene therapy. Asparagine deamidation of AAV capsid proteins has been reported to reduce vector stability and potency of AAV gene therapy products. Deamidation of asparagine residue is a common post-translational modification of proteins that is detected and quantified by liquid chromatography-tandem mass spectrometry (LC-MS)-based peptide mapping. However, artificial deamidation can be spontaneously induced during sample preparation for peptide mapping prior to LC-MS analysis. We have developed an optimized sample preparation method to reduce and minimize deamidation artifacts induced during sample preparation for peptide mapping, which typically takes several hours to complete. To shorten turnaround time of deamidation results and to avoid artificial deamidation, we developed orthogonal RPLC-MS and RPLC-fluorescence detection methods for direct deamidation analysis at the intact AAV9 capsid protein level to routinely support downstream purification, formulation development, and stability testing. Similar trends of increasing deamidation of AAV9 capsid proteins in stability samples were observed at the intact protein level and peptide level, indicating that the developed direct deamidation analysis of intact AAV9 capsid proteins is comparable to the peptide mapping-based deamidation analysis and both methods are suitable for deamidation monitoring of AAV9 capsid proteins.

A novel digital biomarker of sarcopenia in frail elderly: New combination of gait parameters under dual-task walking.

Background: Frailty caused by deterioration in multiple physiological systems has led to a significant increase in adverse events such as falls, disability, and death in frail older people. Similar to frailty, sarcopenia, defined as loss of skeletal muscle mass and strength, is tightly related to mobility disorders, falls, and fractures. With population aging, co-occurrences of frailty and sarcopenia are increasingly common in the elderly, which are more deleterious for the health and independence of older adults. But the high similarity and overlap between the frailty and sarcopenia increase the difficulty of early recognition of frailty with sarcopenia. The purpose of this study is to use detailed gait assessment to determine the more convenient and sensitive digital biomarker of sarcopenia in the frail population. Methods: Ninety-five frail elderly people (age = 86 ± 7 years old, BMI, and body mass index = 23.21 ± 3.40 kg/m2) were screened out by the evaluation of Fried criteria. Then, 41 participants (46%) were identified with sarcopenia, and 51 participants (54%) were identified without sarcopenia. Using a validated wearable platform, participants' gait performance was evaluated under single-task and dual-task (DT). Participants walked back and forth on the 7-m-long trail for 2 min at a habitual speed. Gait parameters of interest include cadence, gait cycle duration, step duration, gait speed, variability of gait speed, stride length, turn duration, and steps in turn. Results: Our results showed that compared with the frail elderly without sarcopenia, the gait performance of the sarcopenic group in single-task and dual-task walking was worse. Overall, the parameters with high performance were the gait speed (DT) (OR 0.914; 95% CI 0.868-0.962) and turn duration (DT) (OR 7.907; 95% CI 2.401-26.039) under dual-task conditions, and the AUC in distinguishing between frail older adults with and without sarcopenia was 0.688 and 0.736, respectively. Turn duration in dual-task testing had larger observed effect than gait speed to identify sarcopenia in the frail population, this result remained significant even after controlling for potential confounds. When gait speed (DT) and turn duration (DT) were combined in the model, AUC increased from 0.688 to 0.763. Conclusion: This study shows that gait speed and turn duration under dual-task are good predictors of sarcopenia in frail elderly, and turn duration (DT) has a better predictive ability. The gait speed (DT) combined with turn duration (DT) is a potential gait digital Biomarker of sarcopenia in the frail elderly. Dual-task gait assessment and detailed gait indexes provide important value for identification of sarcopenia in frail elderly people.

Altered static and dynamic indices of intrinsic brain activity in patients with subcortical ischemic vascular disease: a resting-state functional magnetic resonance imaging analysis.

PURPOSE: To explore the static and dynamic characteristics of intrinsic brain activity (IBA) in subcortical ischemic vascular disease (SIVD) patients with or without cognitive impairment. METHODS: In total, 90 participants were recruited, including 32 SIVD patients with cognitive impairment (SIVD-CI, N = 32), 26 SIVD patients with no cognitive impairment (SIVD-NCI, N = 26), and 32 healthy controls (HC, N = 32) matched for age, gender, and education. All subjects underwent resting-state functional magnetic resonance imaging (rs-fMRI) scanning and neuropsychological tests. Amplitude of low-frequency fluctuation (ALFF) was calculated to reflect static alterations of regional IBA. Sliding window analysis was conducted in order to explore the dynamic characteristics. RESULTS: Both SIVD-CI and SIVD-NCI group showed significantly decreased ALFF in left angular gyrus (ANG), whereas SIVD-CI group showed increased ALFF in right superior frontal gyrus (SFG), compared with HCs. Furthermore, SIVD-CI group showed significantly decreased ALFF dynamics (dALFF) in right precuneus (PreCu) and left dorsal anterior cingulate cortex (dACC), compared with HC and SIVD-NCI groups (Gaussian random field-corrected, voxel-level P < 0.001, cluster-level P < 0.05). No dynamic changes were detected between SIVD-NCI group and HC group. The mean ALFF value in left ANG of SIVD-CI group was correlated with the score of delayed memory scale. CONCLUSION: ANG may be a vulnerable brain region in SIVD patients. Temporal dynamic analysis could serve as a sensitive and promising method to investigate IBA alterations in SIVD patients.

Effect of Energy Utilization and Economic Growth on the Ecological Environment in the Yellow River Basin.

In the 21st century, problems relating to energy, economy, and the environment have become increasingly severe across the world, and critical issues around environmental pollution, ecological imbalance, and an energy crisis have emerged. The Yellow River basin is an important ecological barrier, economic region, and energy base in Northern China. Environmental pollution in the Yellow River basin has become increasingly problematic, especially since the reform and opening up of China, along with the rapid development of the industrial economy and mining for energy resources. In this study, 64 of the 73 prefecture-level cities in the Yellow River basin were selected as the research object, including 18 cities in the downstream region, 26 cities in the midstream region, and 20 cities in the upstream region. The data used in this study were from 2004 to 2019. On the basis of temporal variation and spatial differentiation of the three factors of economy, energy, and environment, the impulse response function and the generalized method of moments (GMM) were adopted to evaluate the effects of energy utilization and economic growth on the ecological environment. Their roles in affecting the ecological environment were analyzed along with the underlying mechanisms. Overall, energy utilization, economic growth, and ecological environment are in good condition, showing a steady upward trend. Regional differences still exist, but the gap is gradually narrowing. There are some differences in the impulse response of the ecological environment to the economic growth and energy utilization in the upstream, midstream, and downstream regions of the Yellow River basin. The effect is leveled out or weakened in the middle and later phases of the impact. Compared with the downstream and upstream regions, economic growth and energy utilization in the midstream regions have less impact on the ecological environment. The two factors of energy utilization potential and economic potential have significant positive impacts on the ecological environment. The current situation of energy utilization has to some extent a positive impact on the ecological environment. Economic scale has a certain negative impact on the ecological environment.

Assembled Photonic Crystal/Gold Nanoparticle Interface: A Dual Amplifying Electrochemiluminescent Aptasensor for the Ultrasensitive Detection of an Amyloid-ß Monomer.

Amyloid-ß (Aß) protein is considered to be a key biomarker that is closely associated with Alzheimer's disease (AD). The level of Aß, particularly its subtle fluctuation, indicates early neuropathological changes, which poses a considerable challenge in predicting AD, considering the detection limit of sensing technologies. Herein, a new label-free sensor based on luminol electrochemiluminescence (ECL) was proposed by developing a close-packed monolayered-SiO2 array with gold (Au) nanoparticles (NPs) entrapped in their gaps as the basal electrode. The well-organized SiO2 NPs with a quasiphotonic crystal structure amplified the ECL signal via light scattering, while Au NPs amplified the signal by directly catalyzing luminol oxidation. Owing to the dual signal amplification, the proposed electrode furnished an ∼64-fold-intensified ECL signal of luminol as the sensing background. Further, the as-prepared ECL electrode served as the substrate to develop an aptasensor for the sensitive detection of Aß. The inhibition of the ECL signal due to the suppressed diffusion of luminol to the sensor surface acts as an indicator to quantify the amount of Aß. The transfer dynamics mechanism provides a label-free sensing strategy and facilitates the high sensitivity of the aptasensor for Aß detection. Under optimal conditions, the developed aptasensor exhibits an ultrasensitive performance for Aß with a very low limit of detection of 5 fM, providing a new prospect for clinical research on Aß and a promising approach in the field of ECL sensing.

The mean diffusivity of forceps minor is useful to distinguish amnestic mild cognitive impairment from mild cognitive impairment caused by cerebral small vessel disease.

Objectives: In recent years, the desire to make a more fine-grained identification on mild cognitive impairment (MCI) has become apparent, the etiological diagnosis of MCI in particular. Nevertheless, new methods for the etiological diagnosis of MCI are currently insufficient. The objective of this study was to establish discriminative measures for amnestic mild cognitive impairment (a-MCI) and MCI caused by cerebral small vessel disease (CSVD). Materials and methods: In total, 20 normal controls (NCs), 33 a-MCI patients, and 25 CSVD-MCI patients performed comprehensive neuropsychological assessments concerning global cognitive function and five cognitive domains as well as magnetic resonance imaging scan with diffusion tensor imaging (DTI). Diffusion parameters including fractional anisotropy and mean diffusivity of 20 major white matter metrics were obtained by ROI-based analyses. The neuropsychological tests and diffusion measurements were compared and binary logistic regression was used to identify the best differential indicator for the two MCI subgroups. The discriminating power was calculated by receiver operating characteristic analysis. Results: Amnestic mild cognitive impairment group showed significant impairment in memory and language function, while CSVD-MCI group revealed more deficits in multi-cognitive domains of memory, language, attention and executive function than controls. Compared to the a-MCI, CSVD-MCI was significantly dysfunctional in the executive function. The CSVD-MCI group had decreased fractional anisotropy and increased mean diffusivity values throughout widespread white matter areas. CSVD-MCI presented more severe damage in the anterior thalamic radiation, forceps major, forceps minor and right inferior longitudinal fasciculus compared with a-MCI group. No significant neuropsychological tests were found in the binary logistic regression model, yet the DTI markers showed a higher discriminative power than the neuropsychological tests. The Stroop test errors had moderate potential (AUC = 0.747; sensitivity = 76.0%; specificity = 63.6%; P = 0.001; 95% CI: 0.617-0.877), and the mean diffusivity value of forceps minor demonstrated the highest predictive power to discriminate each MCI subtype (AUC = 0.815; sensitivity = 88.0%; specificity = 72.7%; P < 0.001; 95% CI: 0.698-0.932). Conclusion: The mean diffusivity of forceps minor may serve as an optimal indicator to differentiate between a-MCI and CSVD-MCI.

Sample Preparation Matters for Peptide Mapping to Evaluate Deamidation of Adeno-Associated Virus Capsid Proteins Using Liquid Chromatography-Tandem Mass Spectrometry.

Adeno-associated viral capsid proteins (AAV VP) are the major components that determine the tissue specificity and immunogenicity, and in vivo transduction performance of the vector. It was reported that asparagine deamidation of AAV capsid proteins leads to charge variants/heterogeneity and altered vector function, reduction of stability, and potency of AAV gene therapy products. Deamidation of asparagine residue is a common post-translational modification of proteins and is mostly detected and quantified by liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based peptide mapping. However, deamidation can be spontaneously introduced during sample preparation before LC-MS/MS analysis. So far, no optimal sample preparations, instead, traditional sample preparation has been used for AAV VP peptide mapping, resulting in exaggerating the original deamidation levels. It is important to accurately monitor and provide true value of asparagine deamidation for development of AAV gene therapy products. In this study, we evaluated denaturation temperatures, digestion durations, and digestion temperatures using three different sample preparation formats for LC-MS/MS-based assessment of deamidation of AAV9 capsid proteins. The results demonstrated that the optimal sample preparation method for AAV9 VP peptide mapping minimized asparagine deamidation artifacts. Although AAV9 was used for method optimization, this study may also provide a guidance on how to control deamidation artifacts for other AAV serotypes.

Better Screening Value of Sylvian Fissure Ratio on Cognitive Decline Among Female Compared to Male: An Observational Study in Elderly Patients With Cerebral Small Vessel Disease in Soochow.

Background: Cognitive decline (CD) occurs frequently in elderly patients with cerebral small vessel disease (CSVD). In China, elderly patients are more likely to enter healthcare in community hospitals where no magnetic resonance imaging (MRI) is available. This study aimed to explore the screening value of Sylvian fissure ratio (SFR) on CD and compare its gender difference from community-transferred patients. Methods: We performed a single-center, observational study (collected between April 1, 2016, and March 1, 2019) to evaluate the association between Montreal Cognitive Assessment (MoCA) and SFR in 203 eligible community-transferred patients. Baseline characteristics of patients were collected during hospitalization. Multiple linear regression analyses were used to estimate the effect of variables on MoCA, and interactions between select variables were analyzed in different models. Receiver operating characteristic (ROC) curve analysis was used to evaluate the discriminative effect of SFR to severe CD. Results: We identified that a meaningful SFR cutoff of 0.05 had important screening value (likelihood ratio test, p = 0.067) on CD. The ratio had a lower screen value in males when compared to females (adjusted ß, -5.54; 95% CI, -8.78 to -2.30 vs. adjusted ß, -1.01; 95% CI, -2.84 to 0.82). The gender difference was further verified by ROC curve analysis, in which this discriminative effect was more potent in females (from 0.878 to 0.948) compared to males (from 0.838 to 0.837). Conclusion: An SFR of 0.05 may be more useful to distinguish CD in female patients with CSVD than male patients in whom the syndrome is suspected clinically.

White Matter Structural Network Analysis to Differentiate Alzheimer's Disease and Subcortical Ischemic Vascular Dementia.

To explore the evaluation of white matter structural network analysis in the differentiation of Alzheimer's disease (AD) and subcortical ischemic vascular dementia (SIVD), 67 participants [31 AD patients, 19 SIVD patients, and 19 normal control (NC)] were enrolled in this study. Each participant underwent 3.0T MRI scanning. Diffusion tensor imaging (DTI) data were analyzed by graph theory (GRETNA toolbox). Statistical analyses of global parameters [gamma, sigma, lambda, global shortest path length (Lp), global efficiency (Eg), and local efficiency (Eloc)] and nodal parameters [betweenness centrality (BC)] were obtained. Network-based statistical analysis (NBS) was employed to analyze the group differences of structural connections. The diagnosis efficiency of nodal BC in identifying different types of dementia was assessed by receiver operating characteristic (ROC) analysis. There were no significant differences of gender and years of education among the groups. There were no significant differences of sigma and gamma in AD vs. NC and SIVD vs. NC, whereas the Eg values of AD and SIVD were statistically decreased, and the lambda values were increased. The BC of the frontal cortex, left superior parietal gyrus, and left precuneus in AD patients were obviously reduced, while the BC of the prefrontal and subcortical regions were decreased in SIVD patients, compared with NC. SIVD patients had decreased structural connections in the frontal, prefrontal, and subcortical regions, while AD patients had decreased structural connections in the temporal and occipital regions and increased structural connections in the frontal and prefrontal regions. The highest area under curve (AUC) of BC was 0.946 in the right putamen for AD vs. SIVD. White matter structural network analysis may be a potential and promising method, and the topological changes of the network, especially the BC change in the right putamen, were valuable in differentiating AD and SIVD patients.

Determination of ß-amyloid oligomer using electrochemiluminescent aptasensor with signal enhancement by AuNP/MOF nanocomposite.

In order to effectively and conveniently detect the ß-amyloid oligomer (AßO) for earlier diagnosis of Alzheimer's disease (AD), a disposable aptamer biosensor has been developed with high performance, facile operation, and low cost. Using a nanocomposite by in situ reduction of chloroauric acid to decorate Au nanoparticles (AuNPs) on Fe-MIL-88NH2 material via Au-N bond to effectively enhance the electrochemiluminescence (ECL) of luminol, the functioned basal electrode provides adequate background for sensing response. When the aptamer is linked via Au-S bond on the surface, the sensor gets the ability of specific recognition and coalescence toward the target (AßO). After incubating the sample on the aptasensor, its ECL signal is inhibited owing to the steric hindrance of the AßO macromolecules. The relative inhibition ratio linearly depends to the logarithm of AßO concentration in the range 0.1 pM to 10 pM, with an LOD of 71 fM. The aptasensor has high selectivity to AßO among its analogs. The recoveries in human serum were 98.9-105.4%. This research provides a new approach for sensitive detection of AßO in clinic laboratories for investigation and diagnosis of AD.

Measuring Regional Eco-Efficiency in China (2003-2016): A "Full World" Perspective and Network Data Envelopment Analysis.

Eco-efficiency enhancement is an inherent requirement of green development and an important indicator of high-quality development in general. It aims to achieve the coordinated development of nature, the economy, and society. Therefore, eco-efficiency measurements should focus on not only total factor input, but also process analysis. Based on the "full world" model in ecological economic theory, this study constructed a theoretical framework for a composite economic-environmental-social system that reflects human welfare and sustainability. To this end, using network data envelopment analysis (DEA), this study established a staged eco-efficiency evaluation model that uses economic, environmental, and social factors to measure the overall and staged eco-efficiency of China's provinces from 2003 to 2016 and analyze its spatiotemporal characteristics. A geographically weighted regression (GWR) model was also used to analyze the influencing factors of eco-efficiency changes and the spatial differentiation in their effect intensity. The findings were as follows: (1) China's overall eco-efficiency is still at a low level. It varies significantly from region to region, and only three regions are at the frontier of production. The eastern region has the highest eco-efficiency, followed by the central region, and the gap between the central and western regions has gradually narrowed. In terms of staged efficiency, the level of eco-efficiency in the production stage is less than in the environmental governance stage, which is less than that in the social input stage. (2) In terms of the efficiency of each stage, the efficiency level of the production stage showed a downward trend throughout the entire process, and the decline in the central and western regions was more obvious. The social input stage and the environmental governance stage both showed upward trends. The social input stage showed a higher level, and the increase was relatively flat during the period of study. Efficiency continued to rise during the environmental governance stage from 2003 to 2010 and rose overall, but with some fluctuations from 2011 to 2016. (3) Geographically weighted regression showed that the effects of the influencing factors on eco-efficiency had obvious spatial heterogeneity. The factors affecting overall, production stage, and social input eco-efficiency were, in order of effect intensity from high to low, economic growth level, marketization level, and social input level. In terms of environmental governance, social input level had the greatest impact, followed by economic growth; marketization level did not show a significant impact.

Bex1 attenuates neuronal apoptosis in rat intracerebral hemorrhage model.

Brain expressed x-linked gene 1 (Bex1) which is at high levels in several populations of central nervous system (CNS) neurons, belongs to a family of small proteins of unknown function, playing roles as adaptors or modulators of intracellular signaling pathways. But its distribution and function in CNS remains unclear. Neuronal apoptosis is the major pathogenesis in secondary brain injury of intracerebral hemorrhage (ICH). In this study, the roles of Bex1 were explored in the pathophysiology of ICH. Western blot, immunohistochemistry, and immunofluorescence showed that obvious up-regulation of Bex1 in neurons adjacent to the hematoma after ICH. Furthermore, the increase of Bex1 expression was accompanied by the enhanced expression of Bax and active caspase-3, and decreased expression of B-cell lymphoma 2 (Bcl-2) following ICH. The in vitro study using Bex1 siRNA transfection in hemin-exposed PC12 cells suggested that Bex1 exerted anti-apoptotic function. Therefore, Bex1 may play the neuronal anti-apoptosis role following ICH, implying a novel molecular target for the therapy of ICH.

Holliday junction-recognizing protein promotes cell proliferation and correlates with unfavorable clinical outcome of hepatocellular carcinoma.

AIM: To investigate the expression and clinical significance of Holliday junction-recognizing protein (HJURP) in hepatocellular carcinoma (HCC). METHODS: In this study, we detected the expression of HJURP protein in samples of 164 patients with HCC, and based on this, we divided the patients into two cohorts: high expression of HJURP and low expression of HJURP. We analyzed the correlation between HJURP expression and the clinicopathological factors using chi-square test. Survival significance of HJURP was defined by Kaplan-Meier method and log-rank test, and the independent prognostic factors were identified by Cox regression model. Using function assays of HCC cell lines, we investigated the influence of HJURP on the proliferation of HCC cells. RESULTS: In our study, the proportion of patients with high HJURP expression was 25.6%, which was significantly associated with the tumor size and Barcelona clinic liver cancer stage. Univariate analysis confirmed that high HJURP expression was remarkably associated with poorer overall survival rates (P=0.003), as well as tumor number (P=0.016), tumor differentiation (P=0.047), TNM stage (P=0.005), and Barcelona clinic liver cancer stage (P=0.004). Multivariate analysis confirmed that high HJURP expression (P<0.001) acted as an independent prognostic risk factor of unfavorable prognosis. Real-time polymerase chain reaction analysis revealed that the expression of HJURP was significantly higher in HCC tissues than that in the corresponding normal liver tissues. Moreover, we demonstrated that HJURP overexpression could accelerate HCC cell line proliferation, whereas HJURP knockdown could attenuate the proliferation. CONCLUSION: High HJURP expression was an independent prognostic biomarker of HCC, predicting poorer prognosis. HJURP also played an important role in HCC cell proliferation.

Phosphoregulation of the C. elegans cadherin-catenin complex.

Adherens junctions play key roles in mediating cell-cell contacts during tissue development. In Caenorhabditis elegans embryos, the cadherin-catenin complex (CCC), composed of the classical cadherin HMR-1 and members of three catenin families, HMP-1, HMP-2 and JAC-1, is necessary for normal blastomere adhesion, gastrulation, ventral enclosure of the epidermis and embryo elongation. Disruption of CCC assembly or function results in embryonic lethality. Previous work suggests that components of the CCC are subject to phosphorylation. However, the identity of phosphorylated residues in CCC components and their contributions to CCC stability and function in a living organism remain speculative. Using mass spectrometry, we systematically identify phosphorylated residues in the essential CCC subunits HMR-1, HMP-1 and HMP-2 in vivo. We demonstrate that HMR-1/cadherin phosphorylation occurs on three sites within its ß-catenin binding domain that each contributes to CCC assembly on lipid bilayers. In contrast, phosphorylation of HMP-2/ß-catenin inhibits its association with HMR-1/cadherin in vitro, suggesting a role in CCC disassembly. Although HMP-1/α-catenin is also phosphorylated in vivo, phosphomimetic mutations do not affect its ability to associate with other CCC components or interact with actin in vitro. Collectively, our findings support a model in which distinct phosphorylation events contribute to rapid CCC assembly and disassembly, both of which are essential for morphogenetic rearrangements during development.

In-line separation by capillary electrophoresis prior to analysis by top-down mass spectrometry enables sensitive characterization of protein complexes.

Intact protein analysis via top-down mass spectrometry (MS) provides a bird's eye view over the protein complexes and complex protein mixtures with the unique capability of characterizing protein variants, splice isoforms, and combinatorial post-translational modifications (PTMs). Here we applied capillary electrophoresis (CE) through a sheathless CE-electrospray ionization interface coupled to an LTQ Velos Orbitrap Elite mass spectrometer to analyze the Dam1 complex from Saccharomyces cerevisiae. We achieved a 100-fold increase in sensitivity compared to a reversed-phase liquid chromatography coupled MS analysis of recombinant Dam1 complex with a total loading of 2.5 ng (12 amol). N-terminal processing forms of individual subunits of the Dam1 complex were observed as well as their phosphorylation stoichiometry upon Mps1p kinase treatment.