Laser micro-structured pressure sensor with modulated sensitivity for electronic skins.

Micro-structured pressure sensors with broad pressure sensing range, high sensitivity and rapid response speeds are highly desired for epidermal electronic skin. The widely used methods to fabricate micro-structured pressure sensors are lithography and biomaterial-replicating, which are either complex in preparation procedure or uncontrollable in micro-structure morphology. In this work, laser micro-structured wearable pressure sensors with high-performance are developed for epidermal electronic skin. Laser micro-engineering, with scalability, high-efficiency, and controllability, is employed to prepare a series of micro-structures on elastomers for modulating and enhancing the sensitivity of the sensors. The device with micro-domes owns a sensitivity of -1.82 kPa-1, which is approximately 17 times better than the one based on long micro-ridges. Due to the reduced viscous properties of the elastomers by laser micro-engineering, the sensor based on micro-domes demonstrates rapid response/relaxation speeds of 0.036 and 0.052 s, respectively, and a detection limit of 0.001 kPa. Additionally, the device has a good durability (6,000 cycles) with a repeatability deviation of 1.44%, confirming its stability. Combined with near field communication technology, the sensor has been investigated as epidermal electronic skin for health monitoring.

Optimization of Retinal Gene Therapy for X-Linked Retinitis Pigmentosa Due to RPGR Mutations.

X-linked retinitis pigmentosa (XLRP) caused by mutations in the RPGR gene is an early onset and severe cause of blindness. Successful proof-of-concept studies in a canine model have recently shown that development of a corrective gene therapy for RPGR-XLRP may now be an attainable goal. In preparation for a future clinical trial, we have here optimized the therapeutic AAV vector construct by showing that GRK1 (rather than IRBP) is a more efficient promoter for targeting gene expression to both rods and cones in non-human primates. Two transgenes were used in RPGR mutant (XLPRA2) dogs under the control of the GRK1 promoter. First was the previously developed stabilized human RPGR (hRPGRstb). Second was a new full-length stabilized and codon-optimized human RPGR (hRPGRco). Long-term (>2 years) studies with an AAV2/5 vector carrying hRPGRstb under control of the GRK1 promoter showed rescue of rods and cones from degeneration and retention of vision. Shorter term (3 months) studies demonstrated comparable preservation of photoreceptors in canine eyes treated with an AAV2/5 vector carrying either transgene under the control of the GRK1 promoter. These results provide the critical molecular components (GRK1 promoter, hRPGRco transgene) to now construct a therapeutic viral vector optimized for RPGR-XLRP patients.

Archeological Echocardiography: Digitization and Speckle Tracking Analysis of Archival Echocardiograms in the HyperGEN Study.

BACKGROUND: Several large epidemiologic studies and clinical trials have included echocardiography, but images were stored in analog format and these studies predated tissue Doppler imaging (TDI) and speckle tracking echocardiography (STE). We hypothesized that digitization of analog echocardiograms, with subsequent quantification of cardiac mechanics using STE, is feasible, reproducible, accurate, and produces clinically valid results. METHODS: In the NHLBI HyperGEN study (N = 2234), archived analog echocardiograms were digitized and subsequently analyzed using STE to obtain tissue velocities/strain. Echocardiograms were assigned quality scores and inter-/intra-observer agreement was calculated. Accuracy was evaluated in: (1) a separate second study (N = 50) comparing prospective digital strain versus post hoc analog-to-digital strain, and (2) in a third study (N = 95) comparing prospectively obtained TDI e' velocities with post hoc STE e' velocities. Finally, we replicated previously known associations between tissue velocities/strain, conventional echocardiographic measurements, and clinical data. RESULTS: Of the 2234 HyperGEN echocardiograms, 2150 (96.2%) underwent successful digitization and STE analysis. Inter/intra-observer agreement was high for all STE parameters, especially longitudinal strain (LS). In accuracy studies, LS performed best when comparing post hoc STE to prospective digital STE for strain analysis. STE-derived e' velocities correlated with, but systematically underestimated, TDI e' velocity. Several known associations between clinical variables and cardiac mechanics were replicated in HyperGEN. We also found a novel independent inverse association between fasting glucose and LS (adjusted ß = -2.4 [95% CI -3.6, -1.2]% per 1-SD increase in fasting glucose; P < 0.001). CONCLUSIONS: Archeological echocardiography, the digitization and speckle tracking analysis of archival echocardiograms, is feasible and generates indices of cardiac mechanics similar to contemporary studies.

Influences of an Aluminum Covering Layer on the Performance of Cross-Like Hall Devices.

This work studies the effects of an aluminum covering on the performance of cross-like Hall devices. Four different Hall sensor structures of various sizes were designed and fabricated. The sensitivity and offset of the Hall sensors, two key points impacting their performance, were characterized using a self-built measurement system. The work analyzes the influences of the aluminum covering on those two aspects of the performance. The aluminum layer covering mainly leads to an eddy-current effect in an unstable magnetic field and an additional depletion region above the active region. Those two points have influences on the sensitivity and the offset voltage, respectively. The analysis guides the designer whether to choose covering with an aluminum layer the active region of the Hall sensor as a method to reduce the flicker noise and to improve the stability of the Hall sensor. Because Hall devices, as a reference element, always suffer from a large dispersion, improving their stability is a crucial issue.

Association of low-grade albuminuria with adverse cardiac mechanics: findings from the hypertension genetic epidemiology network (HyperGEN) study.

BACKGROUND: Albuminuria is a marker of endothelial dysfunction and has been associated with adverse cardiovascular outcomes. The reasons for this association are unclear but may be attributable to the relationship between endothelial dysfunction and intrinsic myocardial dysfunction. METHODS AND RESULTS: In the Hypertension Genetic Epidemiology Network (HyperGEN) Study, a population- and family-based study of hypertension, we examined the relationship between urine albumin-to-creatinine ratio (UACR) and cardiac mechanics (n=1894, all of whom had normal left ventricular ejection fraction and wall motion). We performed speckle-tracking echocardiographic analysis to quantify global longitudinal, circumferential, and radial strain, and early diastolic (e') tissue velocities. We used E/e' ratio as a marker of increased left ventricular filling pressures. We used multivariable-adjusted linear mixed effect models to determine independent associations between UACR and cardiac mechanics. The mean age was 50±14 years, 59% were female, and 46% were black. Comorbidities were increasingly prevalent among higher UACR quartiles. Albuminuria was associated with global longitudinal strain, global circumferential strain, global radial strain, e' velocity, and E/e' ratio on unadjusted analyses. After adjustment for covariates, UACR was independently associated with lower absolute global longitudinal strain (multivariable-adjusted mean global longitudinal strain [95% confidence interval] for UACR Quartile 1 = 15.3 [15.0-15.5]% versus UACR Q4 = 14.6 [14.3-14.9]%, P for trend <0.001) and increased E/e' ratio (Q1 = 25.3 [23.5-27.1] versus Q4 = 29.0 [27.0-31.0], P=0.003). The association between UACR and global longitudinal strain was present even in participants with UACR < 30 mg/g (P<0.001 after multivariable adjustment). CONCLUSIONS: Albuminuria, even at low levels, is associated with adverse cardiac mechanics and higher E/e' ratio.

A genome-wide association study in catfish reveals the presence of functional hubs of related genes within QTLs for columnaris disease resistance.

BACKGROUND: Columnaris causes severe mortalities among many different wild and cultured freshwater fish species, but understanding of host resistance is lacking. Catfish, the primary aquaculture species in the United States, serves as a great model for the analysis of host resistance against columnaris disease. Channel catfish in general is highly resistant to the disease while blue catfish is highly susceptible. F2 generation of hybrids can be produced where phenotypes and genotypes are segregating, providing a useful system for QTL analysis. To identify genes associated with columnaris resistance, we performed a genome-wide association study (GWAS) using the catfish 250 K SNP array with 340 backcross progenies derived from crossing female channel catfish (Ictalurus punctatus) with male F1 hybrid catfish (female channel catfish I. punctatus × male blue catfish I. furcatus). RESULTS: A genomic region on linkage group 7 was found to be significantly associated with columnaris resistance. Within this region, five have known functions in immunity, including pik3r3b, cyld-like, adcyap1r1, adcyap1r1-like, and mast2. In addition, 3 additional suggestively associated QTL regions were identified on linkage groups 7, 12, and 14. The resistant genotypes on the QTLs of linkage groups 7 and 12 were found to be homozygous with both alleles being derived from channel catfish. The paralogs of the candidate genes in the suggestively associated QTL of linkage group 12 were found on the QTLs of linkage group 7. Many candidate genes on the four associated regions are involved in PI3K pathway that is known to be required by many bacteria for efficient entry into the host. CONCLUSION: The GWAS revealed four QTLs associated with columnaris resistance in catfish. Strikingly, the candidate genes may be arranged as functional hubs; the candidate genes within the associated QTLs on linkage groups 7 and 12 are not only co-localized, but also functionally related, with many of them being involved in the PI3K signal transduction pathway, suggesting its importance for columnaris resistance.

Methylation at CPT1A locus is associated with lipoprotein subfraction profiles.

Lipoprotein subfractions help discriminate cardiometabolic disease risk. Genetic loci validated as associating with lipoprotein measures do not account for a large proportion of the individual variation in lipoprotein measures. We hypothesized that DNA methylation levels across the genome contribute to interindividual variation in lipoprotein measures. Using data from participants of the Genetics of Lipid Lowering Drugs and Diet Network (n = 663 for discovery and n = 331 for replication stages, respectively), we conducted the first systematic screen of the genome to determine associations between methylation status at ∼470,000 cytosine-guanine dinucleotide (CpG) sites in CD4(+) T cells and 14 lipoprotein subfraction measures. We modeled associations between methylation at each CpG site and each lipoprotein measure separately using linear mixed models, adjusted for age, sex, study site, cell purity, and family structure. We identified two CpGs, both in the carnitine palmitoyltransferase-1A (CPT1A) gene, which reached significant levels of association with VLDL and LDL subfraction parameters in both discovery and replication phases (P < 1.1 × 10(-7) in the discovery phase, P < .004 in the replication phase, and P < 1.1 × 10(-12) in the full sample). CPT1A is regulated by PPARα, a ligand for drugs used to reduce CVD. Our associations between methylation in CPT1A and lipoprotein measures highlight the epigenetic role of this gene in metabolic dysfunction.

Diastolic wall strain: a simple marker of abnormal cardiac mechanics.

BACKGROUND: Diastolic wall strain (DWS), defined using posterior wall thickness (PWT) measurements from standard echocardiographic images (DWS = [PWT(systole)-PWT(diastole)]/PWT(systole)), has been proposed as a marker of left ventricular (LV) diastolic stiffness. However, the equation for DWS is closely related to systolic radial strain, and whether DWS is associated with abnormal cardiac mechanics (reduced systolic strains and diastolic tissue velocities) is unknown. We sought to determine the relationship between DWS and systolic and diastolic cardiac mechanics. METHODS: We calculated DWS and performed speckle-tracking analysis in a large population- and family-based study (Hypertension Genetic Epidemiology Network [HyperGEN]; N=1907 after excluding patients with ejection fraction [EF] <50% or posterior wall motion abnormalities). We measured global longitudinal, circumferential, and radial strain (GLS, GCS, and GRS, respectively) and early diastolic (e') tissue velocities, and we determined the independent association of DWS with cardiac mechanics using linear mixed effects models to account for relatedness among study participants. We also prospectively performed receiver-operating characteristic (ROC) analysis of DWS for the detection of abnormal cardiac mechanics in a separate, prospective validation study (N=35). RESULTS: In HyperGEN (age 51 ± 14 years, 59% female, 45% African-American, 57% hypertensive), mean DWS was 0.38 ± 0.05. DWS decreased with increasing comorbidity burden (ß-coefficient -0.013 [95% CI -0.015, -0.011]; P<0.0001). DWS was independently associated with GLS, GCS, GRS, and e' velocity (adjusted P<0.05) but not LV chamber compliance (EDV20, P=0.97). On prospective speckle-tracking analysis, DWS correlated well with GLS, GCS, and GRS (R=0.61, 0.57, and 0.73, respectively; P<0.001 for all comparisons). C-statistics for DWS as a diagnostic test for abnormal GLS, GCS, and GRS were: 0.78, 0.79, and 0.84, respectively. CONCLUSIONS: DWS, a simple parameter than can be calculated from routine 2D echocardiography, is closely associated with systolic strain parameters and early diastolic (e') tissue velocities but not LV chamber compliance.

Performance comparison of cross-like Hall plates with different covering layers.

This paper studies the effects of the covering layers on the performance of a cross-like Hall plate. Three different structures of a cross-like Hall plate in various sizes are designed and analyzed. The Hall plate sensitivity and offset are characterized using a self-built measurement system. The effect of the P-type region over the active area on the current-related sensitivity is studied for different Hall plate designs. In addition, the correlation between the P-type covering layer and offset is analyzed. The best structure out of three designs is determined. Besides, a modified eight-resistor circuit model for the Hall plate is presented with improved accuracy by taking the offset into account.

[Spectral inversion models for prediction of total chromium content in subtropical soil].

With the high requirements and long test cycle of traditional testing method of soil heavy metal, this paper tries to es-tablish the quantitative prediction model between soil hyperspectral and soil chromium content( tested by ICP-MS) to realize thIeprediction of soil chromium element quickly and accurately. The paper studied the hyperspectral response characteristics of re dsoil, with 135 soil samples in Fuzhou city. After monitoring the hypersectral reflection of soil samples with ASD (analytica lspectral device) and total chromium contents with ICP-MS, the paper gained the spectral reflection data between 350 and 2 500 nm and soil total chromium contents. Then the paper treated the hyperspectral reflection data with 6 mathematic changes such as reciprocal logarithmic change, differentials and continuum removal in advance. The next step was to calculate the correlation co-fficient of soil chromium and the above spectral information, and select the sensitive spectral bands according to the highest cor-elation coefficient. Finally, six kinds of models were selected to build the soil total chromium content model, and the final opti-al mathematic model between soil chromium and hyperspectral information was significantly determined. Results showed that 520--30, 1 440-- 450, 2 010-- 020, and 2 230-- 240 nm were the main sensitive bands to soil total chromium, y= 120. 68Ce (-7.037x)was the optimal soil total chromium predicting model( in the model, the correlation coefficient R and the RIME of total chromium were 0. 68 and 0. 19 Cµ1(-,) and the inspection correlation coefficient R and the RMSE were 0. 84 µ ?xg-('1) nd 1. 26 Iµ ?xg-(1 )respectively). The model can be used to rapidly monitor soil total chromium with hyperspectral reflection in Fuzhou. area.

Sequential nucleophilic substitutions permit orthogonal click functionalization of multicomponent PEG brushes.

Multicomponent poly(ethylene glycol) (PEG) brushes (i.e., ≥ 2 adjacent PEG brushes) can be used to engineer culture substrates with microscale, nonfouling regions decorated with covalently immobilized ligands that mediate biospecific interactions. However, synthesizing such brushes with orthogonal immobilization chemistries to permit differential biofunctionalization is nontrivial and often requires synthesis of PEG-co-polymers. To simplify synthesis and enhance the versatility of such substrates, we developed a protocol for generating orthogonal click-functionalized multicomponent PEG brushes using sequential nucleophilic substitutions by sodium azide, ethanolamine, and propargylamine. The novel application of propargylamine-mediated substitution functionalizes PEG brushes with acetylene groups, and for the first time, ethanolamine-mediated substitution is shown to be sufficient for passivating the "living" polymer chain ends between brush synthesis steps. Thus, our multicomponent PEG brushes present dual orthogonal chemistries (i.e., azido and acetylene groups) for ligand immobilization via versatile copper-free click reactions, which are useful for in situ surface modifications during cell culture.

[Spectral inversion models for prediction of red soil total nitrogen content in subtropical region (Fuzhou)].

The present paper studied the hyperspectral response characteristics of red soil, with 135 soil samples in Fuzhou city. After monitoring the hypersectral reflection of soil samples with ASD (analytical spectral device) and total nitrogen contents with Vario MAX (for nitrogen and carbon analysis), the paper gained the spectral reflection data between 350-2 500 nm (resolution is 1 nm) and soil total nitrogen contents. Then the paper treated the hyperspectral reflection data with 5 mathematic conversions such as first derivative and second derivative conversions of original reflection, reciprocal logarithmic conversion and its first derivative and second derivative conversion in advance. The next step was to calculate the correlation coefficient of soil nitrogen and the above spectral information, and select the sensitive spectral bands according to the highest correlation coefficient. Finally, by designing different proportions of modeling and validation sample data sets, the paper established the quantitative linear models between soil total nitrogen contents and hyperspectral reflection and its 5 converted information, the final optimal mathematic model between soil nitrogen and hyperspectral information was significantly determined. Results showed that 634-688, 872, 873, 1 414 and 1 415 nm were the main sensitive bands for soil total nitrogen, and Y = 5.384X(664) -1.039 (Y represents soil nitrogen content, X664 is the soil spectral absorbance value at 664 nm) was the optimal soil total nitrogen predicting model (in the model, the determination coefficients R2 and the RMSE of total nitrogen were 0.616 and 0.422 mg X g(-1), the inspection coefficient R2 and the RMSE were 0.608 and 0.546 mg x g(-1) respectively). The model can be used to rapidly monitor soil total nitrogen with hyperspectral reflection in Fuzhou area.

Multi-ancestry genome-wide meta-analysis of 56,241 individuals identifies LRRC4C, LHX5-AS1 and nominates ancestry-specific loci PTPRK , GRB14 , and KIAA0825 as novel risk loci for Alzheimer's disease: the Alzheimer's Disease Genetics Consortium.

Limited ancestral diversity has impaired our ability to detect risk variants more prevalent in non-European ancestry groups in genome-wide association studies (GWAS). We constructed and analyzed a multi-ancestry GWAS dataset in the Alzheimer's Disease (AD) Genetics Consortium (ADGC) to test for novel shared and ancestry-specific AD susceptibility loci and evaluate underlying genetic architecture in 37,382 non-Hispanic White (NHW), 6,728 African American, 8,899 Hispanic (HIS), and 3,232 East Asian individuals, performing within-ancestry fixed-effects meta-analysis followed by a cross-ancestry random-effects meta-analysis. We identified 13 loci with cross-ancestry associations including known loci at/near CR1 , BIN1 , TREM2 , CD2AP , PTK2B , CLU , SHARPIN , MS4A6A , PICALM , ABCA7 , APOE and two novel loci not previously reported at 11p12 ( LRRC4C ) and 12q24.13 ( LHX5-AS1 ). Reflecting the power of diverse ancestry in GWAS, we observed the SHARPIN locus using 7.1% the sample size of the original discovering single-ancestry GWAS (n=788,989). We additionally identified three GWS ancestry-specific loci at/near ( PTPRK ( P =2.4×10 -8 ) and GRB14 ( P =1.7×10 -8 ) in HIS), and KIAA0825 ( P =2.9×10 -8 in NHW). Pathway analysis implicated multiple amyloid regulation pathways (strongest with P adjusted =1.6×10 -4 ) and the classical complement pathway ( P adjusted =1.3×10 -3 ). Genes at/near our novel loci have known roles in neuronal development ( LRRC4C, LHX5-AS1 , and PTPRK ) and insulin receptor activity regulation ( GRB14 ). These findings provide compelling support for using traditionally-underrepresented populations for gene discovery, even with smaller sample sizes.

Pharmacokinetics and Pharmacodynamics of Butorphanol and Dexmedetomidine after Intranasal Administration in Broiler Chickens (Gallus gallus domesticus).

Butorphanol and dexmedetomidine (DXM) can produce analgesia in birds. Intranasal (IN) route of drug administration is easier, and free of risks such as pain and tissue damage compared with intravenous, intramuscular or subcutaneous routes in bird species, including wild birds. Although previous studies have demonstrated the use of IN route for producing sedation, no studies are available on the pharmacokinetics and pharmacodynamics of IN drugs in birds. This study analyzed the pharmacokinetics and sedative-analgesic efficacy of intranasal butorphanol (2 mg/kg), dexmedetomidine (80 µg/kg) and their combination (butorphanol, 2 mg/kg; DXM, 80 µg/kg) in healthy, male, Ross broiler chickens (n = 6/group) aged between 6 and 8 weeks. Maximum plasma concentration (Cmax, p = 0.01), area under the plasma concentration-time curve from time zero to 120 min (AUC0 to 120, p = 0.02) and apparent volume of distribution at steady state (Vss, p = 0.02) of DXM were significantly higher than that of DXM co-administered with butorphanol. The mechanical nociceptive thresholds and the sedation scores of DXM group were significantly higher than the baseline value. Dexmedetomidine (80 µg/kg, IN) was effective in chickens, and the drug absorption was more rapid than that of DXM with butorphanol. However, the duration of action of DXM was short. Lower value of Cmax and nociceptive thresholds showed the nonsignificant efficacy of butorphanol at a dose of 2 mg/kg after IN administration in broiler chickens.

Organic foams stabilized by Biphenyl-bridged organosilica particles.

HYPOTHESIS: Can surface-active particles be designed à la carte just by incorporating functional groups mimicking the structure of the solvent and gas? This is based on the idea that, to achieve good foamability, the particle wettability needs to be finely tuned to adjust the liquid-particle and gas-particle surface tensions. In practice, could particles containing phenyl rings and alkyl chains assemble at the air-liquid interface and stabilize foams based on aromatic solvents? EXPERIMENTS: A library of organosilica particles was prepared by sol-gel synthesis using aromatic organosilane precursors. The particles were characterized by TGA, FTIR and 13C/29Si MAS NMR. The foaming properties were studied after hand shaking and high-speed homogenization. The influence of particle wettability and solvent properties on foam formation was systematically investigated. A comparison was carried out between biphenyl-bridged particles and various stabilizers on foamability in benzyl alcohol. FINDINGS: Biphenyl-bridged particles could stabilize foams in aromatic solvents with a high foam volume fraction up to 96% using Ultra-Turrax. The presence of biphenyl rings and short alkyl chains was crucial for foamability. Organic foams were prepared for aromatic solvents with intermediate surface tension (35-44 mN m-1) and contact angle in the range 32-53°. Biphenyl-bridged particles outperformed polytetrafluoroethylene and fluorinated surfactants in benzyl alcohol.

Strategy based on multiplexed brush architectures for regulating the spatiotemporal immobilization of biomolecules.

Functional surfaces that enable both spatial and temporal control of biomolecules immobilization have attracted enormous attention for various fields including smart biointerface materials, high-throughput bioarrays, and fundamental research in the biosciences. Here, a flexible and promising method was presented for regulating the spatiotemporal arrangement of multiple biomolecules by constructing the topographically and chemically diverse polymer brushes patterned surfaces. A series of polymer brushes patterned surfaces, including antifouling brushes patterned surface, epoxy-presenting brushes patterned surface without and with antifouling background layer, were fabricated to control the spatial distribution of protein and cell adhesion through specific and nonspecific means. The fluorescence measurements demonstrated the effectiveness of spatially regulating the density of surface-immobilized protein through controlling the areal thickness of the poly (glycidyl methacrylate) (PGMA) brush patterns, leading to various complex patterns featuring well-defined biomolecule concentration gradients. Furthermore, a multiplexed surface bearing epoxy groups and azido groups with various areal densities was fabricated for regulating the spatiotemporal arrangement of different proteins, enabling binary biomolecules patterns with higher degrees of functionality and complexity. The presented strategy for the spatiotemporal control of biomolecules immobilization would boost the development of dynamic and multifunctional biosystems.

Identification of active catalysts for the acceptorless dehydrogenation of alcohols to carbonyls.

Acceptorless dehydrogenation into carbonyls and molecular hydrogen is an attractive strategy to valorize (biobased) alcohols. Using 2-octanol dehydrogenation as benchmark reaction in a continuous reactor, a library of metal-supported catalysts is tested to validate the predictive level of catalytic activity for combined DFT and micro-kinetic modeling. Based on a series of transition metals, scaling relations are determined as a function of two descriptors, i.e. the surface binding energies of atomic carbon and oxygen. Then, a volcano-shape relation based on both descriptors is derived, paving the way to further optimization of active catalysts. Evaluation of 294 diluted alloys but also a series of carbides and nitrides with the volcano map identified 12 promising candidates with potentially improved activity for alcohol dehydrogenation, which provides useful guidance for experimental catalyst design. Further screening identifies ß-Mo2N and γ-Mo2N exposing mostly (001) and (100) facets as potential candidates for alcohol dehydrogenation.

Extraction and purification of total flavonoids from Eupatorium lindleyanum DC. and evaluation of their antioxidant and enzyme inhibitory activities.

The health benefits and promising medical treatment potential of total flavonoids from Eupatorium lindleyanum DC. (TFELDC) have been recognized. The process parameters of extracting total flavonoids from Eupatorium lindleyanum DC. by ultrasonic-microwave synergistic extraction (UMSE) were optimized, and they were purified by AB-8 macroporous resin in the current study. In addition, the antioxidant and enzyme inhibitory activities of the purified TFELDC (PTFELDC) were evaluated. The results showed that the optimal parameters of UMSE were as follows: ethanol volume fraction 71.5%, L/S ratio 12.2 ml/g, microwave power 318 W, and extraction time 143 s. After TFELDC were purified by AB-8 macroporous resin, the total flavonoid contents of PTFELDC increased from 208.18 ± 1.60 to 511.19 ± 3.21 mg RE/g FDS. Compared with TFELDC, the content of total flavonoids in PTFELDC was increased by 2.46 times. The antioxidant activities of PTFELDC were assessed using DPPH radical, superoxide anion radical, reducing power, and ferric reducing antioxidant power assays, and the IC50 values were found to be 37.13, 19.62, 81.22, and 24.72 µg/ml, respectively. The enzyme inhibitory activities of PTFELDC were measured using lipase, α-amylase, α-glucosidase, and acetylcholinesterase assays with the IC50 values 1.38, 2.08, 1.63, and 0.58 mg/ml, respectively. By comparing with their positive controls, it was found that PTFELDC had good antioxidant activities, and lipase, α-amylase, and α-glucosidase inhibitory activities, However, the acetylcholinesterase inhibitory activity was relatively weaker. These results suggested that PTFELDC have a promising potential as natural antioxidant, antilipidemic, and hypoglycemic drugs used in functional foods or pharmaceuticals.

Genetically regulated expression in late-onset Alzheimer's disease implicates risk genes within known and novel loci.

Late-onset Alzheimer disease (LOAD) is highly polygenic, with a heritability estimated between 40 and 80%, yet risk variants identified in genome-wide studies explain only ~8% of phenotypic variance. Due to its increased power and interpretability, genetically regulated expression (GReX) analysis is an emerging approach to investigate the genetic mechanisms of complex diseases. Here, we conducted GReX analysis within and across 51 tissues on 39 LOAD GWAS data sets comprising 58,713 cases and controls from the Alzheimer's Disease Genetics Consortium (ADGC) and the International Genomics of Alzheimer's Project (IGAP). Meta-analysis across studies identified 216 unique significant genes, including 72 with no previously reported LOAD GWAS associations. Cross-brain-tissue and cross-GTEx models revealed eight additional genes significantly associated with LOAD. Conditional analysis of previously reported loci using established LOAD-risk variants identified eight genes reaching genome-wide significance independent of known signals. Moreover, the proportion of SNP-based heritability is highly enriched in genes identified by GReX analysis. In summary, GReX-based meta-analysis in LOAD identifies 216 genes (including 72 novel genes), illuminating the role of gene regulatory models in LOAD.

Machine learning suggests polygenic risk for cognitive dysfunction in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a multi-system disease characterized primarily by progressive muscle weakness. Cognitive dysfunction is commonly observed in patients; however, factors influencing risk for cognitive dysfunction remain elusive. Using sparse canonical correlation analysis (sCCA), an unsupervised machine-learning technique, we observed that single nucleotide polymorphisms collectively associate with baseline cognitive performance in a large ALS patient cohort (N = 327) from the multicenter Clinical Research in ALS and Related Disorders for Therapeutic Development (CReATe) Consortium. We demonstrate that a polygenic risk score derived using sCCA relates to longitudinal cognitive decline in the same cohort and also to in vivo cortical thinning in the orbital frontal cortex, anterior cingulate cortex, lateral temporal cortex, premotor cortex, and hippocampus (N = 90) as well as post-mortem motor cortical neuronal loss (N = 87) in independent ALS cohorts from the University of Pennsylvania Integrated Neurodegenerative Disease Biobank. Our findings suggest that common genetic polymorphisms may exert a polygenic contribution to the risk of cortical disease vulnerability and cognitive dysfunction in ALS.