Engineering Neurotoxin-Functionalized Exosomes for Targeted Delivery to the Peripheral Nervous System.

The administration of therapeutics to peripheral nerve tissue is challenging due to the complexities of peripheral neuroanatomy and the limitations imposed by the blood-nerve barrier (BNB). Therefore, there is a pressing need to enhance delivery effectiveness and implement targeted delivery methods. Recently, erythrocyte-derived exosomes (Exos) have gained widespread attention as biocompatible vehicles for therapeutics in clinical applications. However, engineering targeted Exos for the peripheral nervous system (PNS) is still challenging. This study aims to develop a targeted Exo delivery system specifically designed for presynaptic terminals of peripheral nerve tissue. The clostridium neurotoxin, tetanus toxin-C fragment (TTC), was tethered to the surface of red blood cell (RBC)-derived Exos via a facile and efficient bio-orthogonal click chemistry method without a catalyst. Additionally, Cyanine5 (Cy5), a reactive fluorescent tag, was also conjugated to track Exo movement in both in vitro and in vivo models. Subsequently, Neuro-2a, a mouse neuronal cell line, was treated with dye-labeled Exos with/without TTC in vitro, and the results indicated that TTC-Exos exhibited more efficient accumulation along the soma and axonal circumference, compared to their unmodified counterparts. Further investigation, using a mouse model, revealed that within 72 h of intramuscular administration, engineered TTC-Exos were successfully transported into the neuromuscular junction and sciatic nerve tissues. These results indicated that TTC played a crucial role in the Exo delivery system, improving the affinity to peripheral nerves. These promising results underscore the potential of using targeted Exo carriers to deliver therapeutics for treating peripheral neuropathies.

Studies on the Digital Inclusion Among Older Adults and the Quality of Life-A Nanjing Example in China.

Digital inclusion can bridge the digital divide and reduce the social exclusion of older adults, yet it is understudied in China. This research examined factors influencing the digital inclusion of older adults in China and the relationship between digital inclusion and quality of life. Data collected from 312 older people (M = 69.6 years old) in Nanjing were included in a multinomial logit model to tackle these questions. Their attitudes toward technology were the most significant factor predicting their digital inclusion. Other factors included party affiliation, living situation, personal average monthly income, occupation, and capacity for instrumental activities of daily living (IADLs). This study shows digital inclusion has a direct impact on quality of life. It also serves as an intermediate variable that affects older people's attitudes toward technology and their IADL capacities. Most importantly, digital inclusion promotes social integration of older adults and improves the quality of their lives. Hence, it should not be ignored. Older people's attitudes toward technology are one of the keys to promoting their digital inclusion.

Social Technology: An Interdisciplinary Approach to Improving Care for Older Adults.

Population aging is a defining demographic reality of our era. It is associated with an increase in the societal burden of delivering care to older adults with chronic conditions or frailty. How to integrate global population aging and technology development to help address the growing demands for care facing many aging societies is both a challenge and an opportunity for innovation. We propose a social technology approach that promotes use of technologies to assist individuals, families, and communities to cope more effectively with the disabilities of older adults who can no longer live independently due to dementia, serious mental illness, and multiple chronic health problems. The main contributions of the social technology approach include: (1) fostering multidisciplinary collaboration among social scientists, engineers, and healthcare experts; (2) including ethical and humanistic standards in creating and evaluating innovations; (3) improving social systems through working with those who deliver, manage, and design older adult care services; (4) promoting social justice through social policy research and innovation, particularly for disadvantaged groups; (5) fostering social integration by creating age-friendly and intergenerational programs; and (6) seeking global benefit by identifying and generalizing best practices. As an emergent, experimental approach, social technology requires systematic evaluation in an iterative process to refine its relevance and uses in different local settings. By linking technological interventions to the social and cultural systems of older people, we aim to help technological advances become an organic part of the complex social world that supports and sustains care delivery to older adults in need.

Effects of Discontinue Rules on Psychometric Properties of Test Scores.

This paper provides results on a form of adaptive testing that is used frequently in intelligence testing. In these tests, items are presented in order of increasing difficulty. The presentation of items is adaptive in the sense that a session is discontinued once a test taker produces a certain number of incorrect responses in sequence, with subsequent (not observed) responses commonly scored as wrong. The Stanford-Binet Intelligence Scales (SB5; Riverside Publishing Company, 2003) and the Kaufman Assessment Battery for Children (KABC-II; Kaufman and Kaufman, 2004), the Kaufman Adolescent and Adult Intelligence Test (Kaufman and Kaufman 2014) and the Universal Nonverbal Intelligence Test (2nd ed.) (Bracken and McCallum 2015) are some of the many examples using this rule. He and Wolfe (Educ Psychol Meas 72(5):808-826, 2012. https://doi.org/10.1177/0013164412441937 ) compared different ability estimation methods in a simulation study for this discontinue rule adaptation of test length. However, there has been no study, to our knowledge, of the underlying distributional properties based on analytic arguments drawing on probability theory, of what these authors call stochastic censoring of responses. The study results obtained by He and Wolfe (Educ Psychol Meas 72(5):808-826, 2012. https://doi.org/10.1177/0013164412441937 ) agree with results presented by DeAyala et al. (J Educ Meas 38:213-234, 2001) as well as Rose et al. (Modeling non-ignorable missing data with item response theory (IRT; ETS RR-10-11), Educational Testing Service, Princeton, 2010) and Rose et al. (Psychometrika 82:795-819, 2017. https://doi.org/10.1007/s11336-016-9544-7 ) in that ability estimates are biased most when scoring the not observed responses as wrong. This scoring is used operationally, so more research is needed in order to improve practice in this field. The paper extends existing research on adaptivity by discontinue rules in intelligence tests in multiple ways: First, an analytical study of the distributional properties of discontinue rule scored items is presented. Second, a simulation is presented that includes additional scoring rules and uses ability estimators that may be suitable to reduce bias for discontinue rule scored intelligence tests.

Guan (Care/Control): An Ethnographic Understanding of Care for People with Severe Mental Illness from Shanghai's Urban Communities.

This article investigates how the political culture of Guan (care/control) in China is played out across the platforms of the state, the community and the family through the lens of caring for people with severe mental illness in urban Shanghai. Based on ethnographic data collected from six communities in a district of Shanghai, we provide a nuanced understanding of the roles of family members, street committees and other governmental organizations in their daily practices of caring for people with severe mental illness. We show the complicated and intertwined relationships between local governmental agents and the family. We argue that the political culture of Guan, which permeates the everyday life of Chinese people, tends to objectify its subjects and reflects a long history of patriarchy in Chinese society. Without further changing such political cultural arrangements, respect for the agency of mentally ill patients, the effort of bringing humanistic psychiatric reforms to China, will be in vain.

Interleukin-6 deficiency attenuates angiotensin II-induced cardiac pathogenesis with increased myocyte hypertrophy.

Interleukin-6 (IL-6) signaling is critical for cardiomyocyte hypertrophy, while the role of IL-6 in the pathogenesis of myocardium hypertrophy remains controversial. To determine the essential role of IL-6 signaling for the cardiac development during AngII-induced hypertension, and to elucidate the mechanisms, wild-type (WT) and IL-6 knockout (IL-6 KO) mice were infused subcutaneously with either vehicle or AngII (1.5 µg/h/mouse) for 1 week. Immunohistological and serum studies revealed that the extents of cardiac fibrosis, inflammation and apoptosis were reduced in IL-6 KO heart during AngII-stimulation, while cardiac hypertrophy was obviously induced. To investigate the underlying mechanisms, by using myocardial tissue and neonatal cardiomyocytes, we observed that IL-6/STAT3 signaling was activated under the stimulation of AngII both in vivo and in vitro. Further investigation suggested that STAT3 activation enhances the inhibitory effect of EndoG on MEF2A and hampers cardiomyocyte hypertrophy. Our study is the first to show the important role of IL-6 in regulating cardiac pathogenesis via inflammation and apoptosis during AngII-induced hypertension. We also provide a novel link between IL-6/STAT3 and EndoG/MEF2A pathway that affects cardiac hypertrophy during AngII stimulation.

AKT2 deficiency induces retardation of myocyte development through EndoG-MEF2A signaling in mouse heart.

Protein kinase B2 (AKT2) is implicated in diverse process of cardiomyocyte signaling including survival and metabolism. However, the role of AKT2 in myocardium development and the signaling pathway is rarely understood. Therefore, we sought to determine the effect of AKT2 deletion on heart development and its downstream targets. By using experimental animal models and neonatal rat cardiomyocytes (NRCMs), we observed that AKT2 deficiency induces retardation of heart development and increased systemic blood pressure (BP) without affecting cardiac function. Further investigation suggested that deficiency of AKT2 in myocardium results in diminished MEF2A abundance, which induced decreased size of cardiomyocytes. We additionally confirmed that EndoG, which is also regulated by AKT2, is a suppressor of MEF2A in myocardium. Finally, our results proved that AKT2 deficiency impairs the response to ß-adrenergic stimuli that normally causes hypertrophy in cardiomyocytes by downregulating MEF2A expression. Our data are the first to show the important role of AKT2 in determining the size of myocardium, its deficiency causes retardation of cardiomyocyte development. We also proved a novel pathway of heart development involving EndoG and MEF2A regulated by AKT2.

Calculating theoretical base rates of score differences.

OBJECTIVE: In this study, we developed new methods to calculate theoretical base rates of score differences when more than two test scores are involved in score comparisons. The study compares the results of theoretical and observed base rates, and then explores whether these methods can be used in practice. METHODS: We proposed the formulas and the Monte Carlo methods calculating theoretical base rates of score differences between a single test score and a mean of several test scores by overall sample and subsamples. We also compared observed and theoretical base rates of score differences in the Wechsler Intelligence Scale for Children (5th ed.). using the normative sample data. RESULTS: The theoretical base rates obtained from the new methods were close to the observed base rates. CONCLUSIONS: The new methods can derive reasonable theoretical base rates and are usable practically.

It is the examinee's IQ.

In response to the question "Whose IQ is it?" raised by McDermott, Watkins, and Rhoad (2014), this study examined the same concern about assessor bias by applying hierarchical linear modeling to a large and representative standardization sample of 2,200 child records in the Wechsler Intelligence Scale for Children, Fourth Edition (WISC-IV). When differences in child age, gender, ethnicity, parental education level, and some intellectual abilities were cojointly used as covariates to adjust for nonrandom assignment problems, the results revealed that the Level 2 assessor variance was trivial for Full Scale IQ and all WISC-IV scores, ranging from 1%-5%, with the only exception being the Comprehension subtest, which showed a moderate level of between-assessor variance (10%). Evidence shows that WISC-IV scores are valid measures of children's intellectual abilities, with no evidence showing harmful assessor bias. (PsycINFO Database Record

The relationship between mean square differences and standard error of measurement: comment on Barchard (2012).

In the discussion of mean square difference (MSD) and standard error of measurement (SEM), Barchard (2012) concluded that the MSD between 2 sets of test scores is greater than 2(SEM)² and SEM underestimates the score difference between 2 tests when the 2 tests are not parallel. This conclusion has limitations for 2 reasons. First, strictly speaking, MSD should not be compared to SEM because they measure different things, have different assumptions, and capture different sources of errors. Second, the related proof and conclusions in Barchard hold only under the assumptions of equal reliabilities, homogeneous variances, and independent measurement errors. To address the limitations, we propose that MSD should be compared to the standard error of measurement of difference scores (SEMx-y) so that the comparison can be extended to the conditions when 2 tests have unequal reliabilities and score variances.

Predicting performance in the first-year of pharmacy school.

OBJECTIVES: To determine the predictive validity of the Pharmacy College Admission Test (PCAT) scores and other variables for students' success in the first year of doctor of pharmacy (PharmD) programs. METHODS: PCAT scores, entering grade-point averages (GPAs), demographic characteristics, and GPAs for the first year of pharmacy curriculum were collected from the Pharmacy College Application Service (PharmCAS) and from 22 pharmacy programs. RESULTS: PCAT scores and entering GPAs were positively correlated with subsequent GPAs after the first year. Regression analyses showed the contribution of PCAT scores and entering GPAs in predicting first-year pharmacy GPAs. CONCLUSIONS: PCAT scores and prepharmacy GPAs both showed moderate predictive validity in indicating candidates likely to succeed in the first year of the pharmacy program. These findings are consistent with those of previous similar studies.

Surviving the crisis: Adaptive wisdom, coping mechanisms and local responses to avian influenza threats in Haining, China.

Based on ethnographic research conducted in the summer of 2006, this paper examines local responses to the imminent threat of avian flu in Haining County of Zhejiang Province. During our field investigation, we conducted interviews with officials from local medical institutions (including the hospitals, the animal husbandry and veterinary station, and health clinics), to bureaus of public health and agro-economy. We also visited chicken farms, restaurants and farming households. We address the following factors that commonly structured the perceptions and actions of different social actors in the area of study: The changing mode of information-sharing and communication practices in the local communities; the official drive to professionalize the emergency response management system in the county; and the coping mechanisms that helped the villagers and town residents to weather the storm of avian flu. Our field research suggests that collective survival consciousness was translated into a spirit of voluntarism during the crisis. One important practical lesson we have learned from this study is that the adaptive wisdom embedded in local memories demonstrated its operational worth as a resourceful knowledge base for ordinary farmers to deal with food shortage, famine, plague and future pandemics.

Monte Carlo simulation of time-dependent, transport-limited fluorescent boundary measurements in frequency domain.

Recently, we have presented and experimentally validated a unique numerical solver of the coupled radiative transfer equations (RTEs) for rapidly computing time-dependent excitation and fluorescent light propagation in small animal tomography. Herein, we present a time-dependent Monte Carlo algorithm to validate the forward RTE solver and investigate the impact of physical parameters upon transport-limited measurements in order to best direct the development of the RTE solver for optical tomography. Experimentally, the Monte Carlo simulations for both transport-limited and diffusion-limited propagations are validated using frequency domain photon migration measurements for 1.0%, 0.5%, and 0.2% intralipid solutions containing 1 microM indocyanine green in a 49 cm3 cylindrical phantom corresponding to the small volume employed in small animal tomography. The comparisons between Monte Carlo simulations and the numerical solutions result in mean percent error in amplitude and the phase shift less than 5.0% and 0.7 degrees, respectively, at excitation and emission wavelengths for varying anisotropic factors, lifetimes, and modulation frequencies. Monte Carlo simulations indicate that the accuracy of the forward model is enhanced using (i) suitable source models of photon delivery, (ii) accurate anisotropic factors, and (iii) accurate acceptance angles of collected photons. Monte Carlo simulations also show that the accuracy of the diffusion approximation in the small phantom depends upon (i) the ratio d(phantom)/l(tr), where d(phantom) is the phantom diameter and l(tr) is the transport mean free path; and (ii) the anisotropic factor of the medium. The Monte Carlo simulations validates and guides the future development of an appropriate RTE solver for deployment in small animal optical tomography.

Evaluation of ingredient concentration in powders using two-speed photon migration theory and measurements.

Two-speed photon migration in densely packed powder blends wherein the particle diameters are much larger than the incident wavelength are simulated with (i) dynamic simulation of particle sedimentation for generating powder structure, (ii) the complete-random-mixture model for predicting the active pharmaceutical ingredient (API) distribution within the powder bed, and (iii) Monte Carlo for tracking the photon trajectories. The simulation results reveal that while both absorption and isotropic scattering coefficients increase with solid-volume fraction ranging from 0.12 to 0.64, the absorption-to-isotropic-scattering ratio is (i) independent of the solid-volume fraction for particle refractive index ranging from 1.2 to 1.8 and (ii) linearly dependent upon the API volume concentration ranging from 0% to 5%. Frequency domain photon migration measurements of resin powder beds of varying particle size verified the developed simulation method. Measurements of lactose powder beds of varying particle size, solid-volume fraction, and ferric oxide particles content verified the simulation results that evidence independence of the absorption-to-isotropic-scattering ratio upon solid-volume fraction.

Radiative transport in fluorescence-enhanced frequency domain photon migration.

Small animal optical tomography has significant, but potential application for streamlining drug discovery and pre-clinical investigation of drug candidates. However, accurate modeling of photon propagation in small animal volumes is critical to quantitatively obtain accurate tomographic images. Herein we present solutions from a robust fluorescence-enhanced, frequency domain radiative transport equation (RTE) solver with unique attributes that facilitate its deployment within tomographic algorithms. Specifically, the coupled equations describing time-dependent excitation and emission light transport are solved using discrete ordinates (SN) angular differencing along with linear discontinuous finite-element spatial differencing on unstructured tetrahedral grids. Source iteration in conjunction with diffusion synthetic acceleration is used to iteratively solve the resulting system of equations. This RTE solver can accurately and efficiently predict ballistic as well as diffusion limited transport regimes which could simultaneously exist in small animals. Furthermore, the solver provides accurate solutions on unstructured, tetrahedral grids with relatively large element sizes as compared to commonly employed solvers that use step differencing. The predictions of the solver are validated by a series of frequency-domain, phantom measurements with optical properties ranging from diffusion limited to transport limited propagation. Our results demonstrate that the RTE solution consistently matches measurements made under both diffusion and transport-limited conditions. This work demonstrates the use of an appropriate RTE solver for deployment in small animal optical tomography.

Measurements of FRET in a glucose-sensitive affinity system with frequency-domain lifetime spectroscopy.

We report measurements of fluorescence resonance energy transfer (FRET) for glucose sensing in an established concanavalin A-dextran affinity system using frequency-domain lifetime spectroscopy. A dextran (MW 2,000,000) labeled with a small fluorescent donor molecule, Alexa Fluor 568, was used to competitively bind to a sugar-binding protein, concanavalin A, labeled with acceptor molecule, Alexa Fluor 647, in the presence of glucose. The FRET-quenching kinetics of the donor were analyzed from frequency-domain measurements as a function of both glucose and acceptor-protein concentrations using a Förster-type decay kinetics model. The results show that the frequency-domain measurements and donor decay kinetics can quantitatively indicate changes in the competitive binding of 0.09 microM dextran to labeled concanavalin A at a solution concentration of 10.67 microM in the presence of glucose at concentrations ranging from 0 to 224 mg/dL.

Evaluation of photon migration using a two speed model for characterization of packed powder beds and dense particulate suspensions.

A two-speed photon diffusion equation is developed for light propagation in a powder bed of high volume fraction or dense particulate suspension, whereby the light speed is impacted by the refractive index difference between particles and the suspending medium. The equation is validated using Monte Carlo simulation of light propagation coupled with dynamic simulation of particle sedimentation for the non-uniform arrangement of powder particles. Frequency domain experiments at 650 nm for a 77-microm-diameter resin-powder and 50-microm-diameter lactose-powder beds as well as resin-water and lactose-ethanol suspensions confirm the scattering and absorption coefficients derived from the two-speed diffusion equation.

Determination of optical properties in semi-infinite turbid media using imaging measurements of frequency-domain photon migration obtained with an intensified charge-coupled device.

Frequency-domain photon migration measurements across the surface of a tissue-mimicking, semi-infinite phantom are acquired via an intensified charge-coupled device (ICCD) detection system and used in conjunction with the diffusion approximation to determine the optical properties. The absorption and reduced scattering coefficients are determined least accurately when relative measurements of average light intensity I(rel)dc are employed either alone or in a combination with relative modulation amplitude data I(rel)ac and/or relative phase shift data theta(rel). The absorption and reduced scattering coefficients are found accurate to within 15 and 11%, respectively, of the values obtained from standard single-pixel measurements when theta(rel) measurements are employed alone or in combination with I(rel)ac data.

Measurement of low-dose active pharmaceutical ingredient in a pharmaceutical blend using frequency-domain photon migration.

Frequency-domain photon migration (FDPM) measurements of time-dependent light propagation are conducted to provide the powder absorbance for quantitative prediction of terazosin as the active pharmaceutical ingredient (API) in a low-dose (0.72 wt %) oral tablet formulation. Calibration of the FDPM-derived powder absorbance at discrete wavelengths of 514, 650, 687, and 785 nm was performed for API contents ranging between 0 and 1.5 wt % in mixtures showing maximum sensitivity at 650 nm. The relative standard deviation (RSD) of FDPM absorption coefficient measurement at 650 nm in a well-mixed 1.08 wt % terazosin blend was <1.6%, of which no more than 0.12% arose from FDPM instrumental error and the remainder was attributable to the complete-random-mixture model. The applicability of FDPM as an on-line sensor for powder-blending operations was further evaluated by analyzing grab samples taken directly from five locations of a 2-cu-ft Gallay blender at intervals of 5 min within the blending process. FDPM results indicate that homogeneity was largely achieved in the first 10 min, during which the RSD of API content across five sampling locations decreased from 27% to 8%, and the RSD decreased to 5% after 25 min of blending. Evolution of homogeneity within the blending process assessed through FDPM measurements was fit to the first-order model of particle blending further evidencing applicability for monitoring powder-blending processes.

Volume of pharmaceutical powders probed by frequency-domain photon migration measurements of multiply scattered light.

Using probability distribution analysis to describe the propagation of multiply scattered light between a point source and point detector located a known distance apart, mathematical expressions predicting the volume of sampled powder were determined for infinite and semi-infinite powder beds and then compared to experimental measurements of frequency-domain photon migration (FDPM). Our results show that the volume of powder sampled varies with optical properties and, when using FDPM techniques, with modulation frequency. For a typical measurement in lactose powder, the volume of powder sampled by multiply scattered light propagating between a 1000-microm-diameter point source and point detector pair separated by 8 mm is predicted to be 1.8 and 1.5 cm3 at modulated frequencies of 50 and 100 MHz, respectively. Experimental measurements in lactose powder confirm the predictions.