Establishment of a graphene quantum dot (GQD) based steroid binding assay for the nuclear progesterone receptor (pgr).

Previously, we established a homogeneous assay for membrane progesterone receptor alpha (mPRα) ligands by conjugating semiconductor nanoparticles known as graphene quantum dots (GQDs) to mPRα. When mixed with a progesterone-BSA-fluorescein isothiocyanate conjugate (P4-BSA-FITC), fluorescence occurred by fluorescence resonance energy transfer (FRET) but was reduced by the ligand-receptor binding activity. The established way showed ligand specificity as mPRα protein. In this study, we tried to establish the same way for nuclear progesterone receptor (Pgr). The ligand-binding domain (LBD) of zebrafish Pgr (zPgrLBD) was expressed as a fusion protein with glutathione S-transferase (GST) (GST-zPgrLBD). The recombinant protein was then purified and coupled with GQDs to produce GQD-conjugated GST-zPgrLBD (GQD-GST-zPgrLBD). When mixed with a P4-BSA-FITC and activated by 370 nm light, fluorescence at 520 nm appeared by FRET mechanism. Fluorescence at 520 nm was reduced by adding free progesterone to the reaction mixture. Reduction of fluorescence was induced by zPgr ligands but not by steroids or chemicals that do not interact with zPgr. The results showed the formation of a complex of GQD-GST-zPgrLBD and P4-BSA-FITC with ligand-receptor binding. The binding of the compounds was further confirmed by a radiolabeled steroid binding assay. A homogenous ligand-binding assay for nuclear progesterone receptor has been established.

Ensemble learning methods of inference for spatially stratified infectious disease systems.

Individual level models are a class of mechanistic models that are widely used to infer infectious disease transmission dynamics. These models incorporate individual level covariate information accounting for population heterogeneity and are generally fitted in a Bayesian Markov chain Monte Carlo (MCMC) framework. However, Bayesian MCMC methods of inference are computationally expensive for large data sets. This issue becomes more severe when applied to infectious disease data collected from spatially heterogeneous populations, as the number of covariates increases. In addition, summary statistics over the global population may not capture the true spatio-temporal dynamics of disease transmission. In this study we propose to use ensemble learning methods to predict epidemic generating models instead of time consuming Bayesian MCMC method. We apply these methods to infer disease transmission dynamics over spatially clustered populations, considering the clusters as natural strata instead of a global population. We compare the performance of two tree-based ensemble learning techniques: random forest and gradient boosting. These methods are applied to the 2001 foot-and-mouth disease epidemic in the U.K. and evaluated using simulated data from a clustered population. It is shown that the spatially clustered data can help to predict epidemic generating models more accurately than the global data.

Establishment of a steroid binding assay for goldfish membrane progesterone receptor (mPR) by coupling with graphene quantum dots (GQDs).

A homogeneous assay was developed to evaluate ligands that target the membrane progesterone receptor alpha (mPRα) of goldfish. This was achieved by employing graphene quantum dots (GQDs), a type of semiconductor nanoparticle conjugated to the goldfish mPRα. When progesterone-BSA-fluorescein isothiocyanate (P4-BSA-FITC) was combined with the other agents, fluorescence was observed through Förster resonance energy transfer (FRET). However, this fluorescence was quenched by binding between the ligand and receptor. This established method demonstrated the ligand selectivity of the mPRα protein. Then, the methylotrophic yeast Pichia pastoris was used to express the goldfish mPRα (GmPRα) protein. The recombinant purified GmPRα protein was coupled with graphene quantum dots (GQDs) to generate GQD-conjugated goldfish mPRα (GQD-GmPRα). Fluorescence at a wavelength of 520 nm was observed through FRET upon the combination of P4-BSA-FITC and subsequent activation by ultraviolet (UV) light. Adding free P4 to the reaction mixture resulted in a decrease in fluorescence intensity at a wavelength of 520 nm. The fluorescence was reduced by the administration of GmPRα ligands but not by steroids that do not interact with GmPRα. The findings indicated that the interaction between the ligand and receptor led to the formation of a complex involving GQD-GmPRα and P4-BSA-FITC. The interaction between the compounds and GQD-GmPRα was additionally validated by a binding experiment that employed the radiolabeled natural ligand [3H]-17α,20ß-dihydroxy-4-pregnen-3-one. We established a ligand-binding assay for the fish membrane progesterone receptor that is applicable for screening compounds.

Ophthalmic and Neuroimaging Associations In Optic Nerve Hypoplasia/Septo-Optic-Pituitary Dysplasia.

BACKGROUND: Optic nerve hypoplasia (ONH) and septo-optic-pituitary dysplasia (SOD) are neurodevelopmental disorders associated with congenital visual impairment. Our aim was to investigate associations between several ophthalmic and neuroimaging features in patients with ONH/SOD. METHODS: A retrospective chart and neuroimaging review was performed in patients with ONH/SOD. Ophthalmic signs (e.g., monocular best-corrected visual acuity [BCVA], nystagmus, and strabismus) and neuroimaging data were extracted and their associations were investigated. RESULTS: There were 128 patients (70 males) with ONH/SOD who had neuroimaging. Their mean age at the end of the study was 13.2 (SD: 7.5) years. Ophthalmic data were available on 102 patients (58 males). BCVA varied from normal to no light perception. There were statistically significant associations between: (A) Reduced optic nerve or chiasm size on neuroimaging and more severely impaired BCVA and (B) laterality of the reduced optic nerve or chiasm size on neuroimaging and laterality of: (1) The eye with reduced BCVA, (2) small optic disc size, and (3) RAPD, if present (p ≤ 0.0002 each). The presence of symmetrically small optic nerves on MRI was significantly more common in patients with nystagmus than when nystagmus was absent (N = 96, 75% vs. 38.6%, p < 0.0001). The presence of neuronal migration disorders, their type and laterality were not associated with BCVA and laterality of the reduced BCVA. CONCLUSION: The functional and structural associations in ONH are consistent with the impaired visual function that results from the hypoplastic anterior visual pathways. However, these associations were not perfectly concordant making prediction of adult BCVA challenging in these patients.

Repeated multi-domain cognitive training prevents cognitive decline, anxiety and amyloid pathology found in a mouse model of Alzheimer disease.

Education, occupation, and an active lifestyle, comprising enhanced social, physical, and mental components are associated with improved cognitive functions in aged people and may delay the progression of various neurodegenerative diseases including Alzheimer's disease. To investigate this protective effect, 3-month-old APPNL-G-F/NL-G-F mice were exposed to repeated single- or multi-domain cognitive training. Cognitive training was given at the age of 3, 6, & 9 months. Single-domain cognitive training was limited to a spatial navigation task. Multi-domain cognitive training consisted of a spatial navigation task, object recognition, and fear conditioning. At the age of 12 months, behavioral tests were completed for all groups. Then, mice were sacrificed, and their brains were assessed for pathology. APPNL-G-F/NL-G-F mice given multi-domain cognitive training compared to APPNL-G-F/NL-G-F control group showed an improvement in cognitive functions, reductions in amyloid load and microgliosis, and a preservation of cholinergic function. Additionally, multi-domain cognitive training improved anxiety in APPNL-G-F/NL-G-F mice as evidenced by measuring thigmotaxis behavior in the Morris water maze. There were mild reductions in microgliosis in the brain of APPNL-G-F/NL-G-F mice with single-domain cognitive training. These findings provide causal evidence for the potential of certain forms of cognitive training to mitigate the cognitive deficits in Alzheimer disease.

An efficient estimation approach to joint modeling of longitudinal and survival data.

The joint models for longitudinal and survival data have recently received significant attention in medical and epidemiological studies. Joint models typically combine linear mixed effects models for repeated measurement data and Cox models for survival time. When we are jointly modeling the longitudinal and survival data, variable selection and efficient estimation of parameters are especially important for performing reliable statistical analyzes, both of which are currently lacking in the literature. In this paper we discuss the pretest and shrinkage estimation methods for jointly modeling longitudinal data and survival time data when some of the covariates in both longitudinal and survival components may not be relevant for predicting survival times. In this situation, we fit two models: the full model that contains all the covariates and the subset model that contains a reduced number of covariates. We combine the full model estimators and the estimators that are restricted by a linear hypothesis to define pretest and shrinkage estimators. We provide their numerical mean squared errors (MSE) and relative MSE. We show that if the shrinkage dimension exceeds two, the risk of the shrinkage estimators is strictly less than that of the full model estimators. Our proposed methods are illustrated by extensive simulation studies and a real-data example.

Early tactile stimulation influences the development of Alzheimer's disease in gestationally stressed APP NL-G-F adult offspring NL-G-F/NL-G-F mice.

Alzheimer's disease (AD) is associated with cerebral plaques and tangles, reduced synapse number, and shrinkage in several brain areas and these morphological effects are associated with the onset of compromised cognitive, motor, and anxiety-like behaviours. The appearance of both anatomical and behavioural symptoms is worsened by stress. The focus of this study was to examine the effect of neonatal tactile stimulation on AD-like behavioural and neurological symptoms on APP NL-G-F/NL-G-F mice, a mouse model of AD, who have been gestationally stressed. Our findings indicate that neonatal tactile stimulation improves cognition, motor skills, and anxiety-like symptoms in both gestationally stressed and non-stressed adult APP mice and that these alterations are associated with reduced Aß plaque formation. Thus, tactile stimulation appears to be a promising non-invasive preventative strategy for slowing the onset of dementia in aging animals.

Neuroimaging Features in Children with Optic Nerve Hypoplasia and Septo-Optic-Pituitary Dysplasia.

BACKGROUND: Optic nerve hypoplasia (ONH) and septo-optic-pituitary dysplasia (SOD) are common causes of congenital visual impairment. Our primary aim was to investigate the prevalence of abnormal neuroimaging features in patients with these disorders in Manitoba, Canada, and compare them with published reports. METHODS: A retrospective neuroimaging review was performed in patients resident in Manitoba with ONH/SOD. RESULTS: There were 128 patients (M = 70) with ONH/SOD who had neuroimaging. Their mean age (SD) at the end of the study was 13.2 (7.5) years. Males were significantly more likely to have bilateral ONH and a small optic chiasm size, while females were more likely to have a left ONH and a small left optic chiasm size on neuroimaging (p = 0.049). ONH and small optic chiasm size were seen in most patients on neuroimaging. Absent septum pellucidum was noted in 40%, small pituitary gland size in 28%, neuronal migration disorders (NMD) in 20% (>1 type and bilateral in 13 cases), corpus callosum abnormalities were present in 9%, while olfactory bulbs-tracts and olfactory sulci were absent in 8.6% of cases. Unilateral ONH was not significantly associated with other structural brain abnormalities, while NMD were significantly associated with other midline brain abnormalities including a symmetrically small optic chiasm size. CONCLUSION: The prevalence of structural neuroimaging abnormalities in our cohort with ONH/SOD was generally in the same range reported in other studies with corpus callosum abnormalities being relatively less common in our study. Bilateral NMD were relatively common among patients with NMD. The association between sex and ONH laterality requires further study.

Municipal solid waste treatment for bioenergy and resource production: Potential technologies, techno-economic-environmental aspects and implications of membrane-based recovery.

World estimated municipal solid waste generating at an alarming rate and its disposal is a severe concern of today's world. It is equivalent to 0.79 kg/d per person footprint and causing climate change; health hazards and other environmental issues which need attention on an urgent basis. Waste to energy (WTE) considers as an alternative renewable energy potential to recover energy from waste and reduce the global waste problems. WTE reduced the burden on fossil fuels for energy generation, waste volumes, environmental, and greenhouse gases emissions. This critical review aims to evaluate the source of solid waste generation and the possible routes of waste management such as biological landfill and thermal treatment (Incineration, pyrolysis, and gasification). Moreover, a comparative evaluation of different technologies was reviewed in terms of economic and environmental aspects along with their limitations and advantages. Critical literature revealed that gasification seemed to be the efficient route and environmentally sustainable. In addition, a framework for the gasification process, gasifier types, and selection of gasifiers for MSW was presented. The country-wise solutions recommendation was proposed for solid waste management with the least impact on the environment. Furthermore, key issues and potential perspectives that require urgent attention to facilitate global penetration are highlighted. Finally, practical implications of membrane and comparison membrane-based separation technology with other conventional technologies to recover bioenergy and resources were discussed. It is expected that this study will lead towards practical solution for future advancement in terms of economic and environmental concerns, and also provide economic feasibility and practical implications for global penetration.

Tactile stimulation improves cognition, motor, and anxiety-like behaviors and attenuates the Alzheimer's disease pathology in adult APPNL-G-F/NL-G-F mice.

Alzheimer's disease (AD) is one of the largest health crises in the world. There are limited pharmaceutical interventions to treat AD, however, and most of the treatment options are not for cure or prevention, but rather to slow down the progression of the disease. The aim of this study was to examine the effect of tactile stimulation (TS) on AD-like symptoms and pathology in APPNL-G-F/NL-G-F mice, a mouse model of AD. The results show that TS reduces the AD-like symptoms on tests of cognition, motor, and anxiety-like behaviors and these improvements in behavior are associated with reduced AD pathology in APP mice. Thus, TS appears to be a promising noninvasive strategy for slowing the onset of dementia in aging animals.

Visual Acuity Outcomes in Children With Optic Nerve Hypoplasia and Septo-Optic-Pituitary Dysplasia.

BACKGROUND: To investigate best-corrected visual acuity (BCVA) outcomes in patients with optic nerve hypoplasia (ONH)/septo-optic-pituitary dysplasia (SOD). Our primary hypothesis was that BCVA in patients with ONH/SOD does not change significantly over time. METHODS: A chart review was undertaken in patients with a confirmed diagnosis of ONH/SOD. Demographic and clinical ophthalmologic data were extracted. Quantitative BCVA data were investigated across clinic visits after converting acuities to the logarithm of the minimum angle of resolution (logMAR). RESULTS: There were 102 patients (56 males). Median age at the end of the study was 12.7 years. Median duration of follow-up was 4.5 years. BCVA significantly worsened slightly in the most affected eyes (0.056 average increase in logMAR/year, 95% confidence interval [CI]: 0.037 to 0.075) and significantly improved mildly in the lesser or equally affected eyes (0.014 average decrease in logMAR/year, 95% CI: 0.009 to 0.019) (P < 0.0001). CONCLUSIONS: Although the overall BCVA data showed a statistically significant change with time, the actual changes were small and are of doubtful meaningful clinical significance (less than one line change on a Snellen chart). Our data suggest that ONH/SOD are nonprogressive neurodevelopmental disorders. The mild worsening of BCVA in the most affected eyes may be caused by amblyopia, whereas the small improvement in the lesser or equally affected eyes may be caused by developmental maturation. In addition, the changes in BCVA may also be due to increasing reliability of visual assessments with increasing age.

Selected Ophthalmological Features in Children with Septo-Optic Dysplasia and Optic Nerve Hypoplasia.

Septo-optic dysplasia (SOD) and optic nerve hypoplasia (ONH) cause congenital visual impairment. Their aetiology is mostly unknown. Our aim was to investigate the prevalence of selected ophthalmological features in patients with these disorders. A chart review was performed on patients with SOD/ONH. Ophthalmological data were extracted. There were 102 patients (56 males). The median age at the end of the study was 12.7 years. Best-corrected visual acuity ranged from normal to no light perception. Bilateral ONH was more common than unilateral ONH. Strabismus (85%) and to a lesser extent nystagmus (52%) were both very common in our cohort. Patients with esotropia had worse visual acuity than those who had exotropia. The presence of nystagmus was more likely in cases with bilateral ONH. Therefore, patients with SOD/ONH may have normal visual acuity. Many have strabismus, which may cause amblyopia thereby further decreasing visual acuity. Nystagmus occurs commonly and its presence typically indicates bilateral ONH.

Kinematic Properties of a Twisted Double Planetary Chaotic Mixer: A Three-Dimensional Numerical Investigation.

In this study, a numerical investigation based on the CFD method is carried out to study the unsteady laminar flow of Newtonian fluid with a high viscosity in a three-dimensional simulation of a twisted double planetary mixer, which is composed of two agitating rods inside a moving tank. The considered stirring protocol is a "Continuous sine squared motion" by using the dynamic mesh model and user-defined functions (UDFs)to define the velocity profiles. The chaotic advection is obtained in our active mixers by the temporal modulation of rotational velocities of the moving walls in order to enhance the mixing of the fluid for a low Reynolds number and a high Peclet number. For this goal, we applied the Poincaré section and Lyapunov exponent as reliable mathematic tools for checking mixing quality by tracking a number of massless particles inside the fluid domain. Additionally, we investigated the development of fluid kinematics proprieties, such as vorticity, helicity, strain rate and elongation rate, at various time periods in order to view the impact of temporal modulation on the flow properties. The results of the mentioned simulation showed that it is possible to obtain a chaotic advection after a relatively short time, which can deeply enhance mixing fluid efficiency.

Dramatic impacts on brain pathology, anxiety, and cognitive function in the knock-in APPNL-G-F mouse model of Alzheimer disease following long-term voluntary exercise.

BACKGROUND: An active lifestyle is associated with improved cognitive functions in aged people and may prevent or slow down the progression of various neurodegenerative diseases including Alzheimer's disease (AD). To investigate these protective effects, male APPNL-G-F mice were exposed to long-term voluntary exercise. METHODS: Three-month-old AD mice were housed in a cage supplemented with a running wheel for 9 months for long-term exercise. At the age of 12 months, behavioral tests were completed for all groups. After completing behavioral testing, their brains were assessed for amyloid pathology, microgliosis, and cholinergic cells. RESULTS: The results showed that APPNL-G-F mice allowed to voluntarily exercise showed an improvement in cognitive functions. Furthermore, long-term exercise also improved anxiety in APPNL-G-F mice as assessed by measuring thigmotaxis in the Morris water task. We also found reductions in amyloid load and microgliosis, and a preservation of cholinergic cells in the brain of APPNL-G-F mice allowed to exercise in their home cages. These profound reductions in brain pathology associated with AD are likely responsible for the observed improvement of learning and memory functions following extensive and regular exercise. CONCLUSION: These findings suggest the potential of physical exercise to mitigate the cognitive deficits in AD.

Evaluation of Hydrodynamic and Thermal Behaviour of Non-Newtonian-Nanofluid Mixing in a Chaotic Micromixer.

Three-dimensional numerical investigations of a novel passive micromixer were carried out to analyze the hydrodynamic and thermal behaviors of Nano-Non-Newtonian fluids. Mass and heat transfer characteristics of two heated fluids have been investigated to understand the quantitative and qualitative fluid faction distributions with temperature homogenization. The effect of fluid behavior and different Al2O3 nanoparticles concentrations on the pressure drop and thermal mixing performances were studied for different Reynolds number (from 0.1 to 25). The performance improvement simulation was conducted in intervals of various Nanoparticles concentrations (φ = 0 to 5%) with Power-law index (n) using CFD. The proposed micromixer displayed a mixing energy cost of 50-60 comparable to that achieved for a recent micromixer (2021y) in terms of fluid homogenization. The analysis exhibited that for high nanofluid concentrations, having a strong chaotic flow enhances significantly the hydrodynamic and thermal performances for all Reynolds numbers. The visualization of vortex core region of mass fraction and path lines presents that the proposed design exhibits a rapid thermal mixing rate that tends to 0.99%, and a mass fraction mixing rate of more than 0.93% with very low pressure losses, thus the proposed micromixer can be utilized to enhance homogenization in different Nano-Non-Newtonian mechanism with minimum energy.

Complex housing partially mitigates low dose radiation-induced changes in brain and behavior in rats.

PURPOSE: In recent years, much effort has been focused on developing new strategies for the prevention and mitigation of adverse radiation effects on healthy tissues and organs, including the brain. The brain is very sensitive to radiation effects, albeit as it is highly plastic. Hence, deleterious radiation effects may be potentially reversible. Because radiation exposure affects dendritic space, reduces the brain's ability to produce new neurons, and alters behavior, mitigation efforts should focus on restoring these parameters. To that effect, environmental enrichment through complex housing (CH) and exercise may provide a plausible avenue for exploration of protection from brain irradiation. CH is a much broader concept than exercise alone, and constitutes exposure of animals to positive physical and social stimulation that is superior to their routine housing and care conditions. We hypothesized that CHs may lessen harmful neuroanatomical and behavioural effects of low dose radiation exposure. METHODS: We analyzed and compared cerebral morphology in animals exposed to low dose head, bystander (liver), and scatter irradiation on rats housed in either the environmental enrichment condos or standard housing. RESULTS: Enriched condo conditions ameliorated radiation-induced neuroanatomical changes. Moreover, irradiated animals that were kept in enriched CH condos displayed fewer radiation-induced behavioural deficits than those housed in standard conditions. CONCLUSIONS: Animal model-based environmental enrichment strategies, such as CH, are excellent surrogate models for occupational and exercise therapy in humans, and consequently have significant translational possibility. Our study may thus serve as a roadmap for the development of new, easy, safe and cost-effective methods to prevent and mitigate low-dose radiation effects on the brain.

Mixing Enhancement of Non-Newtonian Shear-Thinning Fluid for a Kenics Micromixer.

In this work, a numerical investigation was analyzed to exhibit the mixing behaviors of non-Newtonian shear-thinning fluids in Kenics micromixers. The numerical analysis was performed using the computational fluid dynamic (CFD) tool to solve 3D Navier-Stokes equations with the species transport equations. The efficiency of mixing is estimated by the calculation of the mixing index for different cases of Reynolds number. The geometry of micro Kenics collected with a series of six helical elements twisted 180° and arranged alternately to achieve the higher level of chaotic mixing, inside a pipe with a Y-inlet. Under a wide range of Reynolds numbers between 0.1 to 500 and the carboxymethyl cellulose (CMC) solutions with power-law indices among 1 to 0.49, the micro-Kenics proves high mixing Performances at low and high Reynolds number. Moreover the pressure losses of the shear-thinning fluids for different Reynolds numbers was validated and represented.

A Review on Synthesis, Properties, and Applications of Polylactic Acid/Silica Composites.

Polylactic acid (PLA)/silica composites as multifunctional high-performance materials have been extensively examined in the past few years by virtue of their outstanding properties relative to neat PLA. The fabrication methods, such as melt-mixing, sol-gel, and in situ polymerization, as well as the surface functionalization of silica, used to improve the dispersion of silica in the polymer matrix are outlined. The rheological, thermal, mechanical, and biodegradation properties of PLA/silica nanocomposites are highlighted. The potential applications arising from the addition of silica nanoparticles into the PLA matrix are also described. Finally, we believe that a better understanding of the role of silica additive with current improvement strategies in the dispersion of this additive in the polymer matrix is the key for successful utilization of PLA/silica nanocomposites and to maximize their fit with industrial applications needs.

Kinematic Measurements of Novel Chaotic Micromixers to Enhance Mixing Performances at Low Reynolds Numbers: Comparative Study.

In this work, a comparative investigation of chaotic flow behavior inside multi-layer crossing channels was numerically carried out to select suitable micromixers. New micromixers were proposed and compared with an efficient passive mixer called a Two-Layer Crossing Channel Micromixer (TLCCM), which was investigated recently. The computational evaluation was a concern to the mixing enhancement and kinematic measurements, such as vorticity, deformation, stretching, and folding rates for various low Reynolds number regimes. The 3D continuity, momentum, and species transport equations were solved by a Fluent ANSYS CFD code. For various cases of fluid regimes (0.1 to 25 values of Reynolds number), the new configuration displayed a mixing enhancement of 40%-60% relative to that obtained in the older TLCCM in terms of kinematic measurement, which was studied recently. The results revealed that all proposed micromixers have a strong secondary flow, which significantly enhances the fluid kinematic performances at low Reynolds numbers. The visualization of mass fraction and path-lines presents that the TLCCM configuration is inefficient at low Reynolds numbers, while the new designs exhibit rapid mixing with lower pressure losses. Thus, it can be used to enhance the homogenization in several microfluidic systems.

Enhancement of Mixing Performance of Two-Layer Crossing Micromixer through Surrogate-Based Optimization.

Optimum configuration of a micromixer with two-layer crossing microstructure was performed using mixing analysis, surrogate modeling, along with an optimization algorithm. Mixing performance was used to determine the optimum designs at Reynolds number 40. A surrogate modeling method based on a radial basis neural network (RBNN) was used to approximate the value of the objective function. The optimization study was carried out with three design variables; viz., the ratio of the main channel thickness to the pitch length (H/PI), the ratio of the thickness of the diagonal channel to the pitch length (W/PI), and the ratio of the depth of the channel to the pitch length (d/PI). Through a primary parametric study, the design space was constrained. The design points surrounded by the design constraints were chosen using a well-known technique called Latin hypercube sampling (LHS). The optimal design confirmed a 32.0% enhancement of the mixing index as compared to the reference design.