Synergistic effect of miscible cellulose-based microparticles and pH modulators on the bioavailability of a weakly basic drug and its metabolites.

This study aimed to evaluate the miscibility of cellulose derivatives to improve the release rate and stability of microparticles containing the weakly basic drug itraconazole (ITZ). We also investigated the effect of some organic acids on the microenvironmental pH (pHm) and the release rate of ITZ from the cellulose-based microparticles. The synergistic effect of cellulose-based microparticles and pHm modulators on the bioavailability of ITZ compared with the reference product was investigated in a rabbit model. Differential scanning calorimetry and Fourier-transform infrared spectroscopy (FTIR) analysis showed that ITZ, hydroxypropyl methylcellulose, and hydroxypropyl methylcellulose phthalate were miscible at a ratio of 1.5:3:1 (w/w/w), and the stability of the microparticles was maintained for 6 months under accelerated conditions. In addition, X-ray diffraction, FTIR, and scanning electron microscopy were used to characterize the properties of the microparticles. Through the titration technique and determination of pHm, the combination of fumaric acid and maleic acid (1:2, w/w) was found to be the most effective pHm modulator for microparticles. The integration of cellulose-based microparticles and pHm modulators showed a synergistic effect on the flux and relative bioavailability of ITZ and its active metabolite OH-ITZ (182.60 % and 217.67 %, respectively) when compared with the reference product.

Mesoporous MgO enriched in Lewis base sites as effective catalysts for efficient CO2 capture.

Capturing CO2 has become increasingly important. However, wide industrial applications of conventional CO2 capture technologies are limited by their slow CO2 sorption and desorption kinetics. Accordingly, this research is designed to overcome the challenge by synthesizing mesoporous MgO nanoparticles (MgO-NPs) with a new method that uses PEG 1500 as a soft template. MgO surface structure is nonstoichiometric due to its distinctive shape; the abundant Lewis base sites provided by oxygen vacancies promote CO2 capture. Adding 2 wt % MgO-NPs to 20 wt % monoethanolamine (MEA) can increase the breakthrough time (the time with 90% CO2 capturing efficiency) by ∼3000% and can increase the CO2 absorption capacity within the breakthrough time by ∼3660%. The data suggest that MgO-NPs can accelerate the rate and increase CO2 desorption capacity by up to ∼8740% and ∼2290% at 90 °C, respectively. Also, the excellent stability of the system within 50 cycles is verified. These findings demonstrate a new strategy to innovate MEA absorbents currently widely used in commercial post-combustion CO2 capture plants.

Phyto-Fenton remediation of a dichloro-diphenyl-trichloroethane contaminated site in Ha Tinh Province, Vietnam.

A field trial was conducted at a site in Cam Binh commune, Ha Tinh province, Vietnam, highly contaminated with organo-pesticides. The phyto-Fenton process was applied to remove pesticide residues in soils. In addition to magnetite (Fe3O4) materials added to the soils, fertilizers and elicitors for oxidative burst were also added in the different experimental treatments. Dichloro-diphenyl-trichloroethane (DDT) and isomers were removed in all experimental lots. The removal efficiency was highest in lot B1, a site where only iron materials were added. The removal efficiency and the final content of DDTs in B1 were 98.4% and 0.009 mg kg-1, respectively. In the presence of elicitors, the conversion of DDT to dichloro-diphenyl-dichloroethylene was more favorable. Analysis of soil properties indicated that the phyto-Fenton process can occur at neutral soil pH, and when there are only small changes in soil organic carbon content and cation exchange capacities. Shifts in the composition of the microbial communities were observed. Further studies on the interactions between materials added to soil, plants, and the soil microbiome are needed to understand the mechanism of action of the phyto-Fenton process during soil remediation.

The Role of in silico Research in Developing Nanoparticle-Based Therapeutics.

Nanoparticles (NPs) hold great potential as therapeutics, particularly in the realm of drug delivery. They are effective at functional cargo delivery and offer a great degree of amenability that can be used to offset toxic side effects or to target drugs to specific regions in the body. However, there are many challenges associated with the development of NP-based drug formulations that hamper their successful clinical translation. Arguably, the most significant barrier in the way of efficacious NP-based drug delivery systems is the tedious and time-consuming nature of NP formulation-a process that needs to account for downstream effects, such as the onset of potential toxicity or immunogenicity, in vivo biodistribution and overall pharmacokinetic profiles, all while maintaining desirable therapeutic outcomes. Computational and AI-based approaches have shown promise in alleviating some of these restrictions. Via predictive modeling and deep learning, in silico approaches have shown the ability to accurately model NP-membrane interactions and cellular uptake based on minimal data, such as the physicochemical characteristics of a given NP. More importantly, machine learning allows computational models to predict how specific changes could be made to the physicochemical characteristics of a NP to improve functional aspects, such as drug retention or endocytosis. On a larger scale, they are also able to predict the in vivo pharmacokinetics of NP-encapsulated drugs, predicting aspects such as circulatory half-life, toxicity, and biodistribution. However, the convergence of nanomedicine and computational approaches is still in its infancy and limited in its applicability. The interactions between NPs, the encapsulated drug and the body form an intricate network of interactions that cannot be modeled with absolute certainty. Despite this, rapid advancements in the area promise to deliver increasingly powerful tools capable of accelerating the development of advanced nanoscale therapeutics. Here, we describe computational approaches that have been utilized in the field of nanomedicine, focusing on approaches for NP design and engineering.

Evaluation of Postoperative Practices Regarding Packing of the External Auditory Canal.

BACKGROUND: Packing of the external auditory canal after ear surgery is an established practice in most otologic centers. However, no guidelines exist concerning the management of this process. The aim of the study is to investigate otologists' habits concerning packing of the external ear canal after otologic surgery. A second objective was to collect their opinion concerning the absence of packing. METHODS: This study is a cross-sectional survey. We sent an online questionnaire to the 135 members of the French Otology and Neurotology Association (AFON). It was conducted between March 15, 2020, and May 15, 2020. It consisted of 11 demographic questions and 6 surgical management-related questions concerning 6 major otologic procedures. RESULTS: Fifty-seven members answered the survey. The most frequent packing used was ear wick with silicon sheets (48.6%) among all surgical procedures. Among participants, 62% used the same packing material for all surgical procedures. Of the participants, 96% were reluctant not to pack the external ear canal after otologic surgery. CONCLUSION: This study shows a great variability concerning surgeons' practices. A randomized controlled trial would be helpful to guide surgeons for ear packing after otologic surgery and assess the absence of packing.

High Performance Predictable Quantum Efficient Detector Based on Induced-Junction Photodiodes Passivated with SiO2/SiNx.

We performed a systematic study involving simulation and experimental techniques to develop induced-junction silicon photodetectors passivated with thermally grown SiO2 and plasma-enhanced chemical vapor deposited (PECVD) SiNx thin films that show a record high quantum efficiency. We investigated PECVD SiNx passivation and optimized the film deposition conditions to minimize the recombination losses at the silicon-dielectric interface as well as optical losses. Depositions with varied process parameters were carried out on test samples, followed by measurements of minority carrier lifetime, fixed charge density, and optical absorbance and reflectance. Subsequently, the surface recombination velocity, which is the limiting factor for internal quantum deficiency (IQD), was obtained for different film depositions via 2D simulations where the measured effective lifetime, fixed charge density, and substrate parameters were used as input. The quantum deficiency of induced-junction photodiodes that would be fabricated with a surface passivation of given characteristics was then estimated using improved 3D simulation models. A batch of induced-junction photodiodes was fabricated based on the passivation optimizations performed on test samples and predictions of simulations. Photodiodes passivated with PECVD SiNx film as well as with a stack of thermally grown SiO2 and PECVD SiNx films were fabricated. The photodiodes were assembled as light-trap detector with 7-reflections and their efficiency was tested with respect to a reference Predictable Quantum Efficient Detector (PQED) of known external quantum deficiency. The preliminary measurement results show that PQEDs based on our improved photodiodes passivated with stack of SiO2/SiNx have negligible quantum deficiencies with IQDs down to 1 ppm within 30 ppm measurement uncertainty.

Plastic Recycling Practices in Vietnam and Related Hazards for Health and the Environment.

Waste plastic today is a global threat. The rapid increase in global production and use has led to increasing quantities of plastics in industrial and municipal waste streams. While in industrialized countries plastic waste is taken up by a waste management system and at least partly recycled, in low-income countries adequate infrastructure to collect and treat waste adequately is often not in place. This paper analyzes how plastic waste is handled in Vietnam, a country with a fast-growing industry and growing consumption. The recycling of plastic waste typically takes place in an informal context. To demonstrate this in more detail, two rural settlements-so-called craft villages-are taken as case studies. Technologies and processes for plastic recycling are described and related risks for human health and the environment are shown, as well as the potential for the improvement of this situation.

Accelerated remediation of organochlorine pesticide-contaminated soils with phyto-Fenton approach: a field study.

Phytoremediation and advanced oxidation processes are among the most promising techniques for removing organic pollutants from soils. A field trial was performed for six months to evaluate the effect of nano-Fe3O4 on the degradation of organochlorine pesticide residues including Lindane, p,p'-dichlorodiphenyltrichloroethane (DDT), p,p'-dichlorodiphenyldichloroethylene (DDE), and p,p'-dichlorodiphenyldichloroethane (DDD) in pesticide-contaminated soils in the presence of vetiver in Bac Giang province, Vietnam. Vetiver was planted in three zones with different nano-Fe3O4 concentrations. Soil samples from each zone were periodically collected to determine the remaining concentrations of selected organochlorine pesticides via gas chromatography-electron capture detector. Results indicated that the total DDT concentrations in the examined soil were 1.9-13 times higher than the permissible threshold level (10 µg g-1) established by the national technical regulation on pesticide residues in soil. The (p,p'-DDE + p,p'-DDD)/p,p'-DDT ratios ranged from 13.5 to 114, indicating the absence of recent inputs of technical DDTs at the study area. DDT dechlorination mainly occurred under aerobic pathways to form DDE. Furthermore, DDE degradation in soil was adequately described by the pseudo-first-order kinetics model (R2 > 0.892). In the presence of vetiver, the rate constants of DDE degradation were 0.264, 0.350, and 0.434 month-1 with 0, 25, and 100 mg kg-1 of added nano-Fe3O4, respectively, indicating that the degradation of DDE correlated positively with Fe3O4 concentration in the soil. Additionally, the presence of vetiver and nano-Fe3O4 in the soil increased DDT removal rates, which might be linked to the involvement of Fenton/Fenton-like reactions.

Ectonucleotide pyrophosphatase 2 (ENPP2) plays a crucial role in myogenic differentiation through the regulation by WNT/ß-Catenin signaling.

Ectonucleotide pyrophosphate phosphodiesterase type II (ENPP2), also known as Autotaxin (ATX), is an enzyme present in blood circulation that converts lysophosphatidyl choline (LPC) to lysophosphatidic acid (LPA). While LPA has been demonstrated to play diverse roles in skeletal myogenesis, mainly through in vitro studies, the role of ENPP2 in skeletal myogenesis has not been determined. We previously found that Enpp2 is induced by a positive WNT/ß-Catenin signaling regulator, R-spondin2 (RSPO2), in C2C12 myoblast cells. As RSPO2 promotes myogenic differentiation via the WNT/ß-Catenin signaling pathway, we hypothesized that ENPP2 may act as a key mediator for the crosstalk between WNT and LPA signaling during myogenic differentiation. Herein, we found that ENPP2 function is essential for myogenic differentiation in C2C12 cells. Pharmacological ENPP2 inhibitors or RNAi-mediated Enpp2 gene knockdown severely impaired the myogenic differentiation, including the cell fusion process, whereas administration of the recombinant ENPP2 protein enhanced myogenic differentiation. Consistent with the in vitro results, mice lacking the Enpp2 gene showed a disrupted muscle regeneration after acute muscle injury. The size of newly regenerated myofibers in Enpp2 mutant muscle was significantly reduced compared with wild-type regenerated muscle. Modified expression patterns of myogenic markers in Enpp2 mutant muscle further emphasized the impaired muscle regeneration process. Finally, we convincingly demonstrate that the Enpp2 gene is a direct transcriptional target for WNT/ß-Catenin signaling. Functional TCF/LEF1 binding sites within the upstream region of Enpp2 gene were identified by chromatin immunoprecipitation using anti-ß-Catenin antibodies and reporter assay. Our study reveals that ENPP2 is regulated by WNT/ß-Catenin signaling and plays a key positive role in myogenic differentiation.

Daily Oscillation of the Excitation-Inhibition Balance in Visual Cortical Circuits.

A balance between synaptic excitation and inhibition (E/I balance) maintained within a narrow window is widely regarded to be crucial for cortical processing. In line with this idea, the E/I balance is reportedly comparable across neighboring neurons, behavioral states, and developmental stages and altered in many neurological disorders. Motivated by these ideas, we examined whether synaptic inhibition changes over the 24-h day to compensate for the well-documented sleep-dependent changes in synaptic excitation. We found that, in pyramidal cells of visual and prefrontal cortices and hippocampal CA1, synaptic inhibition also changes over the 24-h light/dark cycle but, surprisingly, in the opposite direction of synaptic excitation. Inhibition is upregulated in the visual cortex during the light phase in a sleep-dependent manner. In the visual cortex, these changes in the E/I balance occurred in feedback, but not feedforward, circuits. These observations open new and interesting questions on the function and regulation of the E/I balance.

Reduced cognitive performance in aged rats correlates with increased excitation/inhibition ratio in the dentate gyrus in response to lateral entorhinal input.

Aging often impairs cognitive functions associated with the medial temporal lobe (MTL). Anatomical studies identified the layer II pyramidal cells of the lateral entorhinal cortex (LEC) as one of the most vulnerable elements within the MTL. These cells provide a major excitatory input to the dentate gyrus hippocampal subfield through synapses onto granule cells and onto local inhibitory interneurons, and a fraction of these contacts are lost in aged individuals with impaired learning. Using optogenetics, we evaluated the functional status of the remaining inputs in an outbred rat model of aging that distinguishes between learning-impaired and learning-unimpaired individuals. We found that aging affects the presynaptic and postsynaptic strength of the LEC inputs onto granule cells. However, the magnitude of these changes was similar in impaired and unimpaired rats. In contrast, the recruitment of inhibition by LEC activation was selectively reduced in the aged impaired subjects. These findings are consistent with the notion that the preservation of an adequate balance of excitation and inhibition is crucial to maintaining proficient memory performance during aging.

Complete Genome Sequences of 12 B1 Cluster Mycobacteriophages, Gareth, JangoPhett, Kailash, MichaelPhcott, PhenghisKhan, Phleuron, Phergie, PhrankReynolds, PhrodoBaggins, Phunky, Vaticameos, and Virapocalypse.

Twelve B1 cluster mycobacteriophages were isolated from soil samples collected in Philadelphia, PA, USA, using Mycobacterium smegmatis mc2 155 as a host, and were sequenced. The genome sequences range in size from 66,887 bp to 68,953 bp in length and have between 99 and 105 putative protein-coding genes.

Ionic current correlations are ubiquitous across phyla.

Ionic currents, whether measured as conductance amplitude or as ion channel transcript numbers, can vary many-fold within a population of identified neurons. In invertebrate neuronal types multiple currents can be seen to vary while at the same time their magnitudes are correlated. These conductance amplitude correlations are thought to reflect a tight homeostasis of cellular excitability that enhances the robustness and stability of neuronal activity over long stretches of time. Although such ionic conductance correlations are well documented in invertebrates, they have not been reported in vertebrates. Here we demonstrate with two examples, identified mouse hippocampal granule cells (GCs) and cholinergic basal forebrain neurons, that the correlation of ionic conductance amplitudes between different ionic currents also exists in vertebrates, and we argue that it is a ubiquitous phenomenon expressed by many species across phyla. We further demonstrate that in dentate gyrus GCs these conductance correlations are likely regulated in a circadian manner. This is reminiscent of the known conductance regulation by neuromodulators in crustaceans. However, in GCs we observe a more nuanced regulation, where for some conductance pairs the correlations are completely eliminated while for others the correlation is quantitatively modified but not obliterated.

Enhanced postsynaptic inhibitory strength in hippocampal principal cells in high-performing aged rats.

Hyperactivity within the hippocampal formation, frequently observed in aged individuals, is thought to be a potential contributing mechanism to the memory decline often associated with aging. Consequently, we evaluated the postsynaptic strength of excitatory and inhibitory synapses in the granule cells of the dentate gyrus and CA1 pyramidal cells of a rat model of aging, in which each individual was behaviorally characterized as aged impaired (AI) or aged unimpaired (AU, with performance comparable to young (Y) individuals). In hippocampal slices of these 3 aged groups (Y, AI, AU), we found that compared to the young, the miniature excitatory and inhibitory currents (mEPSCs and mIPSCs) were larger in amplitude in the granule cells of the AU group and smaller in the AI group. In contrast, in CA1 cells, neither the mEPSCs nor the mIPSCs were affected by age, whereas the extrasynaptic conductance responsible for tonic inhibition was selectively enhanced in CA1 cells of AU individuals. Tonic inhibition conductance was not affected by age in the granule cells. These results support the notion that upregulation of synaptic inhibition could be a necessary condition for the maintenance of performance during aging. These findings also underscore the notions that successful aging requires adaptive upregulation, not merely the preservation of youthful functionality, and that age effects are not homogeneous across hippocampal subfields.

Two distinct mechanisms for experience-dependent homeostasis.

Models of firing rate homeostasis such as synaptic scaling and the sliding synaptic plasticity modification threshold predict that decreasing neuronal activity (for example, by sensory deprivation) will enhance synaptic function. Manipulations of cortical activity during two forms of visual deprivation, dark exposure (DE) and binocular lid suture, revealed that, contrary to expectations, spontaneous firing in conjunction with loss of visual input is necessary to lower the threshold for Hebbian plasticity and increase miniature excitatory postsynaptic current (mEPSC) amplitude. Blocking activation of GluN2B receptors, which are upregulated by DE, also prevented the increase in mEPSC amplitude, suggesting that DE potentiates mEPSCs primarily through a Hebbian mechanism, not through synaptic scaling. Nevertheless, NMDA-receptor-independent changes in mEPSC amplitude consistent with synaptic scaling could be induced by extreme reductions of activity. Therefore, two distinct mechanisms operate within different ranges of neuronal activity to homeostatically regulate synaptic strength.

Complete Genome Sequence of Cluster J Mycobacteriophage Superphikiman.

Mycobacteriophage Superphikiman is a cluster J bacteriophage which was isolated from soil collected in Philadelphia, PA. Superphikiman has a 109,799-bp genome with 239 predicted genes, including 2 tRNA genes.

Endogenous Gαq-Coupled Neuromodulator Receptors Activate Protein Kinase A.

Protein kinase A (PKA) integrates inputs from G-protein-coupled neuromodulator receptors to modulate synaptic and cellular function. Gαs signaling stimulates PKA activity, whereas Gαi inhibits PKA activity. Gαq, on the other hand, signals through phospholipase C, and it remains unclear whether Gαq-coupled receptors signal to PKA in their native context. Here, using two independent optical reporters of PKA activity in acute mouse hippocampus slices, we show that endogenous Gαq-coupled muscarinic acetylcholine receptors activate PKA. Mechanistically, this effect is mediated by parallel signaling via either calcium or protein kinase C. Furthermore, multiple Gαq-coupled receptors modulate phosphorylation by PKA, a classical Gαs/Gαi effector. Thus, these results highlight PKA as a biochemical integrator of three major types of GPCRs and necessitate reconsideration of classic models used to predict neuronal signaling in response to the large family of Gαq-coupled receptors.

A83-01 inhibits TGF-ß-induced upregulation of Wnt3 and epithelial to mesenchymal transition in HER2-overexpressing breast cancer cells.

PURPOSE: The aim of this study is to investigate the mechanisms of interactions between TGF-ß and Wnt/ß-catenin pathways that induce and regulate EMT and promote breast cancer cells to become resistant to treatment. METHODS: The effect of TGF-ß on Wnt/ß-catenin signaling pathway was examined by using a human Wnt/ß-catenin-regulated cDNA plate array and western blot analysis. The interaction of Twist at promoter of Wnt3 was examined by chromatin immunoprecipitation (ChIP) assay. Secreted Wnt3 level was determined by ELISA assay. RESULTS: HER2-overexpressing breast cancer cells treated with TGF-ß have a reduced response to trastuzumab and exhibited EMT-like phenotype. The TGF-ß-induced EMT in HER2-cells was concordant with upregulation of Wnt3 and ß-catenin pathways. The TGF-ß-induced induction of Wnt3 during EMT was found to be Smad3-dependent. ChIP analysis identified occupancy of Twist at promoter region of Wnt3. Knock-down of Twist by shRNA confirmed the significance of Twist in response to TGF-ß regulating Wnt3 during EMT. Subsequently, TGF-ß-induced matrix metalloproteinases, MMP1, MMP7, MMP9, MMP26, Vascular endothelial growth factors (VEGF), and activation of Wnt/ß-catenin signaling were repressed by the shRNA treatment. TGF-ßR1 ALK5 kinase inhibitor, A83-01 can effectively prevent the TGF-ß-induced Twist and Wnt3. Co-treating A83-01 and trastuzumab inhibited TGF-ß-induced cell invasion significantly in both trastuzumab responsive and resistant cells. CONCLUSIONS: Our data demonstrated an important interdependence between TGF-ß and Wnt/ß-catenin pathways inducing EMT in HER2-overexpressing breast cancer cells. Twist served as a linkage between the two pathways during TGF-ß-induced EMT. A83-01 could inhibit the TGF-ß-initiated pathway interactions and enhance HER2-cells response to trastuzumab treatment.

Neuregulin-Dependent Regulation of Fast-Spiking Interneuron Excitability Controls the Timing of the Critical Period.

Maturation of excitatory drive onto fast-spiking interneurons (FS INs) in the visual cortex has been implicated in the control of the timing of the critical period for ocular dominance plasticity. However, the mechanisms that regulate the strength of these synapses over cortical development are not understood. Here we use a mouse model to show that neuregulin (NRG) and the receptor tyrosine kinase erbB4 regulate the timing of the critical period. NRG1 enhanced the strength of excitatory synapses onto FS INs, which inhibited ocular dominance plasticity during the critical period but rescued plasticity in transgenics with hypoexcitable FS INs. Blocking the effects of endogenous neuregulin via inhibition of erbBs rescued ocular dominance plasticity in postcritical period adults, allowing recovery from amblyopia induced by chronic monocular deprivation. Thus, the strength of excitation onto FS INs is a key determinant of critical period plasticity and is maintained at high levels by NRG-erbB4 signaling to constrain plasticity in adulthood. SIGNIFICANCE STATEMENT: Despite decades of experimentation, the mechanisms by which critical periods of enhanced synaptic plasticity are initiated and terminated are not completely understood. Here we show that neuregulin (NRG) and the receptor tyrosine kinase erbB4 determine critical period timing by controlling the strength of excitatory synapses onto FS INs. NRG1 enhanced excitatory drive onto fast spiking interneurons, which inhibited ocular dominance plasticity in juveniles but rescued plasticity in transgenics with hypoexcitable FS INs. Blocking the effects of endogenous neuregulin via inhibition of erbBs rescued ocular dominance plasticity in adults, allowing recovery from amblyopia induced by chronic monocular deprivation. Thus, in contrast to prevailing views of the termination of the critical period, active maintenance of strong excitation onto FS INs constrains plasticity in adults.