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The recruitment of inhibitory GABAA receptors to neuronal synapses requires a complex interplay between receptors, neuroligins, the scaffolding protein gephyrin and the GDP-GTP exchange factor collybistin (CB). Collybistin is regulated by protein-protein interactions at the N-terminal SH3 domain, which can bind neuroligins 2/4 and the GABAAR α2 subunit. Collybistin also harbors a RhoGEF domain which mediates interactions with gephyrin and catalyzes GDP-GTP exchange on Cdc42. Lastly, collybistin has a pleckstrin homology (PH) domain, which binds phosphoinositides, such as phosphatidylinositol 3-phosphate (PI3P/PtdIns3P) and phosphatidylinositol 4-monophosphate (PI4P/PtdIns4P). PI3P located in early/sorting endosomes has recently been shown to regulate the postsynaptic clustering of gephyrin and GABAA receptors and consequently the strength of inhibitory synapses in cultured hippocampal neurons. This process is disrupted by mutations in the collybistin gene (ARHGEF9), which cause X-linked intellectual disability (XLID) by a variety of mechanisms converging on disrupted gephyrin and GABAA receptor clustering at central synapses. Here we report a novel missense mutation (chrX:62875607C>T, p.R356Q) in ARHGEF9 that affects one of the two paired arginine residues in the PH domain that were predicted to be vital for binding phosphoinositides. Functional assays revealed that recombinant collybistin CB3SH3-R356Q was deficient in PI3P binding and was not able to translocate EGFP-gephyrin to submembrane microaggregates in an in vitro clustering assay. Expression of the PI3P-binding mutants CB3SH3-R356Q and CB3SH3-R356N/R357N in cultured hippocampal neurones revealed that the mutant proteins did not accumulate at inhibitory synapses, but instead resulted in a clear decrease in the overall number of synaptic gephyrin clusters compared to controls. Molecular dynamics simulations suggest that the p.R356Q substitution influences PI3P binding by altering the range of structural conformations adopted by collybistin. Taken together, these results suggest that the p.R356Q mutation in ARHGEF9 is the underlying cause of XLID in the probands, disrupting gephyrin clustering at inhibitory GABAergic synapses via loss of collybistin PH domain phosphoinositide binding. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this study was to examine the functional connectivity between the primary visual cortex and other cortical areas during rest in normal subjects and patients with comitant strabismus using functional magnetic resonance imaging (fMRI). Methods: A prospective, observational study was conducted. Ten patients with comitant exotropia and eleven matched healthy subjects underwent resting-state fMRI with their eyes closed. Resting-state fMRI was performed using a 3.0 T MR scanner. The primary visual cortex was subdivided into anterior and posterior subdivisions. The resting-state functional connectivities within the primary visual cortex and between the primary visual cortex and other cortical areas were calculated for each group and compared between the strabismic and normal control groups. fMRI data were analyzed using Statistical Parametric Mapping software and Analysis of Functional NeuroImages software. Results: Compared with the normal controls, patients with comitant strabismus had increased functional connectivity between the posterior primary visual cortex and other cortical areas, especially the visual cortex [Brodmann area 19 (BA19)] and other oculomotor regions, such as the frontal eye field (BA6). Conclusions: The fMRI results suggest that ongoing and permanent cortical changes occur in patients with comitant strabismus. Disrupted brain functional connectivities are associated with abnormal eye movement and loss of stereopsis. Our study provides a neurological basis for understanding the pathophysiology of comitant strabismus, which may prompt new areas of research to more precisely define this basis and extend these findings to enhance diagnosis and treatment. [ABSTRACT FROM AUTHOR]

Spontaneous neural activity has been widely adopted to construct functional connectivity (FC) amongst distant brain regions. Although informative, the functional role and signaling mechanism of the resting state FC are not intuitive as those in stimulus/task-evoked activity. In order to bridge the gap, we investigated anesthetic modulation of both resting-state and sensory-evoked activities. We used two well-studied GABAergic anesthetics of varying dose (isoflurane: 0.5-2.0% and α-chloralose: 30 and 60 mg/kg∙h) and recorded changes in electrophysiology using a pair of laminar electrode arrays that encompass the entire depth of the bilateral somatosensory cortices (S1fl) in rats. Specifically, the study focused to describe how varying anesthesia conditions affect the resting state activities and resultant FC between bilateral hemispheres in comparison to those obtained by evoked responses. As results, isoflurane decreased the amplitude of evoked responses in a dose-dependent manner mostly due to the habituation of repetitive responses. However, α-chloralose rather intensified the amplitude without exhibiting habituation. No such diverging trend was observed for the spontaneous activity, in which both anesthetics increased the signal power. For α-chloralose, overall FC was similar to that obtained with the lowest dose of isoflurane at 0.5% while higher doses of isoflurane displayed increased FC. Interestingly, only α-chloralose elicited relatively much greater increases in the ipsi-stimulus evoked response (i.e., in S1fl ipsilateral to the stimulated forelimb) than those associated with the contra-stimulus response, suggesting enhanced neuronal excitability. Taken together, the findings demonstrate modulation of the FC profiles by anesthesia is highly non-linear, possibly with a distinct underlying mechanism that affects either resting state or evoked activities differently. Further, the current study warrants thorough investigation of the basal neuronal states prior to the interpretation of resting state FC and evoked activities for accurate understanding of neural signal processing and circuitry., (© 2022. The Author(s).)

Sol immobilization is a relevant preparation method, particularly for the preparation of Pd‐based catalysts for the direct synthesis of H2O2. In this preparation, polyvinyl alcohol (PVA) acts as capping agent for Pd particles. Modelling the role of PVA on the Pd nanoparticle size and its promoting effect on the selectivity is important to understand better these catalysts. Here, Pd based catalysts prepared by sol immobilization have been tested in a semi‐batch reactor with an H2/O2 ratio ≈1, analysing the influence of the Pd nanoparticle size and the effect of PVA on the rate constants of the reaction network and their change during the reaction. A stepwise testing protocol coupled with transmission electron microscopy characterization as a function of reaction time has been used. These catalysts were compared with other catalysts prepared by hydrazine reduction and impregnation‐decomposition, where PVA is absent. The results are analysed in terms of rate constants for the various rates in the reaction network in relation with the Pd average particle size and related sites distribution, as a function of the changes occurring during extended catalytic tests. The SI‐series of catalysts (prepared by sol‐immobilization) shows enhanced properties, attributed to the effect of PVA capping agent in forming less defective Pd nanoparticles. This induces both a decrease of direct combustion and secondary hydrogenolysis reactions, and an enhancement of the direct synthesis route. The PVA layer limits H2O2 back‐diffusion with a negative influence on the productivity and selectivity, with its removal leading to initial enhanced performances, but in long‐term to a worsening due to sintering of Pd nanoparticles in extended operations. Straight to the point: The role of polyvinyl alcohol (PVA) capping agent for Pd nanoparticles active in H2O2 direct synthesis is studied and kinetically modelled to single out the different effects in modifying the catalytic performances. PVA enhances the properties leading to less defective Pd nanoparticles, inducing both a decrease of direct combustion and secondary hydrogenolysis reactions, and an enhancement of the direct synthesis route. [ABSTRACT FROM AUTHOR]

Longitudinal monitoring of tumor size in vivo can provide important biological information about disease progression and treatment efficacy that is not captured by other modes of quantification. Ultrasound enables high‐throughput evaluation of orthotopic mouse models via fast acquisition of three‐dimensional tumor images and calculation of volume with a reasonable degree of accuracy. Herein, we compare orthotopic pancreatic tumor volume measurements determined by ultrasound with volume measured by calipers and tumor weight, and found strong correlations between the three modalities over a large range of tumor sizes, suggesting ultrasound can accurately quantify tumor volumes in this model. Furthermore, we demonstrate the unique ability of longitudinal treatment monitoring to reveal a tumor size‐dependent response to Benzoporphyrin Derivative photodynamic therapy (BPD‐PDT) and irinotecan. Small tumors (5–35 mm3) were found to respond well to a single round of PDT, while large tumors (35–65 mm3) showed no response to the same treatment. These results highlight the role that tumor size can play in preclinical interpretation of treatment response and more generally suggest that careful evaluation of subtle biological features such as this must be carefully considered in order to grant a more comprehensive understanding of disease biology in vivo. Tumor volume measured by ultrasound agrees well with volume measured by calipers and tumor weight in an orthotopic mouse model of pancreatic cancer. Using ultrasound to noninvasively monitor tumor growth longitudinally, a size‐dependent response to photodynamic therapy (PDT) and low dose irinotecan is revealed. Small tumors respond to each monotherapy, while large ones only to their synergistic combination. [ABSTRACT FROM AUTHOR]

From the earliest days of heterogeneous catalysis, high surface area solids were extensively used for attaining largest possible densities of active sites and, correspondingly, for maximizing turnover. Since sites are active in the real sense of the word only if they are occupied by reactants, i. e. by molecules still to be converted, the relative fraction of pore volume occupied by reactants (the "effectiveness factor") is a key number for the efficiency of a catalyst in a given reaction. Its determination, so far generally based on reaction rate measurements with purposefully varied catalyst particles, remained to date a challenging task since it must be based on additional assumptions. The "one‐shot determination" of effectiveness factors by IR microimaging, here exemplified on considering the catalytic hydrogenation of benzene to cyclohexane by platinum dispersed on nanoporous glass, is shown to open up a promising route to overcome these limitations. You got one shot! IR microimaging is shown to allow the determination of the effectiveness factor η of a chemical reaction within a porous catalyst during a single experiment ("one‐shot" measurement), exemplified by considering the hydrogenation of benzene to cyclohexane within platinum‐containing nanoporous glass beads. [ABSTRACT FROM AUTHOR]

On our way through a town, the things we see can make us change the way we go. The things that we hear can make us stop or walk on, or the things we feel can cause us to wear a warm jacket or just a t-shirt. All these behaviors are mediated by highly complex processing mechanisms in our brain and reflect responses to many important sensory inputs. The mammalian cerebral cortex, which processes the sensory information, consists of largely specialized sensory areas mainly receiving information from their corresponding sensory modalities. The first cortical regions receiving the input from the outer world are the so called primary sensory cortices. Strikingly, there is convincing evidence that primary sensory cortices do not work in isolation but are substantially affected by other sensory modalities. Here, we will review previous and current literature on this cross-modal interplay. [ABSTRACT FROM AUTHOR]

Recent advances in cellular analysis revealed that the seemingly identical cells are heterogeneous in term of functionality, compositions, and genetic performance. These differences cause difficulty in the diagnostic for a specific model of disease. Detection of biomolecules such as DNA, RNA, and protein or analysis of cell(s), detection of cell surface molecules, and secreted protein, can help us to improve the understanding of a targeted disease and development of new diagnostic and therapeutic approaches. A single‐cell includes the minute quantity of these target molecules. Microfluidic devices have the ability to capture a single‐cell and its lysate into a pico or femtoliter volumes droplet, or micro‐well thus preventing dilution and limiting diffusion. In this review we described the advancement and limitations in microfluidic techniques used toward single‐cells analysis. In systematic life sciences, in order to obtain mammalian tissue and then crushing it to a single‐cell for analysis using microfluidic platform five major levels can be categorized. The isolated single‐cells are prone to on‐chip or off‐chip analysis for the targeted biomolecules. [ABSTRACT FROM AUTHOR]

Lactate, a product of aerobic glycolysis in astrocytes, is required for memory formation and consolidation, and has recently emerged as a signaling molecule for neurons and various cell types in peripheral tissues. In particular lactate stimulates mRNA expression of a few plasticity-related genes. Here, we describe a RNA-seq study that unravels genome-wide transcriptomic responses to this energy metabolite in cortical neurons. Our results show that mRNA expression of 20 immediate-early genes involved in the MAPK signaling pathway and in synaptic plasticity were increased by more than twofold following 1 h of lactate stimulation. This effect was dependent on NMDA receptor (NMDAR) activity since it was prevented by pre-treatment with MK-801. Comparison with published datasets showed that a significant proportion of genes modulated by lactate were similarly regulated by a stimulation protocol activating specifically synaptic NMDARs known to result in upregulation of pro-survival and downregulation of pro-death genes. Remarkably, transcriptional responses to lactate were reproduced by NADH (for 74 of the 113 genes, FDR < 0.05), suggesting a redox-dependent mechanism of action. Longer-term gene expression changes observed after 6 h of lactate treatment affected genes involved in regulating neuronal excitability and genes coding for proteins localized at synapses. Gene set enrichment analyses performed with ranked lists of expressed genes revealed effects on molecular functions involved in epigenetic modulation, and on processes relevant to sleep physiology and behavioral phenotypes such as anxiety and hyperactivity. Overall, these results strengthen the notion that lactate effectively regulates activity-dependent and synaptic genes, and highlight new signaling effects of lactate in plasticity and neuroprotection. [ABSTRACT FROM AUTHOR]

Pulsed laser excitation of NO2 (532-647 nm) or NO3 (623-662 nm) in the presence of H2O was used to initiate the gas-phase reaction NO*2 CH2O → products (Reaction R5) and NO*3 CH2O → products (Reaction R12). No evidence for OH production in Reactions (R5) or (R12) was observed and upper limits for OH production of k5b/k5 < 1 x 10-5 and k12b/k12 < 0:03 were assigned. The upper limit for k5b/k5 renders this reaction insignificant as a source of OH in the atmosphere and extends the studies (Crowley and Carl, 1997; Carr et al., 2009; Amedro et al., 2011) which demonstrate that the previously reported large OH yield by Li et al. (2008) was erroneous. The upper limit obtained for k12b/k12 indicates that non-reactive energy transfer is the dominant mechanism for Reaction (R12), though generation of small but significant amounts of atmospheric HOx and HONO cannot be ruled out. In the course of this work, rate coefficients for overall removal of NO*3 by N2 (Reaction R10) and by H2O (Reaction R12) were determined: k10 = (2.1±0.1)x 10-11 cm³ molecule-1 s-1 and k12 = (1.6±0.3)x 10-10 cm³ molecule-1 s-1. Our value of k12 is more than a factor of 4 smaller than the single previously reported value. [ABSTRACT FROM AUTHOR]

The flow in a liquid plug moving in an annular pipe is analytically solved. The interaction with the two concentric walls of the annular pipe results in two toroidal vortexes within the concentric plug. Focus is put on long plugs with aspect ratio β > 2, which have vortex circulation flow rates and volume ratio independent of the plug length. Based on the analytical results, correlations are derived for the circulation flow rates of the plug and each vortex and for the volume ratio of the two vortexes. Correlations are also developed for evaluating the radial transport of the plug flow. The friction factor for concentric plugs is a function of the aspect ratio and the radius ratio. For very long plugs with β ≫ 1, the friction factor approaches that of the fully developed continuous flow in the annular pipe. [ABSTRACT FROM AUTHOR]

The amide bond formation is of paramount importance in organic synthesis, both within academic research and industrial development and manufacturing of pharmaceutical chemicals and other biologically active compounds. Despite this fact, as well as the ever‐increasing treatment costs of side streams and other environmental concerns regarding handling and transportation of hazardous reagents, contemporary synthesis has elicited few new reactions and methods for the preparation of amides. Herein, we reveal a high yielding and expedite two‐step telescoped synthetic process that comprises a domino oxidative amidation and transamidation for the creation of amides. The process utilizes alcohols and amines as reaction pairs with TEMPO and Fe ions as catalytic system and 1,3‐dichloro‐5,5‐dimethyl hydantoin as a terminal oxidant. The oxidative amidation and transamidation process is conducted under benign reaction conditions and short reaction time (≈ 30 min.) in a two‐step telescoped fashion by means of a multi‐jet oscillating disk (MJOD) continuous‐flow reactor platform. The disclosed process integrates alcohol oxidation and amide formation to afford target amide in yields up to 90 %. The method operates with both primary and secondary amines together, but was hampered when bulky amines and/or alcohols were used as reagent/substrate. [ABSTRACT FROM AUTHOR]

Abstract: In recent years there has been huge interest in the development of microfluidic reactors for the synthesis of small molecules and nanomaterials. Such reaction platforms represent a powerful and versatile alternative to traditional formats since they allow for the precise, controlled, and flexible management of reactive processes. To date, the majority of microfluidic reactors used in small‐molecule synthesis have been manufactured using conventional lithographic techniques from materials such as glasses, ceramics, stainless steel, and silicon. Surprisingly, the fabrication of microfluidic devices from such rigid materials remains ill‐defined, complex, and expensive. Accordingly, the microfluidic toolkit for chemical synthesis would significantly benefit from the development of solvent‐resistant microfluidic devices that can be manufactured using soft‐lithographic prototyping methods. Whilst significant advances in the development of solvent‐resistant polymers have been made, only modest steps have been taken towards simplifying their use as microfluidic reactors. Herein, we emphasize the benefits of using a commercially available, amorphous perfluorinated polymer, CYTOP, as a coating with which to transform PDMS into a chemically inert material for use in organic synthesis applications. Its efficacy is demonstrated through the subsequent performance of photooxidation reactions and reactions under extremely acidic or basic conditions. [ABSTRACT FROM AUTHOR]

Geoffroy’s cat (Leopardus geoffroyi) is a small Neotropical felid whose social behavior remains poorly understood. We used simultaneous radiotelemetry (4 males and 3 females) and camera trapping to examine the spatial structure and dynamics of a population of this species in the Brazilian pampas (part of the Uruguayan Savannah ecoregion), including assessment of interindividual genetic relatedness. Home ranges (HRs) and core areas of males were larger than those of females. Males were significantly heavier than females, and linear regression analyses indicated that body mass of males significantly influenced HR size, whereas the relationship was not significant for females. When we performed a joint analysis comparing our data to those reported previously for other study sites, we observed the same patterns. We detected extensive HR and core area overlap among most of our monitored individuals, with no clear sex-based pattern. Moreover, our molecular data indicated that most of the sampled individuals were unrelated, and that the levels of HR and core area overlap were not significantly influenced by genetic relatedness. These results suggest that some interindividual tolerance and relaxation in territoriality may occur in Geoffroy’s cat. We detected only minor changes in HR and core area size and overlap between seasons, indicating that the spatial structure we observed was temporally stable. On a broader perspective, our cross-site comparisons illustrate the usefulness of performing multiple ecological studies employing comparable methods at different locations to better understand the ecology of wild felid populations. A espécie Leopardus geoffroyi é um felídeo neotropical de pequeno porte, cujo comportamento social é ainda pouco conhecido. O presente estudo examinou a estrutura e a dinâmica espacial de uma população dessa espécie, incluindo a primeira avaliação da relação de parentesco entre seus indivíduos. Além disso, os tamanhos de áreas de vida e a massa corporal da população estudada foram comparados estatisticamente com os resultados de estudos prévios, gerando dados globais para a espécie. O trabalho de campo foi conduzido entre novembro de 2013 e setembro de 2015, em propriedades rurais localizadas na Serra do Caverá, sul do Brasil (na ecorregião da Savana Uruguai). Foram registradas 516 imagens de L. geoffroyi e foram capturados 12 indivíduos desta espécie, sete (4M e 3F) dos quais puderam ser monitorados com rádio-telemetria. Observou-se que os machos possuem áreas de vida, de uso e massa corporal maiores do que as fêmeas. Os resultados das análises de regressão linear indicaram que a massa corporal dos machos influenciou positiva e significativamente o tamanho das áreas de vida dos mesmos, relação esta que não ocorreu entre as fêmeas. Esse resultado ocorreu tanto na população estudada como nos dados globais. Também foi observada uma extensa sobreposição de áreas de vida e de uso, indicando algum grau de socialidade (tolerância) nesta população. Os resultados da análise de parentesco indicaram que a maioria dos indivíduos capturados desta população não eram parentes. Além disso, a relação genética parece não influenciar a sobreposição de área de vida, o que sugere que esta população, na escala estudada, possui uma estrutura sócio-espacial distinta da proposição tradicional na qual os machos tenderiam a dispersar por maiores distâncias e as fêmeas seriam filopátricas. Em uma perspectiva mais ampla, as comparações aqui apresentadas ilustram a utilidade de se realizar estudos ecológicos empregando métodos comparáveis ​​em diferentes locais, a fim de entender melhor a ecologia das populações de felídeos silvestres. [ABSTRACT FROM AUTHOR]

During mammalian retinal development, the multipotent progenitors differentiate into all classes of retinal cells under the delicate control of transcriptional factors. The deficiency of a transcription cofactor, the LIM-domain binding protein Ldb1, has been shown to cause proliferation and developmental defects in multiple tissues including cardiovascular, hematopoietic, and nervous systems; however, it remains unclear whether and how it regulates retinal development. By expression profiling, RNA in situ hybridization and immunostaining, here we show that Ldb1 is expressed in the progenitors during early retinal development, but later its expression gradually shifts to non-photoreceptor cell types including bipolar, amacrine, horizontal, ganglion, and Müller glial cells. Retina-specific ablation of Ldb1 in mice resulted in microphthalmia, optic nerve hypoplasia, retinal thinning and detachment, and profound vision impairment as determined by electroretinography. In the mutant retina, there was precocious differentiation of amacrine and horizontal cells, indicating a requirement of Ldb1 in maintaining the retinal progenitor pool. Additionally, all non-photoreceptor cell types were greatly reduced which appeared to be caused by a generation defect and/or retinal degeneration via excessive cell apoptosis. Furthermore, we showed that misexpressed Ldb1 was sufficient to promote the generation of bipolar, amacrine, horizontal, ganglion, and Müller glial cells at the expense of photoreceptors. Together, these results demonstrate that Ldb1 is not only necessary but also sufficient for the development and/or maintenance of non-photoreceptor cell types, and implicate that the pleiotropic functions of Ldb1 during retinal development are context-dependent and determined by its interaction with diverse LIM-HD (LIM-homeodomain) and LMO (LIM domain-only) binding protein partners. [ABSTRACT FROM AUTHOR]

Infantile strabismus impairs the perception of all attributes of the visual scene. High spatial frequency components are no longer visible, leading to amblyopia. Binocularity is altered, leading to the loss of stereopsis. Spatial perception is impaired as well as detection of vertical orientation, the fastest movements, directions of movement, the highest contrasts and colors. Infantile strabismus also affects other vision-dependent processes such as control of postural stability. But presently, rehabilitative therapies for infantile strabismus by ophthalmologists, orthoptists and optometrists are restricted to preventing or curing amblyopia of the deviated eye, aligning the eyes and, whenever possible, preserving or restoring binocular vision during the critical period of development, i.e., before ~10 years of age. All the other impairments are thus ignored; whether they may recover after strabismus treatment even remains unknown. We argue here that medical and paramedical professionals may extend their present treatments of the perceptual losses associated with infantile strabismus. This hypothesis is based on findings from fundamental research on visual system organization of higher mammals in particular at the cortical level. In strabismic subjects (as in normal-seeing ones), information about all of the visual attributes converge, interact and are thus inter-dependent at multiple levels of encoding ranging from the single neuron to neuronal assemblies in visual cortex. Thus if the perception of one attribute is restored this may help to rehabilitate the perception of other attributes. Concomitantly, vision-dependent processes may also improve. This could occur spontaneously, but still should be assessed and validated. If not, medical and paramedical staff, in collaboration with neuroscientists, will have to break new ground in the field of therapies to help reorganize brain circuitry and promote more comprehensive functional recovery. Findings from fundamental research studies in both young and adult patients already support our hypothesis and are reviewed here. For example, presenting different contrasts to each eye of a strabismic patient during training sessions facilitates recovery of acuity in the amblyopic eye as well as of 3D perception. Recent data also demonstrate that visual recoveries in strabismic subjects improve postural stability. These findings form the basis for a roadmap for future research and clinical development to extend presently applied rehabilitative therapies for infantile strabismus. [ABSTRACT FROM AUTHOR]

Abstract: The temporal closure of one eye in juvenile and young adult mice induces a shift of the ocular dominance (OD) of neurons in the binocular visual cortex. However, OD plasticity typically declines with age and is completely absent in matured mice beyond postnatal day (PD) 110. As it has been shown that the deprivation of one sensory input can induce neuronal alterations in non‐deprived sensory cortices, we here investigated whether cross‐modal interactions have the potential to reinstall OD plasticity in matured mice. Strikingly, using intrinsic signal imaging we could demonstrate that both whisker deprivation and auditory deprivation for only one week reinstated OD plasticity in fully adult mice. These OD shifts were always mediated by an increase of V1 responsiveness to visual stimulation of the open eye, a characteristic feature of OD plasticity normally only found in young adult mice. Moreover, systemic administration of the competitive NMDA receptor antagonist CPP completely abolished cross‐modally induced OD plasticity. Taken together, we demonstrate here for the first time that the deprivation of non‐visual senses has the potential to rejuvenate the adult visual cortex. [ABSTRACT FROM AUTHOR]

The term neurodevelopmental disorder (NDD) is an umbrella term used to group together a heterogeneous class of disorders characterized by disruption in cognition, emotion, and behavior, early in the developmental timescale. These disorders are heterogeneous, yet they share common behavioral symptomatology as well as overlapping genetic contributors, including proteins involved in the formation, specialization, and function of synaptic connections. Advances may arise from bridging the current knowledge on synapse related factors indicated from both human studies in NDD populations, and in animal models. Mounting evidence has shown a link to inhibitory synapse formation, specialization, and function among Autism, Angelman, Rett and Dravet syndromes. Inhibitory signaling is diverse, with numerous subtypes of inhibitory interneurons, phasic and tonic modes of inhibition, and the molecular and subcellular diversity of GABAA receptors. We discuss common ribs of inhibitory synapse dysfunction in the umbrella of NDD, highlighting alterations in the developmental switch to inhibitory GABA, dysregulation of neuronal activity patterns by parvalbumin-positive interneurons, and impaired tonic inhibition. Increasing our basic understanding of inhibitory synapses, and their role in NDDs is likely to produce significant therapeutic advances in behavioral symptom alleviation for interrelated NDDs. [ABSTRACT FROM AUTHOR]

Functional magnetic resonance imaging (fMRI) is widely used in investigations of normal cognition and brain disease and in various clinical applications. Pharmacological fMRI (pharma-fMRI) is a relatively new application, which is being used to elucidate the effects and mechanisms of pharmacological modulation of brain activity. Characterizing the effects of neuropharmacological agents on regional brain activity using fMRI is challenging because drugs modulate neuronal function in a wide variety of ways, including through receptor agonist, antagonist, and neurotransmitter reuptake blocker events. Here we review current knowledge on neurotransmitter-mediated blood-oxygen-level dependent (BOLD) fMRI mechanisms as well as recently updated methodologies aimed at more fully describing the effects of neuropharmacologic agents on the BOLD signal. We limit our discussion to dopaminergic signaling as a useful lens through which to analyze and interpret neurochemical-mediated changes in the hemodynamic BOLD response. We also discuss the need for future studies that use multi-modal approaches to expand the understanding and application of pharma-fMRI. [ABSTRACT FROM AUTHOR]

Abstract: In this study, the technology of micro‐segmented flow was applied for continuous synthesis safely and shape control accurately to lead trinitroresorcinate (LTNR) particles. Besides, a micro chemical reaction and crystallization system were built. Crystal shape control technology of LTNR and micro‐segmented flow technology were first combined using the system. Additionally, the effects of the flowing rate and chemical additives on LTNR micro‐particles preparation were researched for shape control. The LTNR micro‐particles were analyzed by XRD, DSC, laser scanning confocal microscope and laser particle size analyzer. The results shows that the LTNR particles size can be controlled from 20 to 400 μm by the flow rate and the concentration of hexadecyl trimethyl ammonium bromide (CTAB), while the shape of LTNR can be controlled by the concentration of glycerol and CTAB. Besides, there is a good linear relationship between the size and the activation energy. This illustrates that the LTNR particles with smaller size are more stable and have higher heat release. This study demonstrated the power of micro‐segmented flow for generation of LTNR micro‐particles with high quality and for tuning of particle properties. [ABSTRACT FROM AUTHOR]

Abstract: A particle suspended in a fluid within a microfluidic channel experiences a direct acoustic radiation force (ARF) when traveling surface acoustic waves (TSAWs) couple with the fluid at the Rayleigh angle, thus producing two components of the ARF. Most SAW‐based microfluidic devices rely on the horizontal component of the ARF to migrate prefocused particles laterally across a microchannel width. Although the magnitude of the vertical component of the ARF is more than twice the magnitude of the horizontal component, it is long ignored due to polydimethylsiloxane (PDMS) microchannel fabrication limitations and difficulties in particle focusing along the vertical direction. In the present work, a single‐layered PDMS microfluidic chip is devised for hydrodynamically focusing particles in the vertical plane while explicitly taking advantage of the horizontal ARF component to slow down the selected particles and the stronger vertical ARF component to push the particles in the upward direction to realize continuous particle separation. The proposed particle separation device offers high‐throughput operation with purity >97% and recovery rate >99%. It is simple in its fabrication and versatile due to the single‐layered microchannel design, combined with vertical hydrodynamic focusing and the use of both the horizontal and vertical components of the ARF. [ABSTRACT FROM AUTHOR]

In recent years, a broad range of nanocrystals have been synthesized in droplet-based microfluidic reactors which provide obvious advantages, such as accurate manipulation, better reproducibility and reliable automation. In this review, we initially introduce general concepts of droplet reactors followed by discussions of their main functional regions including droplet generation, mixing of reactants, reaction controlling, in situ monitoring, and reaction quenching. Subsequently, the enhanced mass and heat transport properties are discussed. Next, we focus on research frontiers including sequential multistep synthesis, intelligent synthesis, reliable scale-up synthesis, and interfacial synthesis. Finally, we end with an outlook on droplet reactors, especially highlighting some aspects such as large-scale production, the integrated process of synthesis and post-synthetic treatments, automated droplet reactors with in situ monitoring and optimizing algorithms, and rapidly developing strategies for interfacial synthesis. [ABSTRACT FROM AUTHOR]

Polymer particles are promising particulate materials for renowned biomedical applications such as targeted drug delivery, tissue engineering, and biosensing. Surface properties of the polymer particles are of key importance for biomedical applications because they directly interact with biological systems. Particularly, wrinkled as well as porous surfaces possess an enhanced ability for cell attachment without any additional chemical modification. Therefore, a key objective is to fabricate the particles with desired degree of wrinkles and porosity. Many methods such as solvent evaporation, plasma treatment, emulsion instability, and electrospraying are being employed for the generation of porous, wrinkled and/or textured surfaces. Advantageously, an application of microfluidics can support the induction of surface instabilities on droplets in a case of droplet-based systems. Furthermore, microfluidics allows tuning of size and shape of the generated droplets as well as particles with desired surface textures. In this minireview article, surface characteristics (especially surface wrinkles and porosity) of the hydrophobic and hydrophilic polymer particles are presented for the potential applications toward biological as well as biomedical field. In addition, the impact of microfluidics is highlighted in order to produce the polymer particles of functional surface properties. [ABSTRACT FROM AUTHOR]

Radical decarboxylation has emerged as an attractive method for the formation of C-C bonds starting from easily accessible carboxylic acids. In this review, we attempt to bring the readers up to date in this rapidly expanding field. Specifically, we will cover recent advances in Csp3-C bond formation via the radical decarboxylation of aliphatic carboxylic acids and their activated forms, such as N-hydroxyphthalimide esters (NHP esters), alkyl diacyl peroxides, alkyl peresters, and aryliodine(III) dicarboxylates. The scope and limitation of these transformations will be discussed, highlighting gaps in knowledge and research and examining the mechanisms underlying radical decarboxylation. We aim to make this review a stepping stone for further development in this field. 1 Introduction 2 Aliphatic Carboxylic Acids 3 N-Hydroxyphthalimide Esters (NHP Esters) 4 Alkyl Diacyl Peroxides 5 Alkyl Peresters 6 Aryliodine(III) Dicarboxylates 7 Conclusion [ABSTRACT FROM AUTHOR]

Colloidal organic/inorganic metal-halide perovskite nanocrystals have recently emerged as a potential low-cost replacement for the semiconductor materials in commercial photovoltaics and light emitting diodes. However, unlike III–V and IV–VI semiconductor nanocrystals, studies of colloidal perovskite nanocrystals have yet to develop a fundamental and comprehensive understanding of nucleation and growth kinetics. Here, we introduce a modular and automated microfluidic platform for the systematic studies of room-temperature synthesized cesium–lead halide perovskite nanocrystals. With abundant data collection across the entirety of four orders of magnitude reaction time span, we comprehensively characterize nanocrystal growth within a modular microfluidic reactor. The developed high-throughput screening platform features a custom-designed three-port flow cell with translational capability for in situ spectral characterization of the in-flow synthesized perovskite nanocrystals along a tubular microreactor with an adjustable length, ranging from 3 cm to 196 cm. The translational flow cell allows for sampling of twenty unique residence times at a single equilibrated flow rate. The developed technique requires an average total liquid consumption of 20 μL per spectra and as little as 2 μL at the time of sampling. It may continuously sample up to 30 000 unique spectra per day in both single and multi-phase flow formats. Using the developed plug-and-play microfluidic platform, we study the growth of cesium lead trihalide perovskite nanocrystals through in situ monitoring of their absorption and emission band-gaps at residence times ranging from 100 ms to 17 min. The automated microfluidic platform enables a systematic study of the effect of mixing enhancement on the quality of the synthesized nanocrystals through a direct comparison between single- and multi-phase flow systems at similar reaction time scales. The improved mixing characteristics of the multi-phase flow format results in high-quality perovskite nanocrystals with kinetically tunable emission wavelength, ranging as much as 25 nm at equivalent residence times. Further application of this unique platform would allow rapid parameter optimization in the colloidal synthesis of a wide range of nanomaterials (e.g., metal or semiconductor), that is directly transferable to continuous manufacturing in a numbered-up platform with a similar characteristic length scale. [ABSTRACT FROM AUTHOR]

The unique electrical, optical and biological properties of silver nanomaterials have attracted significant attention of many researchers. Since the size and shape of silver nanomaterials have significant effects on the properties of silver nanomaterials, extensive research has focused on synthesis and characterization of silver nanomaterials. However, almost all of the syntheses of silver nanomaterials were carried out in traditional batch reactors, which typically suffer from inhomogeneous mixing and corresponding spatial variations under reaction conditions, ultimately leading to poor quality of the final nanomaterials. Recently, the emerging microfluidic technology not only furnishes novel strategies for the synthesis of silver nanomaterials but also brings great opportunities and impetus to improve the quality and yield of silver nanomaterials due to enhanced mass and heat transfer. The current paper reviews recent achievements in the synthesis of silver nanomaterials in flow microreactors. Various strategies adopted for the synthesis of silver nanomaterials in microreactors are presented and compared, including synthesis in single-phase and multi-phase flow microreactors. In addition, the factors that affect the size and size distribution of silver nanomaterials in flow microreactors synthesis are also discussed briefly. This review article presents a comprehensive summary of the method of synthesizing silver nanomaterials in different microfluidic reactors proposed in the last two decades, and provides some analysis of the advantages and disadvantages of the various methods. The factors that affect the size and size distribution of silver nanomaterials during the microfluidic synthesis process are also presented. [ABSTRACT FROM AUTHOR]

Recently, a line of evidence has demonstrated that the vertebrate retina possesses a novel retrograde signaling pathway. In this pathway, phototransduction is initiated by the photopigment melanopsin, which is expressed in a small population of retinal ganglion cells. These ganglion cell photoreceptors then signal to dopaminergic amacrine cells (DACs) through glutamatergic synapses, influencing visual light adaptation. We have previously demonstrated that in Mg2+-containing solution, α-amino-3- hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) receptors mediate this glutamatergic transmission. Here, we demonstrate that removing extracellular Mg2+ enhances melanopsin-based DAC light responses at membrane potentials more negative than -40 mV. Melanopsin-based responses in Mg2+-free solution were profoundly suppressed by the selective N-methyl-D-aspartate (NMDA) receptor antagonist D-AP5. In addition, application of NMDA to the retina produced excitatory inward currents in DACs. These data strongly suggest that DACs express functional NMDA receptors. We further found that in the presence of Mg2+, D-AP5 reduced the peak amplitude of melanopsin-based DAC responses by ~70% when the cells were held at their resting membrane potential (-50 mV), indicating that NMDA receptors are likely to contribute to retrograde signal transmission to DACs under physiological conditions. Moreover, our data show that melanopsin-based NMDA-receptor-mediated responses in DACs are suppressed by antagonists specific to either the NR2A or NR2B receptor subtype. Immunohistochemical results show that NR2A and NR2B subunits are expressed on DAC somata and processes. These results suggest that DACs express functional NMDA receptors containing both NR2A and NR2B subunits. Collectively, our data reveal that, along with AMPA receptors, NR2A-and NR2B-containing NMDA receptors mediate retrograde signal transmission from ganglion cell photoreceptors to DACs. [ABSTRACT FROM AUTHOR]

A major hallmark of cortical organization is the existence of a variable number of layers, i.e., sheets of neurons stacked on top of each other, in which neurons have certain commonalities. However, even for the neocortex, variable numbers of layers have been described and it is just a convention to distinguish six layers from each other. Whether cortical layers are a structural epiphenomenon caused by developmental dynamics or represent a functionally important modularization of cortical computation is still unknown. Here we present our insights from the reeler mutant mouse, a model for a developmental, "molecular lesion"-induced loss of cortical layering that could serve as ground truth of what an intact layering adds to the cortex in terms of functionality. We could demonstrate that the reeler neocortex shows no inversion of cortical layers but rather a severe disorganization that in the primary somatosensory cortex leads to the complete loss of layers. Nevertheless, the somatosensory system is well organized. When exploring an enriched environment with specific sets of whiskers, activity-dependent gene expression takes place in the corresponding modules. Precise whisker stimuli lead to the functional activation of somatotopically organized barrel columns as visualized by intrinsic signal optical imaging. Similar results were obtained in the reeler visual system. When analyzing pathways that could be responsible for preservation of tactile perception, lemniscal thalamic projections were found to be largely intact, despite the smearing of target neurons across the cortical mantle. However, with optogenetic experiments we found evidence for a mild dispersion of thalamic synapse targeting on layer IV-spiny stellate cells, together with a general weakening in thalamocortical input strength. This weakening of thalamic inputs was compensated by intracortical mechanisms involving increased recurrent excitation and/or reduced feedforward inhibition. In conclusion, a layer loss so far only led to the detection of subtle defects in sensory processing by reeler mice. This argues in favor of a view in which cortical layers are not an essential component for basic perception and cognition. A view also supported by recent studies in birds, which can have remarkable cognitive capacities despite the lack of a neocortex with multiple cortical layers. In conclusion, we suggest that future studies directed toward understanding cortical functions should rather focus on circuits specified by functional cell type composition than mere laminar location. [ABSTRACT FROM AUTHOR]

The application of a microreactor system for the continuous synthesis of nanostructured Co3O4@SiO2 core-shell particles was investigated and compared to the standard lab experiment in batch operation. TEM images reveal that the synthesis of nanostructured core-shell particles in a laminar-flow reactor is generally possible. However, the particle size distribution for both SiO2 and core-shell particles synthesized continuously in a microreactor is broader, probably due to axial dispersion under laminar-flow conditions. [ABSTRACT FROM AUTHOR]

An important ancient Athenian institution was the ephēbeia: an institution with a military character during the later fourth century BC, which eventually acquired a paideutic one during the Hellenistic and Roman ages. Two Byzantine lexica, the lexicon of Photius and the Lexeis Rhētorikai, inform us on the functions of an office connected with the classical Athenian ephēbeia, namely the sophronistēs. The article investigates the possible sources (Hellenistic, Romanera, Byzantine) from which both Byzantine lexica received the entry. What arises is the role of a lost Roman-era lexicon of Attic realia, the Athenian Onomasticon, to the transmission of this entry. The article argues that the Athenian Onomasticon might have severely downplayed on the military character of the classical Athenian ephēbeia; it also stresses the need for an edition of the fragments of the Athenian Onomasticon, a process that will shed light upon the working habits of its compiler. [ABSTRACT FROM AUTHOR]

Condensation promotes CO2 hydrogenation to CH3OH beyond equilibrium through in situ product separation. Although primordial for catalyst and reactor design, triggering conditions as well as the impact on sub-equilibrium reaction behaviour remain unclear. Herein we used an in-house designed micro-view-cell to gain chemical and physical insights into reaction and phase behaviour under high-pressure conditions over a commercial Cu/ZnO/Al2O3 catalyst. Raman microscopy and video monitoring, combined with online gas chromatography analysis, allowed the complete characterisation of the reaction bulk up to 450 bar (1 bar=0.1 MPa) and 350 °C. Dew points of typical effluent streams related to a parametric study suggest that the improving reaction performance and reverting selectivities observed from 230 °C strongly correlate with (i) a regime transition from kinetic to thermodynamic, and (ii) a phase transition from a single supercritical to a biphasic reaction mixture. Our results advance a rationale behind transitioning CH3OH selectivities for an improved understanding of CO2 hydrogenation under high pressure. [ABSTRACT FROM AUTHOR]

Dark rearing is known to delay the time course of the critical period for ocular dominance plasticity in the visual cortex. Recent evidence suggests that a period of dark exposure (DE) may enhance or reinstate plasticity even after closure of the critical period, mediated through modification of the excitatory-inhibitory balance and/or removal of structural brakes on plasticity. Here, we investigated the effects of a week of DE on the recovery from a month of monocular deprivation (MD) in the primary visual cortex (V1) of juvenile mice. Optical imaging of intrinsic signals revealed that ocular dominance in V1 of mice that had received DE recovered slightly more quickly than of mice that had not, but the level of recovery after three weeks was similar in both groups. Two-photon calcium imaging showed no significant difference in the recovery of orientation selectivity of excitatory neurons between the two groups. Parvalbumin-positive (PVþ) interneurons exhibited a smaller ocular dominance shift during MD but again no differences in subsequent recovery. The percentage of PV+ cells surrounded by perineuronal nets, a structural brake on plasticity, was lower in mice with than those without DE. Overall, DE causes a modest enhancement of mouse visual cortex plasticity. [ABSTRACT FROM AUTHOR]

Nanoparticles have drawn significant attention in biomedicine due to their unique optical, thermal, magnetic and electrical properties which are highly related to their size and morphologies. Recently, microfluidic systems have shown promising potential to modulate critical stages in nanosynthesis, such as nucleation, growth and reaction conditions so that the size, size distribution, morphology, and reproducibility of nanoparticles are optimized in a high throughput manner. In this review, we put an emphasis on a decade of developments of microfluidic systems for engineering nanoparticles in various applications including imaging, biosensing, drug delivery, and theranostic applications. [ABSTRACT FROM AUTHOR]

Polyionic macromolecules affect the synthesis of polymer, metal, and composite nanoparticles. Their application in microfluidic nanoparticle syntheses is of great interest because these processes work with high mixing rates and result in high homogeneities and yields of the desired products. Thus, the microfluidic synthesis of silver triangles in the presence of polystyrenesulfonate leads to a very narrow size distribution and allows a fine tuning of the geometrical and optical properties. From the electronic and chemical properties of these particles, it can be concluded that the electrical effect of adsorbed polyionic macromolecules plays a key role in their electrical self-stabilization and reaction behavior. A similar effect caused by the electrical forces of polyionic additives is found in the microfluidic synthesis of polymer nanoparticles, in which the ratio of polyionic macromolecules to monomer decides about in situ assembling and determines the size and shape of the product particles. This electrical effect can also be used for ex situ heterogeneous nanoparticle assembling and for generation of hierarchically composed particles. In summary, polyionic additives can also be used as an efficient tool for controlling symmetry breaking (nonspherical shape) as well as homogeneous and heterogeneous assembling during the particle formation. [ABSTRACT FROM AUTHOR]

Targeting the vascular endothelial growth factor signaling axis in glioblastoma inevitably leads to tumor recurrence and a more aggressive phenotype. Therefore, other angiogenic pathways, like the angiopoietin/tunica interna endothelial cell kinase ( TIE) signaling axis, have become additional targets for therapeutic intervention. Here, we explored whether targeting the receptor tyrosine kinase TIE-2 using a novel, highly potent, orally available small molecule TIE-2 inhibitor ( BAY-826) improves tumor control in syngeneic mouse glioma models. BAY-826 inhibits TIE-2 phosphorylation in vitro and in vivo as demonstrated by suppression of Angiopoietin-1- or Na3 VO4-induced TIE-2 phosphorylation in glioma cells or extracts of lungs from BAY-826-treated mice. There was a trend toward prolonged survival upon single-agent treatment in two of four models ( SMA-497 and SMA-540) and there was a significant survival benefit in one model ( SMA-560). Co-treatment with BAY-826 and irradiation was ineffective in one model ( SMA-497), but provided synergistic prolongation of survival in another ( SMA-560). Decreased vessel densities and increased leukocyte infiltration were observed, but might be independent processes as the effect was also observed in single treatment modalities. These data demonstrate that TIE-2 inhibition may improve tumor response to treatment in highly vascularized tumors such as glioblastoma. [ABSTRACT FROM AUTHOR]

The confinement of chemical reactions within small droplets has received much attention in the last few years. This approach has been proved successful for the in-depth study of naturally occurring chemical processes as well as for the synthesis of different sets of nanomaterials with control over their size, shape and properties. Different approaches such as the use of self-contained structures or microfluidic generated droplets have been followed over the years with success. However, novel approaches have emerged during the last years based on the deposition of femtolitre-sized droplets on surfaces using tip-assisted lithographic methods. In this feature article, we review the advances made towards the use of these ultra-small droplets patterned on surfaces as confined nano-reactors. [ABSTRACT FROM AUTHOR]

Size-controlled and morphologically homogeneous lead trinitroresorcinate (LTNR) particles were synthesized in aqueous solutions using segmented flow. The experimental setup consisted of syringe pumps connected with silicone tubing to a segmented flow microfluidic platform made of polymethyl methacrylate (PMMA) containing silicone-based microchannels immersed in a thermostatted bath. As a starting point for the optimization of the experimental conditions, LTNR particles were first synthesized through conventional batch synthesis. The optimized batch conditions were adapted to segmented flow arrangements. Characterization studies on LTNR formed through batch and segmented flow methods were carried out, and it was found that in the latter LTNR particles exhibited superior particle morphology and narrower particle size distribution. In addition, the heat release of LTNR prepared by segmented flow increased by 353.52 J g−1 in comparison to that formed through batch synthesis. Finally, it was found demonstrated that segmented flow methods result in a 13 % increase in yield for the synthesis of LTNR. This study demonstrated the feasibility of synthesising primary explosives using a segmented flow microfluidic platform. [ABSTRACT FROM AUTHOR]

The primary visual cortex (V1) is widely used to study brain plasticity, which is not only crucial for normal brain function, such as learning and memory, but also for recovery after brain injuries such as stroke. In standard cage (SC) raised mice, experiencedependent ocular dominance (OD) plasticity in V1 declines with age and is compromised by a lesion in adjacent and distant cortical regions. In contrast, mice raised in an enriched environment (EE), exhibit lifelong OD plasticity and are protected from losing OD plasticity after a stroke-lesion in the somatosensory cortex. Since SC mice with an access to a running wheel (RW) displayed preserved OD plasticity during aging, we investigated whether physical exercise might also provide a plasticity promoting effect after a cortical stroke. To this end, we tested if adult RW-raised mice preserved OD plasticity after stroke and also if short-term running after stroke restored OD plasticity to SC mice. Indeed, unlike mice without a RW, adult RW mice continued to show OD plasticity even after stroke, and a 2 weeks RW experience after stroke already restored lost OD plasticity. Additionally, the experience-enabled increase of the spatial frequency and contrast threshold of the optomotor reflex of the open eye, normally lost after a stroke, was restored in both groups of RWmice. Our data suggest that physical exercise alone can not only preserve visual plasticity into old age, but also restore it after a cortical stroke. [ABSTRACT FROM AUTHOR]