Although 22q11.2 deletion syndrome (22q11DS) is associated with early-life behavioral abnormalities, affected individuals are also at high risk for the development of schizophrenia symptoms, ...including psychosis, later in life. Auditory thalamocortical (TC) projections recently emerged as a neural circuit that is specifically disrupted in mouse models of 22q11DS (hereafter referred to as 22q11DS mice), in which haploinsufficiency of the microRNA (miRNA)-processing-factor-encoding gene Dgcr8 results in the elevation of the dopamine receptor Drd2 in the auditory thalamus, an abnormal sensitivity of thalamocortical projections to antipsychotics, and an abnormal acoustic-startle response. Here we show that these auditory TC phenotypes have a delayed onset in 22q11DS mice and are associated with an age-dependent reduction of miR-338-3p, a miRNA that targets Drd2 and is enriched in the thalamus of both humans and mice. Replenishing depleted miR-338-3p in mature 22q11DS mice rescued the TC abnormalities, and deletion of Mir338 (which encodes miR-338-3p) or reduction of miR-338-3p expression mimicked the TC and behavioral deficits and eliminated the age dependence of these deficits. Therefore, miR-338-3p depletion is necessary and sufficient to disrupt auditory TC signaling in 22q11DS mice, and it may mediate the pathogenic mechanism of 22q11DS-related psychosis and control its late onset.
One of the most important functions of astrocytes is removal of glutamate released during synaptic transmission. Surprisingly, the mechanisms by which astrocyte glutamate uptake is acutely modulated ...remain to be clarified. Astrocytes express metabotropic glutamate receptors (mGluRs) and other G protein-coupled receptors (GPCRs), which are activated during neuronal activity. Here, we test the hypothesis that astrocytic group I mGluRs acutely regulate glutamate uptake by astrocytes in situ. This hypothesis was tested in acute mouse hippocampal slices. Activation of astrocytic mGluRs, using a tetanic high-frequency stimulus (HFS) applied to Schaffer collaterals, led to potentiation of the amplitude of the synaptically evoked glutamate transporter currents (STCs) and associated charge transfer without changes in kinetics. Similar potentiation of STCs was not observed in the presence of group I mGluR antagonists or the PKC inhibitor, PKC 19-36, suggesting that HFS-induced potentiation of astrocyte glutamate uptake is astrocytic group I mGluR and PKC dependent. Pharmacological stimulation of a transgenic GPCR (MrgA1R), expressed exclusively in astrocytes, also potentiated STC amplitude and charge transfer, albeit quicker and shorter lasting compared with HFS-induced potentiation. The amplitude of the slow, inward astrocytic current due to potassium (K(+)) influx was also enhanced following activation of the endogenous mGluRs or the astrocyte-specific MrgA1 Gq GPCRs. Taken together, these findings suggest that astrocytic group I mGluR activation has a synergistic, modulatory effect on the uptake of glutamate and K(+).
Mitochondrial ATP synthesis, calcium buffering, and trafficking affect neuronal function and survival. Several genes implicated in mitochondrial functions map within the genomic region associated ...with 22q11.2 deletion syndrome (22q11DS), which is a key genetic cause of neuropsychiatric diseases. Although neuropsychiatric diseases impose a serious health and economic burden, their etiology and pathogenesis remain largely unknown because of the dearth of valid animal models and the challenges in investigating the pathophysiology in neuronal circuits. Mouse models of 22q11DS are becoming valid tools for studying human psychiatric diseases, because they have hemizygous deletions of the genes that are deleted in patients and exhibit neuronal and behavioral abnormalities consistent with neuropsychiatric disease. The deletion of some 22q11DS genes implicated in mitochondrial function leads to abnormal neuronal and synaptic function. Herein, we summarize recent findings on mitochondrial dysfunction in 22q11DS and extend those findings to the larger context of schizophrenia and other neuropsychiatric diseases.
Mitochondrial ATP synthesis, calcium buffering, and trafficking affect neuronal function and survival. Several genes implicated in mitochondrial functions map within the genomic region associated ...with 22q11.2 deletion syndrome (22q11DS), which is a key genetic cause of neuropsychiatric diseases. Although neuropsychiatric diseases impose a serious health and economic burden, their etiology and pathogenesis remain largely unknown because of the dearth of valid animal models and the challenges in investigating the pathophysiology in neuronal circuits. Mouse models of 22q11DS are becoming valid tools for studying human psychiatric diseases, because they have hemizygous deletions of the genes that are deleted in patients and exhibit neuronal and behavioral abnormalities consistent with neuropsychiatric disease. The deletion of some 22q11DS genes implicated in mitochondrial function leads to abnormal neuronal and synaptic function. Herein, we summarize recent findings on mitochondrial dysfunction in 22q11DS and extend those findings to the larger context of schizophrenia and other neuropsychiatric diseases.
Six mitochondrial genes represented within the 22q11.2 genomic region can affect different aspects of mitochondrial function, such as ATP synthesis, calcium regulation, redox balance, fatty acid metabolism, and trafficking. These defects give rise to deficits in synaptic and neural circuit function, which underlie neuropsychiatric disease. Also see the video here.
Abstract Astrocyte Gq GPCR and IP3 receptor-dependent Ca2+ elevations occur spontaneously in situ and in vivo . These events vary considerably in size, often remaining confined to small territories ...of astrocyte processes called “microdomains” and sometimes propagating over longer distances that can include the soma. It has remained unclear whether these events are driven by constitutive (basal) GPCR signaling activity, neuronal action potential-dependent or quantal vesicular release, or some combination of these mechanisms. Here, we applied manipulations to increase or inhibit neuronal vesicular neurotransmitter release together with low-level stimulation of Schaffer collaterals in acute mouse hippocampal slices in an effort to determine the mechanisms underlying spontaneous astrocyte Ca2+ events. We found no significant change in spontaneous microdomain astrocyte Ca2+ elevations when neuronal action potentials were significantly enhanced or blocked. The astrocyte Ca2+ activity was also not affected by inhibitors of group I mGluRs. However, blockade of miniature neurotransmitter release using Bafilomycin A1 significantly reduced the frequency of microdomain astrocyte Ca2+ elevations. We then tested whether astrocyte Ca2+ microdomains can be evoked by low intensity SC stimulation. Importantly, microdomains could not be reproduced even using single, low intensity pulses to the SCs at a minimum distance from the astrocyte. Evoked astrocyte Ca2+ responses most often included the cell soma, were reduced by group I mGluR antagonists, and were larger in size compared to spontaneous Ca2+ microdomains. Overall, our findings suggest that spontaneous microdomain astrocyte Ca2+ elevations are not driven by neuronal action potentials but require quantal release of neurotransmitter which cannot be replicated by stimulation of Schaffer collaterals.
A feature in patients with constitutional DNA-mismatch repair deficiency is agenesis of the corpus callosum, the cause of which has not been established. Here we report a previously unrecognized ...consequence of deficiency in MSH2, a protein known primarily for its function in correcting nucleotide mismatches or insertions and deletions in duplex DNA caused by errors in DNA replication or recombination. We documented that Msh2 deficiency causes dysmyelination of the axonal projections in the corpus callosum. Evoked action potentials in the myelinated corpus callosum projections of Msh2-null mice were smaller than wild-type mice, whereas unmyelinated axons showed no difference. Msh2-null mice were also impaired in locomotive activity and had an abnormal response to heat. These findings reveal a novel pathogenic consequence of MSH2 deficiency, providing a new mechanistic hint to previously recognized neurological disorders in patients with inherited DNA-mismatch repair deficiency.
Astrocytic glutamate transporters, GLAST and GLT-1 (rodent analogs of EAAT1 and EAAT2, respectively) constitute the major pathway of glutamate uptake in the central nervous system. Uptake of ...synaptically released glutamate by astrocytes is essential for maintaining a healthy level of excitatory activity in the brain. It is also known that astrocytes in situ possess a myriad of G-protein coupled receptors (GPCRs) of the Gi, G s, and Gq families. Stimulation of glutamatergic afferents not only leads to astrocytic glutamate uptake but also has been shown to stimulate group I (Gq type) metabotropic glutamate receptor (mGluR) mediated intracellular Ca2+ elevations in astrocytes both in vivo and in situ. Activation of mGluRs has been associated with short and long-term plastic changes of glutamate transport in cultured astroglia and in Purkinje neurons in cerebellar slices. This led us to hypothesize that astrocytic Gq GPCRs modulate glutamate transport. This hypothesis was tested in acute mouse hippocampal slices using two different approaches: (1) activation of astrocytic mGluRs in slices from wild-type mice using a tetanic high frequency stimulus (200Hz, 1s) applied to the Schaffer collaterals (SCs); (2) activation of a transgenic Gq GPCR (the MrgA1R) which is selectively expressed by astrocytes. Synaptically evoked glutamate transporter currents (STCs) were isolated from the total evoked astrocytic currents and analyzed for changes in amplitude, rise time, rise slope and decay time constant. High frequency stimulation (HFS) of SCs led to potentiation of the amplitude of the STCs without changes in kinetics. Similar potentiation was not observed in the presence of group I mGluRs or the PKC inhibitor, PKC 19-36, suggesting that HFS induced potentiation of glutamate uptake is group I mGluR - PKC dependent. Activation of the MrgA1Rs selectively expressed by astrocytes also potentiated the STC amplitude indicating the sufficiency of astrocytic Gq GPCR activation for potentiation of glutamate uptake. Surprisingly, the amplitude of the slow inward astrocytic current due to potassium uptake is also enhanced following activation of either the endogenous mGluRs or the astrocyte-specific MrgA1Rs. These findings collectively suggest that astrocytic Gq GPCR activation has a synergistic modulatory effect on the uptake of both glutamate and potassium.
In the island operation mode of the microgrid, the rated capacity and feeder impedance of each parallel distributed generation inverter are different and the output power is difficult to be ...reasonably distributed when the traditional droop control strategy is adopted, which reduces the stability of the system. In order to solve this problem, the power transmission characteristics of low-voltage microgrid are analyzed and the leading factors affecting the reasonable power distribution are obtained. A control strategy of virtual resistor is proposed and the difference between the actual output power and the expected output power is used to control the power compensation coefficient and proportional integration to adjust the reference voltage of each DG inverter. The control strategy can automatically adjust the change in the output power of the distributed power supply in real time, adjust the voltage change caused by the line impedance mismatch in time, improve the power quality, reduce the system circulation, and realize the reasonable distribution of power. Finally, the simulation model verifies the effectiveness of the strategy.
The present study was conducted during the
Rabi
season of 2021–2022. Twenty two pea genotypes were grouped into five clusters based on
D
2
values which indicated no correlation between geographical ...and genetic divergence. Cluster II had the lowest intra-cluster distance and cluster III had the highest. The maximum inter-cluster distance was between clusters IV and V, followed by I and V, which may serve as potential genotypes for a hybridization program. Based on the mean performance of different clusters, clusters IV and V had better cluster mean values for most of the studied characters viz., plant height (cm), number of branches per plant, days to first flowering, days to 50% flowering, shelling percentage, number of pods per plant, pod yield per plant (g), non-reducing sugars (%) and drying duration (min). Thus, genotypes from these clusters could be used as divergent parents to improve a specific trait.
Developing Efficient Web-Based Xml Tool Devaraju, S.; Prakash, D.Saravana
International journal of recent technology and engineering,
09/2019, Letnik:
8, Številka:
3
Journal Article
Odprti dostop
The “XML TOOL” is used to design and develop the efficient web based application. The main objective of this application is to design and develop web based software for creation of XML, DTD, Schema ...and Validation of XML against a DTD or Schema, thereby reducing the discrepancies of the existing manual system which is quite inefficient and time consuming. The user can create XML by giving the name of the file, the names of the tags, description of tags, its sub tags, the attributes and the various other values. The user can create DTD and XSD by providing values for the tag names, the sub tags names, the attribute names and the various rules associated with it. The XML, DTD and XSD files are created automatically based on the values provided by the user. The user can check if the XML is well formed or not. The user can manually edit the XML, DTD or XSD that is auto created. The user can validate the XML against either a DTD or an XSD. If the XML is valid then a success message is be displayed in green color. If the XML is either not well formed or not valid, then the associated errors are displayed in red color.
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