372 research outputs found
Cortical AAV-CNTF gene therapy combined with intraspinal mesenchymal precursor cell transplantation promotes functional and morphological outcomes after spinal cord injury in adult rats
Ciliary neurotrophic factor (CNTF) promotes survival and enhances long-distance regeneration of injured axons in parts of the adult CNS. Here we tested whether CNTF gene therapy targeting corticospinal neurons (CSN) in motor-related regions of the cerebral cortex promotes plasticity and regrowth of axons projecting into the female adult F344 rat spinal cord after moderate thoracic (T10) contusion injury (SCI). Cortical neurons were transduced with a bicistronic adeno-associated viral vector (AAV1) expressing a secretory form of CNTF coupled to mCHERRY (AAV-CNTFmCherry) or with control AAV only (AAV-GFP) two weeks prior to SCI. In some animals, viable or nonviable F344 rat mesenchymal precursor cells (rMPCs) were injected into the lesion site two weeks after SCI to modulate the inhibitory environment. Treatment with AAV-CNTFmCherry, as well as with AAV-CNTFmCherry combined with rMPCs, yielded functional improvements over AAV-GFP alone, as assessed by open-field and Ladderwalk analyses. Cyst size was significantly reduced in the AAV-CNTFmCherry plus viable rMPC treatment group. Cortical injections of biotinylated dextran amine (BDA) revealed more BDA-stained axons rostral and alongside cysts in the AAV-CNTFmCherry versus AAV-GFP groups. After AAV-CNTFmCherry treatments, many sprouting mCherry-immunopositive axons were seen rostral to the SCI, and axons were also occasionally found caudal to the injury site. These data suggest that CNTF has the potential to enhance corticospinal repair by transducing parent CNS populations
Promotion of Hendra virus replication by microRNA 146a
Hendra virus is a highly pathogenic zoonotic paramyxovirus in the genus Henipavirus. Thirty-nine outbreaks of Hendra virus have been reported since its initial identification in Queensland, Australia, resulting in seven human infections and four fatalities. Little is known about cellular host factors impacting Hendra virus replication. In this work, we demonstrate that Hendra virus makes use of a microRNA (miRNA) designated miR-146a, an NF-κB-responsive miRNA upregulated by several innate immune ligands, to favor its replication. miR-146a is elevated in the blood of ferrets and horses infected with Hendra virus and is upregulated by Hendra virus in human cells in vitro. Blocking miR-146a reduces Hendra virus replication in vitro, suggesting a role for this miRNA in Hendra virus replication. In silico analysis of miR-146a targets identified ring finger protein (RNF)11, a member of the A20 ubiquitin editing complex that negatively regulates NF-κB activity, as a novel component of Hendra virus replication. RNA interference-mediated silencing of RNF11 promotes Hendra virus replication in vitro, suggesting that increased NF-κB activity aids Hendra virus replication. Furthermore, overexpression of the IκB superrepressor inhibits Hendra virus replication. These studies are the first to demonstrate a host miRNA response to Hendra virus infection and suggest an important role for host miRNAs in Hendra virus disease
Dynamic Behavior of Geogrid-Reinforced Soil
Geosynthetic materials particularly geogrids are widely used as reinforcement and is a proven technology for enhancing the performance of the foundation soil system under monotonic loadings. But the dynamic behavior of the reinforced foundation soil has not been well understood so far, and therefore dynamic loads (square wave pulse) of frequencies 0.2, 0.4 and 1 hertz under an amplitude of displacement of 2mm have been studied by carrying out dynamic plate loading tests on both unreinforced and the reinforced sandy beds. The size of the square plate is 150mm x 150mm x 30mm
Encoding and retrieval in a CA1 microcircuit model of the hippocampus
Recent years have witnessed a dramatic accumulation of
knowledge about the morphological, physiological and molecular characteristics,
as well as connectivity and synaptic properties of neurons in
the mammalian hippocampus. Despite these advances, very little insight
has been gained into the computational function of the different neuronal
classes; in particular, the role of the various inhibitory interneurons in
encoding and retrieval of information remains elusive. Mathematical and
computational models of microcircuits play an instrumental role in exploring
microcircuit functions and facilitate the dissection of operations
performed by diverse inhibitory interneurons. A model of the CA1 microcircuitry
is presented using biophysical representations of its major cell
types: pyramidal, basket, axo-axonic, bistratified and oriens lacunosummoleculare
cells. Computer simulations explore the biophysical mechanisms
by which encoding and retrieval of spatio-temporal input patterns
are achieved by the CA1 microcircuitry. The model proposes functional
roles for the different classes of inhibitory interneurons in the encoding
and retrieval cycles
Toll‐like Receptor 4 Signaling in Neurons Enhances Calcium‐Permeable AMPA Receptor Currents and Drives Post‐Traumatic Epileptogenesis
ObjectiveTraumatic brain injury is a major risk factor for acquired epilepsies, and understanding the mechanisms underlying the early pathophysiology could yield viable therapeutic targets. Growing evidence indicates a role for inflammatory signaling in modifying neuronal excitability and promoting epileptogenesis. Here we examined the effect of innate immune receptor Toll-like receptor 4 (TLR4) on excitability of the hippocampal dentate gyrus and epileptogenesis after brain injury.MethodsSlice and in vivo electrophysiology and Western blots were conducted in rats subject to fluid percussion brain injury or sham injury.ResultsThe studies identify that TLR4 signaling in neurons augments dentate granule cell calcium-permeable α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor (CP-AMPAR) currents after brain injury. Blocking TLR4 signaling in vivo shortly after brain injury reduced dentate network excitability and seizure susceptibility. When blocking of TLR4 signaling after injury was delayed, however, this treatment failed to reduce postinjury seizure susceptibility. Furthermore, TLR4 signal blocking was less efficacious in limiting seizure susceptibility when AMPAR currents, downstream targets of TLR4 signaling, were transiently enhanced. Paradoxically, blocking TLR4 signaling augmented both network excitability and seizure susceptibility in uninjured controls. Despite the differential effect on seizure susceptibility, TLR4 antagonism suppressed cellular inflammatory responses after injury without impacting sham controls.InterpretationThese findings demonstrate that independently of glia, the immune receptor TLR4 directly regulates post-traumatic neuronal excitability. Moreover, the TLR4-dependent early increase in dentate excitability is causally associated with epileptogenesis. Identification and selective targeting of the mechanisms underlying the aberrant TLR4-mediated increase in CP-AMPAR signaling after injury may prevent epileptogenesis after brain trauma. ANN NEUROL 2020;87:497-515
Assessment of the scale, coverage and outcomes of the Avahan HIV prevention program for female sex workers in Tamil Nadu, India: is there evidence of an effect?
<p>Abstract</p> <p>Background</p> <p>Avahan, the India AIDS Initiative, a large-scale HIV prevention program, using peer-mediated approaches and STI services, was implemented for high-risk groups for HIV in six states in India. This paper describes the assessment of the program among female sex workers (FSWs) in the southern state of Tamil Nadu.</p> <p>Methods</p> <p>An analytical framework based on the Avahan impact evaluation design was used. Routine program monitoring data, two rounds of cross-sectional biological and behavioural surveys among FSWs in 2006 (Round 1) and 2009 (Round 2) and quality assessments of clinical services for sexually transmitted infections (STIs) were used to assess trends in coverage, condom use and prevalence of STIs, HIV and their association with program exposure. Logistic regression analysis was used to examine trends in intermediate outcomes and their associations with intervention exposure.</p> <p>Results</p> <p>The Avahan program in Tamil Nadu was scaled up and achieved monthly reported coverage of 79% within four years of implementation. The cross-sectional survey data showed an increasing proportion of FSWs being reached by Avahan, 54% in Round 1 and 86% in Round 2 [AOR=4.7;p=0.001]. Quality assessments of STI clinical services showed consistent improvement in quality scores (3.0 in 2005 to 4.5 in 2008). Condom distribution by the program rose to cover all estimated commercial sex acts. Reported consistent condom use increased between Round 1 and Round 2 with occasional (72% to 93%; AOR=5.5; p=0.001) and regular clients (68% to 89%; AOR=4.3; p=0.001) while reactive syphilis serology declined significantly (9.7% to 2.2% AOR=0.2; p=0.001). HIV prevalence remained stable at 6.1% between rounds. There was a strong association between Avahan exposure and consistent condom use with commercial clients; however no association was seen with declines in STIs.</p> <p>Conclusions</p> <p>The Avahan program in Tamil Nadu achieved high coverage of FSWs, resulting in outcomes of improved condom use, declining syphilis and stabilizing HIV prevalence. These expected outcomes following the program logic model and declining HIV prevalence among general population groups suggest potential impact of high risk group interventions on HIV epidemic in Tamil Nadu.</p
Studies on the Influence of Abiotic Factors in the Gonadal Index of Sea urchin Salmacis virgulata from the Gulf of Mannar, South East Coast of India
The present study was conducted to find out whether the abiotic factors in Gulf of Mannar viz., Sea Surface Temperature (SST) and Day light photoperiod would have an effect on the Gonado somatic index of the dominant sea urchin species Salmacis virgulata. A sampling survey for 20 months was conducted from October-2013 to May-2015 in Vedalai landing centre, along the Gulf of Mannar. The freshly collected sea urchin were brought to Mandapam CMFRI and their Gonado Somatic Index (GSI) was estimated. The remote sensing data of the SST from Gulf of Mannar sourced from ICOADS and the daylight photoperiod were compared with the GSI data for 20 months in order to assess the synchrony among the three parameters. The pearson correlation coefficient of the association among the GSI, SST and Photoperiod revealed that there was no significant correlation (p>0.001). The result of the present study revealed that the Gonado Somatic Index of S. virgulata is independent of abiotic factors, which is in contrast to the temperate sea urchin species, where SST and Photoperiod play a major role in gonadal development
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