Corticotropin-Releasing Factor Facilitates Epileptiform–activity In The Entorhinal Cortex Via CRF2 Signaling Mechanisms

Temporal lobe epilepsy (TLE) is characterized by hyperexcitability of limbic structures. The entorhinal cortex (EC) is involved in the initiation and maintenance of TLE. Layers II and III of the EC in particular are hyperexcitable and are more susceptible to epileptogenesis. TLE is influenced in a complex manner by the stress-released epileptogenic neuropeptide, corticotropin-releasing factor or hormone (CRF/CRH). Nevertheless, the action site and underlying mechanisms of CRF in epilepsy are not fully understood. Here we found that the EC expresses high levels of CRF and CRF2 receptors without the expression of CRF1 receptors. CRF increased the frequency of picrotoxin (PTX)-induced epileptiform activity via CRF2 receptors and requires cyclic AMP (cAMP). However, application of selective protein kinase A (PKA) inhibitors reduced, not completely blocked CRF-induced enhancement of epileptiform activity suggesting that PKA is only partially required. Furthermore, endogenously released CRF is also involved in the epileptogenesis. Among various ionic conductances maintaining neuronal excitability, the hyperpolarization-activated cyclic nucleotide-gated (HCN) channels and the conducting current Ih has strongly been implicated in TLE. Whereas, layer III of the EC shows preferential neuronal loss in TLE, layer II is spared and becomes hyperexcitable. Since the stellate neurons of layer II express high levels of HCN channels, we investigated the role of HCN channels in CRF- mediated facilitation of epileptiform activity. In the presence of HCN-channel blocker-ZD7288, CRF failed to increase the frequency of epileptiform activity but still augmented the numbers of synchronizing events within an epileptiform activity and the duration of epileptiform activity. This suggests that part of the effects of CRF on epilepsy is mediated via HCN channels. Furthermore, using perforated patch clamp recordings we found that CRF increased Ih recorded from layer II stellate neurons via activation of CRF2 receptors. cAMP, not PKA was responsible for CRF-mediated facilitation of Ih. At the cellular level, CRF depolarized the membrane potential resulting in increase in neuronal excitability and action potential firing. These mechanisms facilitate an increase in epileptiform activity mediated by CRF, in the EC. Our results provide a novel cellular and molecular mechanism whereby CRF modulates epilepsy

Modeling and Analysis of Repeated Ordinal Data Using Copula Based Likelihoods and Estimating Equation Methods

Repeated or longitudinal ordinal data occur in many fields such as biology, epidemiology, and finance. These data normally are analyzed using both likelihood and non-likelihood methods. The first part of this dissertation discusses the multivariate ordered probit model which is a likelihood method based on latent variables. We show that this latent variable model belong to a very general class of Copula models. We use the copula representation for the multivariate ordered probit model to obtain maximum likelihood estimates of the parameters. We apply the methodology in the analysis of real life data examples. Though likelihood methods are preferable, there are computational challenges implementing them. Alternatives are the non-likelihood models. These are partially specified models, that is, in these models only the functional forms of the marginals are known but joint distributions are unknown. In addition, the dependence among the observations is modeled using an appropriate correlation structure. The second part of the dissertation outlines the estimating equations approach for the analysis of longitudinal ordinal data for these non-likelihood models. We study the asymptotic properties of the estimates for both likelihood and non-likelihood methods. Comparisons based on simulations show that the maximum likelihood estimates arising from copula models are more efficient than the estimates obtained from estimating equations. The third part of this dissertation describes how ordinal data can be viewed as multinomial random vectors and points out the theoretical challenges in finding restrictions on the correlation parameters for dependent multinomial random vectors

A new particle image velocimetry technique for three-dimensional flows.

A technique has been developed whereby the three-dimensional (3-D) motion of particles in a fluid flow is automatically analyzed. A CCD (Charge Coupled Device) camera was used in conjunction with a tri-split lens and a mirror arrangement to simultaneously record stereo and orthogonal views of the particle-seeded flow field. A two-stage calibration algorithm has been implemented to determine the coefficients for each view separately. The images were digitally enhanced to aid in separating the particles from the background. Algorithms were developed to match individual particles in the stereo and orthogonal views. The positional information obtained from the stereo views was used to match the particle images in orthogonal views. A 3-D cross-correlation algorithm has been implemented to follow the particles from frame to frame and compute the velocity vectors. Experiments have been carried out to obtain the velocity profiles in a cubical test section. The results obtained from the experimental investigation were compared with numerical simulation data obtained from FLUENT and STAR-CD.Dept. of Mechanical, Automotive, and Materials Engineering. Paper copy at Leddy Library: Theses & Major Papers - Basement, West Bldg. / Call Number: Thesis1995 .K87. Source: Dissertation Abstracts International, Volume: 56-11, Section: B, page: 6349. Co-Advisers: K. Sridihar; G. W. Rankin. Thesis (Ph.D.)--University of Windsor (Canada), 1995

Study of surface texture using Fourier transform methods.

Dept. of Mechanical, Automotive, and Materials Engineering. Paper copy at Leddy Library: Theses & Major Papers - Basement, West Bldg. / Call Number: Thesis1989 .K873. Source: Masters Abstracts International, Volume: 40-07, page: . Thesis (M.A.Sc.)--University of Windsor (Canada), 1989

Subject-verb agreement dependency in Turkish Broca's aphasia:impairments in event occurrence and consequences for discourse-linking

Background: Inflecting the verb for agreement requires an intact discourse-semantic ability in addition to that for morphosyntax, since the use of person involves a link between the participants in the speech act and the morphosyntactic expression of this feature. Unlike the first person (the Speaker), the second person (the Addressee) requires additional discourse processing, termed "discourse-linking". Individuals with Broca's aphasia may have impaired discourse-linking, which may affect their ability to process second person pronouns and produce verb morphology for the second person. Aims: This study investigated whether the discourse-linking involved in processing second person pronouns contributes to sentence production deficits in Broca's aphasia. Methods & Procedures: The sample consisted of 16 Turkish individuals with Broca's aphasia (mean age: 54.8 years; SD: 14.0) who were matched in age with a control group of 16 neurologically intact Turkish individuals (mean age: 54.9; SD: 13.1). Each group completed a language task with first and second person singular or plural agreement conditions. Target agreement morphology was elicited using sentence-initial first and second person singular or plural pronouns. The plural (reference to a group) has a more complex discourse-representation than the singular (reference to an individual). Outcomes & Results: The group of individuals with Broca's aphasia showed the following production hierarchy: first person singular (highest accuracy rate) > first person plural > second person singular > second person plural (lowest accuracy rate). There was no discrepancy between test conditions for the control group. Conclusions: The discourse-linking involved in processing second person pronouns contributes to sentence production deficits and this deficit is exacerbated by plurality in Broca's aphasia. We suggest that cognitive-semantic intervention which focusses on the broader underlying impairment in deciphering event occurrence features (participant-time-location) could improve the use of the second person and other discourse-linked constructions (e.g., past time reference, object pronouns) which are selectively affected in Broca's aphasia

Sustainable Revolution for a Greener Planet – Possibilities in the Indian Context

The key challenge of the urbanisation process is the rise in population at a rapid pace. Although the reason is the aim of a better life for people, it is costing the environment and healthy living to a great extent in diverse ways. This sudden rise in population attracts uninvited guests like pollution, traffic, congestion, lack of green spaces, urban heat island effect, etc. The paper aims to study the environmental effects of the increased urban population, to bring sustainable awareness and environmental justice to the planet. The study draws comparisons of effects between the countries of the world and India, which in turn helps in formulating diverse ways to raise a sustainable revolution, and their applicability in developing countries like India. The approach helps understand the impact that can cause if not implemented at the earliest. The 2022 ranking of the Environmental Performance Index (EPI) and Sustainable Development Report (SDR) shows that India occupied the 180th position out of 180 countries, and the 121st position out of 163 respectively, indicating the necessity for a sustainable revolution in the context of India at a much bigger scale than the present. This not only shows different parameters affecting the planet but also the roles of diverse people in the revolution. The sustainable revolution can be achieved by the use of renewable energy techniques, energy-saving fixtures, control mechanisms, and responsive measures. The key methodology here is to apply these to the cities around the globe which would draw inspiration and awareness to others, thereby transforming the whole planet into sustainable practice. This revolution should start right from the smaller products at the building and the community level. The concern for health and luxury needs to be combined to form a single sustainable by-product. The perspective of products for a single-use needs to be changed and addressed. Sustainable awareness of different products, materials, and standards should be raised among diverse individuals, like students, teachers, employees, government servants, etc. Awareness campaigns at various places would help to revolutionise sustainable practice on a large scale, especially when the results are seen straight away. The paper concludes with the diverse ways of raising sustainable revolution that help in making a greener planet, which reduces expenses drastically and boosts people’s confidence. Once, people get used to this, it would be a game-changer for the planet’s health. The paper also discusses the role of government and people, where the former play a key role in taking the revolution to further heights

The Claustrum in Relation to Seizures and Electrical Stimulation

The neural mechanisms of altered consciousness that accompanies most epileptic seizures are not known. We have reported alteration of consciousness resulting from electrical stimulation of the claustrum via a depth electrode in a woman with refractory focal epilepsy. Additionally, there are reports that suggest possible claustral involvement in focal epilepsy, including MRI findings of bilaterally increased T2 signal intensity in patients with status epilepticus (SE). Although its cytoarchitecture and connectivity have been studied extensively, the precise role of the claustrum in consciousness processing, and, thus, its contribution to the semiology of dyscognitive seizures are still elusive. To investigate the role of the claustrum in rats, we studied the effect of high-frequency stimulation (HFS) of the claustrum on performance in the operant chamber. We also studied the inter-claustral and the claustro-hippocampal connectivity through cerebro-cerebral evoked potentials (CCEPs), and investigated the involvement of the claustrum in kainate (KA)-induced seizures. We found that HFS of the claustrum decreased the performance in the operant task in a manner that was proportional to the current intensity used. In this article, we present previously unpublished data about the effect of stimulating extra-claustral regions in the operant chamber task as a control experiment. In these animals, stimulation of the corpus callosum, the largest interhemispheric commissure, as well as the orbitofrontal cortex in the vicinity of the claustrum did not produce that same effect as with claustral stimulation. Additionally, CCEPs established the presence of effective connectivity between both claustra, as well as between the claustrum and bilateral hippocampi indicating that these connections may be part of the circuitry involved in alteration of consciousness in limbic seizures. Lastly, some seizures induced by KA injections showed an early involvement of the claustrum with later propagation to the hippocampi. Further work is needed to clarify the exact role of the claustrum in mediating alteration of consciousness during epileptic seizures

FAK acts as a suppressor of RTK-MAP kinase signalling in Drosophila melanogaster epithelia and human cancer cells

Receptor Tyrosine Kinases (RTKs) and Focal Adhesion Kinase (FAK) regulate multiple signalling pathways, including mitogen-activated protein (MAP) kinase pathway. FAK interacts with several RTKs but little is known about how FAK regulates their downstream signalling. Here we investigated how FAK regulates signalling resulting from the overexpression of the RTKs RET and EGFR. FAK suppressed RTKs signalling in Drosophila melanogaster epithelia by impairing MAPK pathway. This regulation was also observed in MDA-MB-231 human breast cancer cells, suggesting it is a conserved phenomenon in humans. Mechanistically, FAK reduced receptor recycling into the plasma membrane, which resulted in lower MAPK activation. Conversely, increasing the membrane pool of the receptor increased MAPK pathway signalling. FAK is widely considered as a therapeutic target in cancer biology; however, it also has tumour suppressor properties in some contexts. Therefore, the FAK-mediated negative regulation of RTK/MAPK signalling described here may have potential implications in the designing of therapy strategies for RTK-driven tumours