Target Validation and Pharmacological Characterization of Novel NMDAR Modulators

The N-methyl-D aspartate receptors (NMDARs) are ligand-gated ion channels, which play important roles in learning and memory. Excessive activity of NMDARs is implicated in damage due to stroke and neurodegenerative diseases, whereas hypoactivity of NMDARs contributes to schizophrenia. The initial goal of my dissertation is to evaluate the potential role of the GluN2D-containing NMDARs in neuropathological, behavioral and cognitive alterations associated with schizophrenia and characterize the pharmacology and mechanisms of action of NMDAR modulators which could potentially be used to modulate these receptors in schizophrenia. A subanesthetic dose of the NMDAR antagonist ketamine elicits symptoms of schizophrenia. This property led to the well-supported theory of NMDARs-hypofunction in schizophrenia. We found that ketamine increases [14C]-2-deoxy-glucose uptake in the medial prefrontal cortex and entorhinal cortex in wild type (WT) but not in GluN2D-knock out (KO) mice. Ketamine also increases locomotor activity and gamma-band oscillatory power in WT but not in GluN2D-KO mice. These results suggest a critical role of GluN2D-containing NMDARs in ketamine-induced schizophrenia-like symptoms in mice. Also, consistent with a role for GluN2D in schizophrenia is that the GluN2D-KO mice displayed impaired spatial memory acquisition and reduced parvalbumin (PV)-immunopositive staining compared to control mice. To develop NMDAR modulator for treating schizophrenia and other neurological diseases, we characterized several different naphthalene and phenanthrene based compounds for their positive allosteric modulator (PAM), negative allosteric modulator (NAM) and competitive antagonistic activity at NMDARs. We discovered that UBP684 and UBP753 are general NMDAR PAMs, UBP792 is a GluN2C/GluN2D-preferring NAM and UBP791 is a GluN2C/GluN2D-preferring competitive antagonist. Subsequent studies identified the mechanisms of action of the new compounds. The general PAMs UBP684/UBP753 increase agonist efficacy. They increase the channel open probability (Popen), and prolong the deactivation time upon glutamate removal. They bind to both the inactive and active states of the receptor and stabilize the glutamate-bound state of the GluN2 ligand-binding domain (LBD). The GluN2C/GluN2D-selective NAM UBP792 is a non-competitive antagonist and acts in a voltage-independent manner. Like the PAMs UBP684 and UBP753, UBP792 also acts by stabilizing the GluN2 LBD

Evidence for a Role of GluN2C/GluN2D-Containing NMDA Receptors in Neuronal Oscillations

Synchronization of neuronal firing leads to neural oscillations (brain waves) which are critical to working memory, cognition, and perception. NMDA receptors (NMDARs) play a vital role in establishing appropriate neural oscillations and modulating brain activity. Abnormalities in NMDARs have been linked to diseases such as schizophrenia causing impairments in working memory, cognition, and perception, which is thought to be due to abnormal brain wave patterns. Consistent with this hypothesis, general NMDA receptor blockers produce exaggerated neuronal oscillations and schizophrenia-like symptoms. Several NMDAR subtypes exist, and novel disease treatments may depend on targeting a select group of NMDAR subtypes. The drug UBP791 is a competitive antagonist that has a higher binding affinity for GluN2C/2D over GluN2A/2B. The selectivity of UBP791 allows for discrimination between these receptor subtypes and identifying the role of various NMDARs.https://digitalcommons.unmc.edu/surp2021/1015/thumbnail.jp

Effects of varieties and planting geometries on growth and yield of rain-fed rice in Dailekh, Nepal

A study was conducted at outreach sites of Horticulture Research Station, Dailekh with the objective of understanding effects of variety selection and spacing under rain-fed condition, during two rainy seasons of 2016 and 2017. Experiment was conducted in two factorial Randomized Complete Block Design where the research sites were replication itself. First factor was variety, including Khumal-10 and farmer’s variety. The second factor was spacings at (20x20) cm, (20x15) cm, (15x15) cm, and farmer’s practice. Effect of Khumal-10 was significantly superior in each of the parameters studied, except days to heading and maturity. Khumal-10, alone contributed 21.6% more yield compared to the farmer’s variety and also had the tallest plant (127.5 cm) and longest panicle (23.4 cm). Similarly, transplantation at spacing of (15x15) cm was significantly outstanding with 28.6% more grain yield, unlike in transplantation with farmer’s practice. Furthermore, integrated management of rice with Khumal-10 transplanted at spacing of (15x15) cm is recommended for Dailekh condition, since it resulted significantly promising grain yield of 5.5 t/ha, which is 71.9% more in comparison to grain yield from farmer’s variety transplanted in farmers´ practice.  Also, the economic benefit was highest with 75.8% more B:C ratio in case of improved variety Khumal-10 transplanted at (15x15) cm spacing

Rice production in Chitwan district of Nepal: An analysis from economic and environmental perspectives

Rice (Oryza sativa L.) is the major staple food in the Nepalese context. Chitwan district of Nepal was purposively selected to analyze the rice production from the socio-economic and environmental perspective. A total of 100 rice growing farmers, 50 organic and 50 inorganic were selected as the sample for the purpose of the study using the simple random method of sampling. Primary data were collected through a pre-tested semi-structure interview schedule and key informant interviews; secondary data were collected reviewing related publications. Descriptive statistics, multiple regression and chi-square test were used for data analysis. The multiple regression revealed that the four explanatory variables included in the model: age of the household head, primary occupation of the household head, number of family members involved in agriculture and subsidy in inputs for rice farming were found to have positive and statistically significant effect on rice yield (P<0.01). Moreover, chi-square test revealed that the farming practices that contributes to climate change mitigation such as: minimum tillage practice (P<0.05), crop diversification (P<0.01), green manuring (P<0.01), agro forestry practice (P<0.05), incorporating crop residues (P<0.1), weed management practice (P<0.01) and pest management practice (P<0.01)were found to be well adopted by the organic rice farmers, in contrast, the farming practices of inorganic rice farmers were statistically and significantly different in this respect. Government should make such policy that could grave the attention of the Nepalese people towards organic agriculture; moreover, encouraging them to make it their primary occupation

Factors affecting the productivity of coffee in Gulmi and Arghakhanchi districts of Nepal

Coffee is one of the major potential cash crops with lucrative export value grown in mid-hills of Nepal. Nepalese coffee production has suffered long by low productivity. Research was conducted from February to May, 2019 to analyze the factors affecting the productivity of coffee in Arghakhanchi and Gulmi districts of Nepal. These two districts were, purposively selected for this study taking account of comparative advantage and past studies recommendations for coffee sector. Altogether, 100 coffee growing households 50 from each, Arghakhanchi and Gulmi, were sampled by using multistage sampling technique. A pre-tested semi-structured interview schedule was used to collect the primary information while secondary information was collected reviewing the relevant publications. Ordinary Least Square (OLS) regression model was used to determine the factors affecting the productivity of coffee. The study revealed that the number of active family members involved in coffee production (0.000), adoption of income diversification through intercropping (0.005), training (0.072) and technical assistance (0.021) had positive and significant effect on coffee productivity. Encouraging the household to have coffee production as their primary occupation, providing technical assistance on rational land utilization and intercropping and strengthening the skill and knowledge of farmers through trainings could significantly support in increasing the productivity of coffee

Technical efficiency of rice production in terai district of Nepal

   This paper aimed to estimate the technical efficiency of rice production, also identifying the factors affecting technical efficiency. Jhapa, the Terai district of Nepal, having the highest rice production in the country, was purposely selected for the study. The primary information was collected from 100 rice growing farmers, randomly selected from the sampling frame, using the pre-tested semi-structured interview schedule. Also, two Key Informant Surveys were done. Besides, the secondary information was collected by reviewing the related literatures. Descriptive statistics, stochastic frontier model with Cobb-Douglas production function, and tobit model were used for data analysis. The stochastic production frontier model revealed that with the increase in seed, chemical fertilizer, human labor, and tractor power by 1 percent, the rice yield increases by 0.25 (P<0.05), 0.15 (P<0.01), 0.13 (P<0.05) and 0.21 (P<0.01) percent respectively. The average technical efficiency of the rice growing farmers in the study area was estimated 92%; in addition, majority of the farmers (62%) were operating at an efficiency level of 0.91- 0.95 followed by 32% at 0.86- 0.90. The tobit regression model revealed that farming experience (P<0.01), membership of the organization (P<0.01), and major occupation being agriculture (P<0.05) have statistically significant and positive on technical efficiency; while, schooling years (P<0.05) and number of economically active family members (P<0.05) have statistically significant but negative effect. There is still scope to increase the rice yield through efficient use of available resources with existing technologies

Adoption of improved wheat varieties in eastern and western Terai of Nepal

The research was conducted from March to May 2019 for assessment on adoption of improved wheat varieties in two major wheat growing districts of Nepal, Sunsari, and Kailali; one representing eastern and another western Terai. A pre-tested interview schedule was used to collect the primary information; in addition, two Key Informant Surveys were performed. Furthermore, relevant literatures were reviewed for secondary information. The simple random method of sampling was used within the selected areas that were identified in consultation with Agriculture Knowledge Centre and agricultural officials of the local government. Altogether, 194 samples were taken for the purpose of the study, omitting the outliers and incomplete responses. Descriptive statistics, probit regression, and indexing were used for data analysis. Probit econometric model revealed that membership dummy (1% level), age (1% level) number of family members involved in agriculture (1% level), subsidy dummy (5% level), number of schooling years (5%) and loan dummy (10% level) significantly determined the adoption of improved wheat varieties developed after NARC establishment. Furthermore, indexing identified- lack of availability of quality improved seeds (I= 0.80) as the major problem associated with the wheat production followed by poor availability of fertilizers (0.77), labour shortage (0.57), lack of proper irrigation (0.46) and lack of agricultural machines (0.39). The government agricultural institutions should assure access to quality seeds and fertilizers to the farmers; in addition, subsidy on irrigation and agricultural machines allied with agricultural loan to the educated youths could be the point of attraction  for wheat cultivation which leads to increased wheat productivity

Socio-economics of wheat production in Kailali and Sunsari districts of Nepal

For socio-economic assessment on wheat production, research was conducted from March to June, 2019 in two major wheat growing districts of Nepal, Kailai and sunsari. The primary information was collected by face to face interview using the pre-tested semi-structured interview schedule, two Key Informant Surveys were also done.In addition, the secondary information were collected from the review of related literatures. The survey areas were selected by consultating with Agriculture Knowledge Centre and agricultural officials of the local government; sample were selected by using simple random sampling. All total, 194 samples were selected for this study; the outliers and incomplete responses were omitted. The descriptive statistics revealed that Nepal 297 (66.16 %) has the highest area coverage in Sunsari while Gautam (36.50%) has the highest coverage in Kailali. Multiple regression model revealed that wheat cultivated area (p= 0.000), adoption of NARC released varieties (p= 0.000), gender of the household head (p= 0.017), age of the household head (p= 0.040), membership of organization (p= 0.094) and number of family members between age group 15 to 59 years (p= 0.085) have significant effect on wheat production. Furthermore, the unpaired t-test showed that the mean productivity of wheat in Kailali (2.99 Mt./ha) is significantly higher than that of Sunsari (2.81t./ha) at 5% level of significance. To increase the wheat productivity, the concerned government agricultural institutions should: assure access to NARC released improved varieties, make policy to consolidate the fragmented land, encourage the economically active population and the household heads towards wheat production by providing the efficient technical and financial support

Adoption of certain improved varieties of wheat (Triticum aestivum L.) in seven different provinces of Nepal

This study used farm level data to analyze the adoption of improved wheat varieties in Nepal. The seven districts each having the highest wheat area coverage in their respective provinces was selected. Pre-tested interview schedule was used to collect the primary information. The relevant literatures were reviewed for secondary information. The simple random method of sampling was used and 651 samples were taken. Descriptive statistics, probit regression and indexing were applied. This study showed that 94.1% of the area was covered by the improved wheat varieties, while 3.3% by local and 2.6% by the Indian varieties. In addition, of the improved varieties, NL 297 had the highest area coverage (30.88 %) followed by Vijay (23.24%), Gautam (12.95%), NL 971 (8.94%) and Aditya (5.34%) respectively. Probit econometric model revealed that membership of organization (1% level of significance), subsidy by the government (1% level), gender of the household head (5% level) and family member in foreign employment (10%) significantly determined the adoption of improved wheat varieties developed after NARC establishment. The indexing identified and ranked- lack of availability of quality improved seeds (I= 0.75) as the first followed by poor availability of fertilizers (0.65), labour shortage (0.61), lack of proper irrigation (0.55) and lack of agricultural machines (0.45) that were associated wheat production in study site. The concerned government institutions should assure the availability of quality improved seeds and fertilizers to the farmers; the subsidy on irrigation and agricultural machines allied with financial grant could attract the farmers towards wheat cultivation which ultimately contributes to increase wheat productivity

Mechanical characteristics and durability of HMA made of recycled aggregates

The application of recycled aggregates in the asphalt industry has been investigated in recent decades. However, low percentages of these materials have practically been used in asphalt mixtures because of the limitations set by the relevant specifications due to their performance uncertainties. This research investigates the feasibility of increasing the percentage of recycled aggregates to 100% in hot mix asphalt (HMA). Recycled concrete aggregate (RCA), recycled glass (RG), and reclaimed asphalt pavement (RAP) were used to develop HMAs suitable for roads with light to medium traffic. First, potential mix designs were proposed using an innovative approach considering the industry’s needs. Next, the volumetric properties, tensile strength, moisture sensitivity and resilient modulus response of the mixtures under different temperature conditions were determined and compared. In general, the proposed recycled material HMA exhibited superior mechanical and resilient modulus performances, i.e., 45 to 145% increase in stiffness, and up to 99% higher in Marshall stability. Furthermore, higher tensile strength ratios of the recycled material mixtures indicated a greater resistance to water damage, and hence greater durability. The findings of this research provide evidence-based insights into the increased proportion of recycled materials in the construction of asphalt pavements, thereby promoting sustainable pavement construction materials