Background: Saccade and pupil responses are potential neurodegenerative disease biomarkers due to overlap between oculomotor circuitry and disease-affected areas. Instruction-based tasks have previously been examined as biomarker sources, but are arduous for patients with limited cognitive abilities; additionally, few studies have evaluated multiple neurodegenerative pathologies concurrently. Methods: The Ontario Neurodegenerative Disease Research Initiative recruited individuals with Alzheimer’s disease (AD), mild cognitive impairment (MCI), amyotrophic lateral sclerosis (ALS), frontotemporal dementia, progressive supranuclear palsy, or Parkinson’s disease (PD). Patients (n=274, age 40-86) and healthy controls (n=101, age 55-86) viewed 10 minutes of frequently changing video clips without instruction while their eyes were tracked. We evaluated differences in saccade and pupil parameters (e.g. saccade frequency and amplitude, pupil size, responses to clip changes) between groups. Results: Preliminary data indicates low-level behavioural alterations in multiple disease cohorts: increased centre bias, lower overall saccade rate and reduced saccade amplitude. After clip changes, patient groups generally demonstrated lower saccade rate but higher microsaccade rate following clip change to varying degrees. Additionally, pupil responses were blunted (AD, MCI, ALS) or exaggerated (PD). Conclusions: This task may generate behavioural biomarkers even in cognitively impaired populations. Future work should explore the possible effects of factors such as medication and disease stage.

Background: Improvements in sleep-onset, maintenance, and daytime functioning, are all important outcomes for the treatment of insomnia. These improvements are usually assessed by objective or patient-reported (subjective) measures or both. Some sleep-promoting drugs do not report consistently aligned subjective and objective outcomes. Therefore, we examined concordance in change from baseline (CFB) in sleep parameters (objective/subjective measures) and daytime functioning (subjective measures) in the clinical program of lemborexant (LEM), a dual-orexin receptor antagonist. Methods: Study E2006-G000-304 (NCT02783729), a 1-month, placebo (PBO)- and active-controlled (zolpidem; not discussed here) study, and Study E2006-G000-303 (NCT02952820), a 12-month, randomized, PBO-controlled study (first 6-months), evaluated the efficacy/safety of LEM 5mg (LEM5) and LEM 10mg (LEM10) in subjects with insomnia disorder. The primary/secondary endpoints in both studies included multiple objective/subjective sleep parameters and patient-reported measures, which were assessed for concordance. Results: In both studies, statistically significant improvements with LEM5/LEM10 were reported in multiple objective and patient-reported measures versus PBO, showing a concordance of results, with observed improvements continuing through 12 months. LEM was well tolerated; most treatment-emergent adverse events were mild/moderate. Conclusions: When deciding which sleep agent to prescribe, it is important that improvement can be demonstrated in both objective and patient-reported measures. LEM treatment showed concordance among observed measures.

Background: Some sleep-promoting medications are associated with cognitive impairment, making treatment of comorbid obstructive-sleep-apnea (OSA) and insomnia (COMISA) challenging. Lemborexant is a dual-orexin-receptor-antagonist approved for insomnia treatment. This post-hoc analysis evaluated cognition in the subgroup of subjects with mild-OSA (apnea-hypopnea-index ≥5–<15 events/h-of-sleep). Methods: Study E2006-G000-304 was a 1-month, randomized, double-blind, placebo (PBO)- and active-comparator (zolpidem-ER 6.25mg [ZOL])-controlled study of lemborexant 5/10mg (LEM5/LEM10). Subjects ≥55y with insomnia disorder/sleep maintenance problems were enrolled (N=1006). A cognitive-performance assessment battery (CPAB) was performed at morning waketime of Days(D)2/3 and D30/31. Change-from-baseline (CFB) for mean power-of-attention (PoA), continuity-of-attention (CoA), quality-of-memory (QoM), and speed-of-memory-retrieval (SoMR) for CPAB tasks was analyzed. Results: The mild-OSA subgroup comprised 410 (40.8%) subjects. On D2/3 and D30/31, CFB for PoA, CoA, QoM, and SoMR for LEM5/LEM10 were not significantly different than PBO. On D2/3, PoA and QoM were significantly worse with ZOL vs PBO; QoM was significantly better with LEM5/LEM10 vs ZOL. On D30/31, SoMR was significantly worse with ZOL vs PBO and significantly better with LEM5/LEM10 vs ZOL. LEM safety in the subgroup was consistent with the overall study population. Conclusions: Memory and attention domains in subjects with COMISA characterized by mild-OSA were not impacted by LEM, unlike ZOL.

Support: Eisai Inc.

Sustainability of maize production systems is threatened by poor economic returns and resource intensiveness. Therefore, an experiment was conducted at the ICAR-Indian Agricultural Research Institute, New Delhi during 2016–17 to 2017–18 to assess the effect of tillage and microbial inoculantsintegrated phosphorus (P) management on productivity, quality, economic outcome and energy dynamics of maize. Three tillage practices viz., CT–R (conventional tillage with no residue), ZT–R (zero tillage with no residue) and ZT + R (zero tillage with wheat crop residue at 2.5 Mg/ha) were assigned in main plots and five P management practices viz., P1 (control–NK as per recommendation, but no P), P2 (17.2 kg P/ha), P3 (17.2 kg P/ha + PSB), P4 (17.2 kg P/ha + compost inoculants) and P5 (34.4 kg P/ha) were allocated in subplots in three times replicated split-plot design. The maximum grain yield (5.96 Mg/ha), protein content (9.13%), protein yield (546 kg/ha) and gross energy returns (209 × 103 MJ/ha) were recorded under ZT + R while higher benefit: cost ratio (B: C ratio – the amount of economic gain per unit investment) (1.53) and energy efficiency (12.5) was noticed under ZT–R. Among the P management practices, the application of 34.4 kg P/ha recorded the highest grain yield (6.45 Mg/ha), protein content (9.34%), protein yield (603 kg/ha), B: C ratio (1.65) and energy efficiency (10.1). The results suggested that the application of P at the rate of 34.4 kg/ha under ZT + R is an economically robust approach for the quality maize production in semi-arid region.

Availability of resistance sources among cultivated varieties helps in easy utilization as donor owing to no deleterious linkage drag. In the present investigation, 121 rice varieties were screened for their resistance against a virulent isolate of Fusarium fujikuroi (Ff-10) and genotyped using reported microsatellite markers. Among 121 varieties, only eight varieties, namely Luna Sankhi, Improved Tapaswini, Sarasa, Sadabahar, CR-311, Kshira, Wifa-10 and Binadhan-8, were found to be highly resistant (HR), seven varieties were resistant (R), 31 were moderately resistant (MR), 10 were moderately susceptible (MS), 11 were susceptible (S) and the rest 54 were highly susceptible (HS). The allele diversity of molecular markers classified the population into three clusters. The highly resistant varieties were grouped in major clusters II and III, whereas the remaining genotypes were distributed in all three clusters. Analysis of molecular variance (AMOVA) resulted in 95% of the maximum diversity within the test population and 5% diversity between populations. Population structure analysis grouped the genotypes into two sub-populations based on relatedness, where most of the resistant genotypes were grouped into one sub-population and other genotypes were distributed among sub-populations. Re-examination of reported markers' trait associations with bakanae resistance in the experimental population identified marker RM-3698 as associated with resistance accounting 8.4% explained phenotypic variation. This study shows that simple sequence repeat markers can be used to assess allelic diversity and population structure of bakanae resistance in rice varieties. The highly resistant genotypes, along with resistance markers, could be used as donors in marker-assisted bakanae improvement breeding programmes.

We present the pulse arrival times and high-precision dispersion measure estimates for 14 millisecond pulsars observed simultaneously in the 300 $-$ 500 MHz and 1260 $-$ 1460 MHz frequency bands using the upgraded Giant Metrewave Radio Telescope. The data spans over a baseline of 3.5 years (2018-2021), and is the first official data release made available by the Indian Pulsar Timing Array collaboration. This data release presents a unique opportunity for investigating the interstellar medium effects at low radio frequencies and their impact on the timing precision of pulsar timing array experiments. In addition to the dispersion measure time series and pulse arrival times obtained using both narrowband and wideband timing techniques, we also present the dispersion measure structure function analysis for selected pulsars. Our ongoing investigations regarding the frequency dependence of dispersion measures have been discussed. Based on the preliminary analysis for five millisecond pulsars, we do not find any conclusive evidence of chromaticity in dispersion measures. Data from regular simultaneous two-frequency observations are presented for the first time in this work. This distinctive feature leads us to the highest precision dispersion measure estimates obtained so far for a subset of our sample. Simultaneous multi-band upgraded Giant Metrewave Radio Telescope observations in 300 $-$ 500 MHz and 1260 $-$ 1460 MHz are crucial for high-precision dispersion measure estimation and for the prospect of expanding the overall frequency coverage upon the combination of data from the various Pulsar Timing Array consortia in the near future. Parts of the data presented in this work are expected to be incorporated into the upcoming third data release of the International Pulsar Timing Array.

The Diwani hills are located SE of Balaram–Abu Road in the Banaskantha district of north Gujarat. The crystalline rocks of the Diwani hill area are a diverse assemblage of Precambrian metamorphic and igneous rocks. These rocks are petrologically more complex and date back to the Aravallis or earlier. The mineralogical assemblages such as grt–sp–opx–qz of these rocks indicate their origin in anhydrous or dry conditions, implying metamorphism under pyroxene granulite facies. These granulitic rocks were subjected to Delhi orogenic deformation and were later intruded by the Erinpura granite. Textural and microstructural relationships, mineral chemistry, P–T–X pseudosection modelling and the oxidation state of pelitic granulites from the Diwani hill area of north Gujarat are all part of the current approach. The winTWQ program and pseudosection modelling in the NCKFMASHTO model system utilizing Perple_X software were used to restrict the P–T evolution of these pelitic granulites. The unification of these estimates shows that the pelitic granulites reached their pressure and temperature maxima at 8.6 kbar and 770 °C, respectively. The oxygen fugacity (log fO2) versus temperature computations at 6.2 kbar revealed log fO2–T values of −13.0 and 765 °C, respectively. The electron microprobe dating of monazite grains separated from the granulites of the Diwani hills yields ages ranging from 769 Ma to 855 Ma. The electron microprobe dating presented here from the Diwani hills provides evidence for a Neoproterozoic (Tonian) metamorphic event in the Aravalli–Delhi Mobile Belt.

Background: Eye movements reveal neurodegenerative disease processes due to overlap between oculomotor circuitry and disease-affected areas. Characterizing oculomotor behaviour in context of cognitive function may enhance disease diagnosis and monitoring. We therefore aimed to quantify cognitive impairment in neurodegenerative disease using saccade behaviour and neuropsychology. Methods: The Ontario Neurodegenerative Disease Research Initiative recruited individuals with neurodegenerative disease: one of Alzheimer’s disease, mild cognitive impairment, amyotrophic lateral sclerosis, frontotemporal dementia, Parkinson’s disease, or cerebrovascular disease. Patients (n=450, age 40-87) and healthy controls (n=149, age 42-87) completed a randomly interleaved pro- and anti-saccade task (IPAST) while their eyes were tracked. We explored the relationships of saccade parameters (e.g. task errors, reaction times) to one another and to cognitive domain-specific neuropsychological test scores (e.g. executive function, memory). Results: Task performance worsened with cognitive impairment across multiple diseases. Subsets of saccade parameters were interrelated and also differentially related to neuropsychology-based cognitive domain scores (e.g. antisaccade errors and reaction time associated with executive function). Conclusions: IPAST detects global cognitive impairment across neurodegenerative diseases. Subsets of parameters associate with one another, suggesting disparate underlying circuitry, and with different cognitive domains. This may have implications for use of IPAST as a cognitive screening tool in neurodegenerative disease.

OBJECTIVES/GOALS: #NAME? METHODS/STUDY POPULATION: Cell culture & protein identification: human T cells were purified from healthy blood, then activated & cultured for 5d. CAR-T cells were collected from infusion bags of cancer patients undergoing CAR-T. Silver staining of naive & activated healthy T-cell lysates was compared; B-II spectrin was upregulated and confirmed by Western blot. Migration assays: naive & activated T-cells were imaged during migration on ICAM-1 and ICAM-1 + CXCL12 coated plates. T-cells were transfected with BII-spectrin cDNA & the chemokine dependence of migration was compared with controls. In-vivo studies: in a melanoma mouse model, BII-spectrin transfected or control T-cells were injected; tumors were followed with serial imaging. Human patient records were examined to correlate endogenous BII-spectrin levels and CAR-T response. RESULTS/ANTICIPATED RESULTS: Activated T-cells downregulate the cytoskeletal protein B-II spectrin compared to naive cells, leading to chemokine-independent migration in in vitro assays and off-target trafficking when CAR-T cells are given in vivo. Restoration of B-II spectrin levels via transfection restores chemokine-dependence of activated T-cells. In a mouse melanoma model, control mice injected with standard activated T-cells showed fewer cells in the tumor site and more cells in the off-target organs (spleen, lungs) when compared to mice injected with B-II spectrin transfected cells. Furthermore, among 3 human patients undergoing CAR-T therapy, those with higher endogenous B-II spectrin levels experienced fewer side-effects, measured by the neurotoxicity and cytokine release syndrome grades. DISCUSSION/SIGNIFICANCE: A major hurdle to widespread CAR-T therapy for cancer is significant, often fatal side-effects. Our work shows that the protein B-II spectrin is downregulated during CAR-T production, and that restoring B-II spectrin levels decreases side-effects while increasing tumor clearance--hopefully translating to better CAR-T regimens for the future.

We report a new zircon U–Pb age of 1257 ± 6 Ma for the Punugodu granite (PG) pluton in the Eastern Dharwar Craton (EDC), Southern India. The Mesoproterozoic PG is alkali feldspar hypersolvus granite emplaced at shallow crustal level, as evident from the presence of rhyodacite xenoliths and hornfelsic texture developed in the metavolcanic country rocks of the Neoarchaean Nellore Schist Belt (NSB). Geochemically, the PG is metaluminous, ferroan and alkali-calcic, and is characterized by high SiO2 and Na2O + K2O, Ga/Al ratios >2.6, high-field-strength elements and rare earth element (REE) contents with low CaO, MgO and Sr, indicating its similarity to anorogenic, alkali (A-type) granite. The highly fractionated REE patterns with negative europium anomalies of PG reflect its evolved nature and feldspar fractionation. Mafic (MME) to hybrid (HME) microgranular enclaves represent distinct batches of mantle-derived magmas that interacted, mingled and undercooled within the partly crystalline PG host magma. Felsic microgranular enclaves (FME) having similar mineralogical and geochemical characteristics to the host PG most likely represent fragments of marginal rock facies of the PG pluton. The PG appears to be formed from an oceanic island basalt (OIB)-like source in an anorogenic, within-plate setting. The emplacement of PG (c. 1257 Ma) in the vicinity of Mesoproterozoic Kanigiri Ophiolite (c. 1334 Ma) shows an age gap of nearly 77 Ma, which probably suggests PG emplacement in an extensional environment along a terrain boundary at the western margin of the Neoarchaean NSB in the EDC.

Anthracnose caused by Colletotrichum truncatum is a major soybean disease in India. Genetic resistance is the viable option to combat yield losses due to this disease. In the current study, 19 soybean genotypes were evaluated for anthracnose disease resistance at five locations (Medziphema, Palampur, Dharwad, Jabalpur and Indore) for three consecutive years (2017–2019) to identify stable and superior genotypes as resistant sources and to elucidate genotype (G) × environment (E) interactions. Genotype effect, environment effect and G × E interactions were found significant (P < 0.001) where G × E interactions contributed highest (42.44) to the total variation followed by environment (29.71) and genotype (18.84). Through Weighted Average of Absolute Scores (WAASB) stability analysis, PS 1611 (WAASB score = 0.33) was found to be most stable and through WAASBY superiority analysis NRC 128 (WAASBY score = 94.31) and PS 1611 (WAASBY score = 89.43) were found to be superior for mean performance and stability. These two genotypes could be candidate parents for breeding for durable and stable anthracnose resistance. Through principal component analysis, disease score was found to be positively associated with relative humidity, wind speed at 2 m above ground level, effect of temperature on radiation use efficiency and global solar radiation based on latitude and Julian day. Among the five locations, Indore was found to be highly discriminative with the highest mean disease incidence and could differentiate anthracnose-resistant and susceptible genotypes effectively, therefore can be considered an ideal location for breeding for field resistance against anthracnose disease.

Weeds are a major biotic constraint to the production of crops. Studies on the critical period of weed control (CPWC) consider the yield loss due to the presence of all weeds present in the crop cycle. The CPWC is the time interval between the critical timing of weed removal (CTWR) and the critical weed-free period (CWFP), and the weed presence before and after the extremes of CTWR and CWFP may not significantly reduce crop yield. The crop yield is taken into consideration and weed density or biomass of individual weeds (annual or perennial) is not so important while calculating the CPWC. Only weed density or biomass is considered for calculating weed control efficiency of a particular management practice for which the weed seed bank is also a criterion. However, weed biomass is the outcome after competition experienced by each weed species with the fellow crop and the weeds. Consequently, the weed pressure in the subsequent season will be the cumulative effect of the preceding season too, which is unaccounted for in CPWC. It is argued that in organic farming or low-input farming systems, where herbicides are not used, the concept of CPWC can be misleading and should be avoided. It is concluded that CTWR is more meaningful than the CPWC.

The ablation zones of debris-covered glaciers in Himalaya exhibit heterogeneous processes and melt patterns. Although sub-debris melt is measured at ablation stakes, the high variability of debris thickness necessitates distributed melt measurements at the glacier scale. Focusing on Annapurna III Glacier, we used uncrewed aerial system (UAS) photogrammetry to estimate total volume loss and slope-perpendicular glacier melt between May and November 2019 using flow-corrected point clouds. Results indicated the average elevation change was −1.10 ± 0.19 m, while the mean melt was −0.87 m w.e., equating to a mean melt rate of −0.47 cm w.e. d−1. However, the spatial pattern was highly variable due to complex local processes necessitating future study over short intervals. The evaluation of specific areas showed the interplay of debris thickness variability, subseasonal debris redistribution, supraglacial channel reconfiguration and the imprint of relict ice cliffs in leading to contemporary melt rates. Ice cliffs had higher melt distances (mean −3.9 ± 0.19 m) compared to non-cliff areas (mean −0.75 ± 0.19 m) and were the predominant control on the spatial patterns of seasonal melt rates. Crucially, the definition of ice cliff areas from thinning data has a profound impact on derived melt rates and melt enhancement. Our study demonstrates the possibility and utility of deriving fully-distributed slope-perpendicular melt measurements.

Conservation agriculture (CA) practices are becoming more important in Mediterranean rainfed areas due to their potential to minimize climatic risk, reduce soil erosion, and improve soil quality and water availability. Due to minimum soil disturbance and crop residue retention, the soil environment for crop growth and development can differ between CA and conventional tillage (CT) practice. However, breeding targets for improving yield performance in CA system remain poorly explored. The objective of this study was to assess the performance of elite genotypes of barley, chickpea, lentil, and wheat grown under CA, a promising alternative agricultural practice in the Mediterranean rainfed conditions. A three-year field study, with contrasting rainfall pattern, was conducted in the International Center for Agriculture Research in the Dry Areas’s research field in Morocco to evaluate the tillage × genotype interaction and its consequence for yield performance of barley, chickpea, lentil, and wheat. Thirteen elite genotypes for each crop were planted under both CA and CT systems. Wheat and chickpea produced significantly higher grain yield (+62% for wheat and +43% for chickpea) under CA than in CT, while lentil and barley performed equally under both systems. Significant effect of tillage × genotype was more frequent for chickpea and wheat than for barley and lentil. Increased yield under CA, mainly in dry year, was associated with higher harvest index (HI). For each crop species yield was mainly influenced by rainfall amount and distribution (75–88% yield variation), and tillage × genotype was of little importance. The overall results suggest that a specific breeding program for CA in lentil, chickpea, wheat, and barley may not be efficient. Few tillage × genotype interaction, especially in dry years, indicated that breeding target on increasing HI, tolerance to drought (high yield in dry years), and potential yield (high yield in wet year) can help to improve yield performance of chickpea, lentil, and wheat genotypes in CA system. Varieties with wider adaptability considering drought tolerance, higher yield with stability, and adoption of CA practices are important in the context of the Mediterranean rainfed environment. Integrating trade-off analysis between yield potential and stability in a rainfall gradient in both CT and CA in the national certification scheme of varieties may be more efficient than developing breeding programs for each type of tillage system.