Biology subjects

Nandi, A.

Publications and source records attributed to Nandi, A..

26 records · Page 2Linked to original sources

bioRxiv2020

Neural Circuit Dynamics for Sensory Detection

We consider the question of how sensory networks enable the detection of sensory stimuli in a combinatorial coding space. We are specifically interested in the olfactory system, wherein recent experimental studies have reported the existence of rich, enigmatic response patterns associated with stimulus onset and offset. This study aims to identify the functional relevance of such response patterns, i.e., what benefits does such neural activity provide in the context of detecting stimuli in a natural environment. We study this problem through the lens of normative, optimization-based modeling. Here, we define the notion of a low dimensional latent representation of stimulus identity, which is generated through action of the sensory network. The objective of our optimization framework is to ensure high fidelity tracking of a nominal representation in this latent space in an energy efficient manner. It turns out that the optimal motifs emerging from this framework possess morphological similarity with prototypical onset and offset responses observed in vivo. Furthermore, this objective can be exactly achieved by a network with reciprocal excitatory-inhibitory competitive dynamics, similar to interactions between principal neurons (PNs) and local neurons (LNs) in the early olfactory system of insects. The derived model also makes several predictions regarding maintenance of robust latent representations in the presence of confounding background information and tradeoffs between the energy of sensory activity and resultant behavioral measures such as speed and accuracy of stimulus detection. Significance StatementA key area of study in olfactory coding involves understanding the transformation from high-dimensional sensory stimulus to low-dimensional decoded representation. Here, we treat not only the dimensionality reduction of this mapping but also its temporal dynamics, with specific focus on stimuli that are temporally continuous. We examine through optimization-based synthesis how sensory networks can track representations without prior assumption of discrete trial structure. We show that such tracking can be achieved by canonical network architectures and dynamics, and that the resulting responses resemble observations from neurons in the insect olfactory system. Thus, our results provide hypotheses regarding the functional role of olfactory circuit activity at both single neuronal and population scales.

systems biology↗

bioRxiv2020

BACTERIAL GROWTH INDUCED BIOCEMENTATION TECHNOLOGY, 'SPACE BRICK' - A PROPOSAL FOR EXPERIMENT AT MICROGRAVITY AND PLANETARY ENVIRONMENTS

We present results of our investigation of microbial induced calcite precipitation for manufacturing space bricks and a proposal for study of this activity in low-earth orbit (LEO). Sporosarcina pasteurii, a urease producing bacterial strain was used to consolidate lunar simulant soil (LSS) in the form of a brick with non-trivial strength properties. Potential of a naturally occurring polymer namely, guar gum, as an additive was investigated for enhancement in compressive strength of bio-consolidated samples. Experimental results of bio-brick exhibited an approximate 10-fold increase in compressive strength with guar gum supplementation in soil. We present results of microstructural analysis of the space bricks and also propose a payload design for related experiments in LEO.

bioengineering↗

bioRxiv2020

Investigating the impact of combination phage and antibiotic therapy: a modeling study

Antimicrobial resistance (AMR) is a serious threat to global health today. The spread of AMR, along with the lack of new drug classes in the antibiotic pipeline, has resulted in a renewed interest in phage therapy, which is the use of bacteriophages to treat pathogenic bacterial infections. This therapy, which was successfully used to treat a variety of infections in the early twentieth century, had been largely dismissed due to the discovery of easy to use antibiotics. However, the continuing emergence of antibiotic resistance has motivated new interest in the use of phage therapy to treat bacterial infections. Though various models have been developed to address the AMR-related issues, there are very few studies that consider the effect of phage-antibiotic combination therapy. Moreover, some of biological details such as the effect of the immune system on phage have been neglected. To address these limitations, we utilized a mathematical model to examine the role of the immune response in concert with phage-antibiotic combination therapy compounded with the effects of the immune system on the phages being used for treatment. We explore the effect of phage-antibiotic combination therapy by adjusting the phage and antibiotics dose or altering the timing. The model results show that it is important to consider the host immune system in the model and that frequency and dose of treatment are important considerations for the effectiveness of treatment. Our study can lead to development of optimal antibiotic use and further reduce the health risks of the human-animal-plant-ecosystem interface caused by AMR.

microbiology↗

bioRxiv2019

Kinetochore capture by spindle microtubules: why fission yeast may prefer pivoting to search-and-capture

The mechanism by which microtubules find kinetochores during spindle formation is a key question in cell biology. Previous experimental studies have shown that although search-and-capture of kinetochores by dynamic microtubules is a dominant mechanism in many organisms, several other capture mechanisms are also possible. One such mechanism reported in Schizosaccharomyces pombe shows that microtubules can exhibit a prolonged pause between growth and shrinkage. During the pause, the microtubules pivoted at the spindle pole body search for the kinetochores by performing an angular diffusion. Is the latter mechanism purely accidental, or could there be any physical advantage underlying its selection? To compare the efficiency of these two mechanisms, we numerically study distinct models and compute the timescales of kinetochore capture as a function of microtubule number N. We find that the capture timescales have non-trivial dependences on microtubule number, and one mechanism may be preferred over the other depending on this number. While for small N (as in fission yeast), the typical capture times due to rotational diffusion are lesser than those for search-and-capture, the situation is reversed beyond a certain N. The capture times for rotational diffusion tend to saturate due to geometrical constraints, while those for search-and-capture reduce monotonically with increasing N making it physically more efficient. The results provide a rationale for the common occurrence of classic search-and-capture process in many eukaryotes which have few hundreds of dynamic microtubules, as well as justify exceptions in cells with fewer microtubules.

biophysics↗

bioRxiv2019

Model ensembles with different response variables for base and meta models: malaria disaggregation regression combining prevalence and incidence data

Maps of infection risk are a vital tool for the elimination of malaria. Routine surveillance data of malaria case counts, often aggregated over administrative regions, is becoming more widely available and can better measure low malaria risk than prevalence surveys. However, aggregation of case counts over large, heterogeneous areas means that these data are often underpowered for learning relationships between the environment and malaria risk. A model that combines point surveys and aggregated surveillance data could have the benefits of both but must be able to account for the fact that these two data types are different malariometric units. Here, we train multiple machine learning models on point surveys and then combine the predictions from these with a geostatistical disaggregation model that uses routine surveillance data. We find that, in tests using data from Colombia and Madagascar, using a disaggregation regression model to combine predictions from machine learning models trained on point surveys improves model accuracy relative to using the environmental covariates directly.

epidemiology↗

bioRxiv2019

Cyto-architecture constrains a photoactivation induced tubulin gradient in the syncytial Drosophila embryo

Drosophila embryogenesis begins with nuclear division in a common cytoplasm forming a syncytial cell. Morphogen gradient molecules spread across nucleo-cytoplasmic domains to pattern the body axis of the syncytial embryo. The diffusion of molecules across the syncytial nucleo-cytoplasmic domains is potentially constrained by association with the components of cellular architecture, however the extent of restriction has not been examined so far. Here we use photoactivation (PA) to generate a source of cytoplasmic or cytoskeletal molecules in order to monitor the kinetics of their spread in the syncytial Drosophila embryo. Photoactivated PA-GFP and PA-GFP-Tubulin within a fixed anterior area diffused along the antero-posterior axis. These molecules were enriched in cortical cytoplasm above the yolk-filled center suggesting that the cortical cytoplasm is phase separated from the yolk-filled center. The length scales of diffusion were extracted using exponential fits under steady state assumptions. PA-GFP spread to greater distance as compared to PA-GFP-Tubulin. Both gradients were steeper and more restricted when generated in the center of the embryo probably due to a higher density of nucleo-cytoplasmic domains. The length scale of diffusion for PA-GFP-Tubulin gradient increased in mutant embryos containing short plasma membrane furrows and disrupted tubulin cytoskeleton. The PA-GFP gradient shape was unaffected by cyto-architecture perturbation. Taken together, these data show that PA-GFP-Tubulin gradient is largely restricted by its incorporation in the microtubule network and intact plasma membrane furrows. This photoactivation based analysis of protein spread across allows for interpretation of the dependence of gradient formation on the syncytial cyto-architecture.

developmental biology↗

bioRxiv2018

First in-human PET study of 3 novel tau radiopharmaceuticals: RO6958948

Background[11C]RO-963, [11C]RO-643 and [18F]RO-948 (previously referred as [11C]RO6924963, [11C]RO6931643, and [18F]RO6958948, respectively) have been reported as promising PET tracers for tau imaging based on in vitro and preclinical PET data (1,2). Here we describe the first human evaluation of these novel radiotracers.\n\nMethodsAmyloid PET positive Alzheimers disease (AD) patients and young healthy subjects (YC) each received two different tau tracers. Dynamic 90 min scans were obtained after bolus injection of [11C]RO-963, [11C]RO-643 or [18F]RO-948. Arterial blood sampling was performed in 11 healthy controls (HC) and 11 AD. Regions were defined on MRI, and PET data were quantified by plasma reference graphical analysis (for VT) and target cerebellum ratio (SUVR60-90). SUVR images were also analyzed voxelwise. Five older healthy subjects (OC) each received two scans with [18F]RO-948 for evaluation of test-retest variability. Four AD subjects received a repeat [18F]RO-948 scan over about 1 year. Six additional HC (3M: 3F; 41-67y) each received one whole body dosimetry scan with [18F]RO-948.\n\nResultsIn YC, peak SUV values were observed in the temporal lobe with values of approximately 3.0 for [11C]RO-963, 1.5 for [11C]RO-643 and 3.5 for [18F]RO-948. Over all brain regions and subjects, the trend was that [18F]RO-948 had the highest peak SUV value, followed by [11C]RO-963, and then [11C]RO-643. Regional analysis of SUVR and VT for [11C]RO-643 and [18F]RO-948 clearly discriminated AD and HC groups. Compartmental modeling confirmed that [11C]RO-643 had lower brain entry than both [18F]RO-963 and [18F]RO-948, and [18F]RO-948 showed a better contrast between (predicted) areas of high vs low tau accumulation. Thus, our subsequent analysis focused on [18F]RO-948. Both voxelwise and region-based analysis of [18F]RO-948 binding in HC vs AD revealed multiple areas where AD and HC significantly differed. Of 22 high-binding regions, 13 showed significant group difference (following ANOVA, F=45, p<10-5). Voxelwise analysis also revealed a set of symmetrical clusters where AD>HC (threshold of p<0.001, cluster size k>50).\n\nConclusions[18F]RO-948 demonstrates superior characteristics to [11C]RO-643 and [18F]RO-963 for characterization of tau pathology in AD. Regional binding data and kinetic properties of RO-948 compare favorably with existing other tau PET tracers.

neuroscience↗

bioRxiv2018

PET Brain imaging of α7-nAChR with ASEM Reproducibility, occupancy, receptor density, and changes in schizophrenia

The 7 nicotinic acetylcholine receptor (nAChR) increasingly has been implicated in normal brain physiology, as well as in neuropsychiatric disorders. The a7-nAChR primarily is located in cerebral cortex and sub-cortical regions, compared to the 4{beta}2 nAChR subtype that has a more subcortical distribution. The highly cortical distribution suggests a role of a7-nAChR in cognition. We expanded the first-in-human PET imaging of 7-nAChR with [18F]ASEM from five to 21 healthy non-smoking volunteers and added preliminary evidence of binding in six male patients with schizophrenia. Study aims included 1) confirmation of test-retest reproducibility of [18F]ASEM binding in normal volunteers, 2) demonstration of specificity of [18F]ASEM binding by competition with DMXB-A, an 7-nAChR partial agonist previously tested in clinical trials of patients with schizophrenia, 3) estimation of [18F]ASEM binding potentials and 7-nAChR density in vivo in humans, and 4) 7-nAChR binding in patients with schizophrenia compared to healthy volunteers.\n\nTest-retest PET confirmed reproducibility (>90%) (variability [≤] 7%) of [18F]ASEM volume of distribution (VO_SCPLOWTC_SCPLOW) estimates in healthy volunteers. Repeated sessions of PET in five healthy subjects included baseline and effect of inhibition after oral administration of 150 mg DMXB-A. From reduction of binding potentials, we estimated the dose-dependent occupancy of 7-nAChR by DMXB-A at 17-49% for plasma concentrations at 60-200 nM DMXB-A. In agreement with evidence post-mortem, 7-nAChR density (Bmax) averaged 0.67-0.82 nM and inhibitor affinity constant (KO_SCPLOWIC_SCPLOW) averaged 170-385 nM. Median VO_SCPLOWTC_SCPLOW in a feasibility study of six patients with schizophrenia was lower than in healthy volunteers in cingulate cortex, frontal cortex, and hippocampus. Mann-Whitney test identified cingulate cortex and hippocampus as regions with significantly lower median VO_SCPLOWTC_SCPLOW in patients than in healthy volunteers when a single outlier patient was excluded from analysis (P = 0.02, corrected for multiple comparisons).

neuroscience↗