Nejatbakhsh A et al. (2023) Inf Process Med Imaging "Learning Probabilistic Piecewise Rigid Atlases of Model Organisms via Generative Deep Networks."

Dey N, Paninski L, Venkatachalam V, Nejatbakhsh A, Yemini E, Varol E

[Inf Process Med Imaging, 2023]

Atlases are crucial to imaging statistics as they enable the standardization of inter-subject and inter-population analyses. While existing atlas estimation methods based on fluid/elastic/diffusion registration yield high-quality results for the human brain, these deformation models do not extend to a variety of other challenging areas of neuroscience such as the anatomy of <i>C. elegans</i> worms and fruit flies. To this end, this work presents a general probabilistic deep network-based framework for atlas estimation and registration which can flexibly incorporate various deformation models and levels of keypoint supervision that can be applied to a wide class of model organisms. Of particular relevance, it also develops a deformable piecewise rigid atlas model which is regularized to preserve inter-observation distances between neighbors. These modeling considerations are shown to improve atlas construction and key-point alignment across a diversity of datasets with small sample sizes including neuron positions in <i>C. elegans</i> hermaphrodites, fluorescence microscopy of male <i>C. elegans</i>, and images of fruit fly wings. Code is accessible at https://github.com/amin-nejat/Deformable-Atlas.

Skuhersky M et al. (2022) BMC Bioinformatics "Toward a more accurate 3D atlas of C. elegans neurons."

Yemini E, Tegmark M, Wu T, Nejatbakhsh A, Boyden E, Skuhersky M

[BMC Bioinformatics, 2022]

BACKGROUND: Determining cell identity in volumetric images of tagged neuronal nuclei is an ongoing challenge in contemporary neuroscience. Frequently, cell identity is determined by aligning and matching tags to an "atlas" of labeled neuronal positions and other identifying characteristics. Previous analyses of such C.elegansdatasets have been hampered by the limited accuracy of such atlases, especially for neurons present in the ventral nerve cord, and also by time-consuming manual elements of the alignment process. RESULTS: We present a novel automated alignment method for sparse and incomplete point clouds of the sort resulting from typical C.elegansfluorescence microscopy datasets. This method involves a tunable learning parameter and a kernel that enforces biologically realistic deformation. We also present a pipeline for creating alignment atlases from datasets of the recently developed NeuroPAL transgene. In combination, these advances allow us to label neurons in volumetric images with confidence much higher than previous methods. CONCLUSIONS: We release, to the best of our knowledge, the most complete full-body C.elegans3D positional neuron atlas, incorporating positional variability derived from at least 7 animals per neuron, for the purposes of cell-type identity prediction for myriad applications (e.g., imaging neuronal activity, gene expression, and cell-fate).

Ryu J et al. (2024) PLoS Comput Biol "Versatile multiple object tracking in sparse 2D/3D videos via deformable image registration."

Gangadharan S, Paninski L, Nejatbakhsh A, Seyedolmohadesin M, Torkashvand M, Kim J, Ryu J, Venkatachalam V

[PLoS Comput Biol, 2024]

Tracking body parts in behaving animals, extracting fluorescence signals from cells embedded in deforming tissue, and analyzing cell migration patterns during development all require tracking objects with partially correlated motion. As dataset sizes increase, manual tracking of objects becomes prohibitively inefficient and slow, necessitating automated and semi-automated computational tools. Unfortunately, existing methods for multiple object tracking (MOT) are either developed for specific datasets and hence do not generalize well to other datasets, or require large amounts of training data that are not readily available. This is further exacerbated when tracking fluorescent sources in moving and deforming tissues, where the lack of unique features and sparsely populated images create a challenging environment, especially for modern deep learning techniques. By leveraging technology recently developed for spatial transformer networks, we propose ZephIR, an image registration framework for semi-supervised MOT in 2D and 3D videos. ZephIR can generalize to a wide range of biological systems by incorporating adjustable parameters that encode spatial (sparsity, texture, rigidity) and temporal priors of a given data class. We demonstrate the accuracy and versatility of our approach in a variety of applications, including tracking the body parts of a behaving mouse and neurons in the brain of a freely moving C. elegans. We provide an open-source package along with a web-based graphical user interface that allows users to provide small numbers of annotations to interactively improve tracking results.

Yemini E et al. (2020) Cell "NeuroPAL: A Multicolor Atlas for Whole-Brain Neuronal Identification in C.elegans."

Paninski L, Mena GE, Yemini E, Venkatachalam V, Lin A, Samuel ADT, Varol E, Nejatbakhsh A, Hobert O, Sun R

[Cell, 2020]

Comprehensively resolving neuronal identities in whole-brain images is a major challenge. We achieve this in C.elegans by engineering a multicolor transgene called NeuroPAL (a neuronal polychromatic atlas of landmarks). NeuroPAL worms share a stereotypical multicolor fluorescence map for the entire hermaphrodite nervous system that resolves all neuronal identities. Neurons labeled with NeuroPAL do not exhibit fluorescence in the green, cyan, or yellow emission channels, allowing the transgene to be used with numerous reporters of gene expression or neuronal dynamics. We showcase three applications that leverage NeuroPAL for nervous-system-wide neuronal identification. First, we determine the brainwide expression patterns of all metabotropic receptors for acetylcholine, GABA, and glutamate, completing a map of this communication network. Second, we uncover changes in cell fate caused by transcription factor mutations. Third, we record brainwide activity in response to attractive and repulsive chemosensory cues, characterizing multimodal coding for these stimuli.

Tekieli T et al. (2021) Development "Visualizing the organization and differentiation of the male-specific nervous system of C. elegans."

Hobert O, Tekieli T, Yemini E, Nejatbakhsh A, MASOUDI N, Paninski L, Wang C, Fernandez RW, Varol E

[Development, 2021]

Sex differences in the brain are prevalent throughout the animal kingdom and particularly well appreciated in the nematode C. elegans, where male animals contain a little studied set of 93 male-specific neurons. To make these neurons amenable for future study, we describe here how a multicolor reporter transgene, NeuroPAL, is capable of visualizing the distinct identities of all male specific neurons. We used NeuroPAL to visualize and characterize a number of features of the male-specific nervous system. We provide several proofs of concept for using NeuroPAL to identify the sites of expression of gfp-tagged reporter genes and for cellular fate analysis by analyzing the effect of removal of several developmental patterning genes on neuronal identity acquisition. We use NeuroPAL and its intrinsic cohort of more than 40 distinct differentiation markers to show that, even though male-specific neurons are generated throughout all four larval stages, they execute their terminal differentiation program in a coordinated manner in the fourth larval stage. This coordinated wave of differentiation, which we call "just-in-time" differentiation, couples neuronal maturation programs with the appearance of sexual organs.

Quartey MO et al. (2021) Sci Rep "The A(1-38) peptide is a negative regulator of the A(1-42) peptide implicated in Alzheimer disease progression."

Pennington PR, Heistad RM, Nyarko JNK, Barnes JR, Bolanos MAC, Parsons MP, Knudsen KJ, De Carvalho CE, Leary SC, Mousseau DD, Buttigieg J, Maley JM, Quartey MO

[Sci Rep, 2021]

The pool of -Amyloid (A) length variants detected in preclinical and clinical Alzheimer disease (AD) samples suggests a diversity of roles for A peptides. We examined how a naturally occurring variant, e.g. A(1-38), interacts with the AD-related variant, A(1-42), and the predominant physiological variant, A(1-40). Atomic force microscopy, Thioflavin T fluorescence, circular dichroism, dynamic light scattering, and surface plasmon resonance reveal that A(1-38) interacts differently with A(1-40) and A(1-42) and, in general, A(1-38) interferes with the conversion of A(1-42) to a -sheet-rich aggregate. Functionally, A(1-38) reverses the negative impact of A(1-42) on long-term potentiation in acute hippocampal slices and on membrane conductance in primary neurons, and mitigates an A(1-42) phenotype in Caenorhabditis elegans. A(1-38) also reverses any loss of MTT conversion induced by A(1-40) and A(1-42) in HT-22 hippocampal neurons and APOE 4-positive human fibroblasts, although the combination of A(1-38) and A(1-42) inhibits MTT conversion in APOE 4-negative fibroblasts. A greater ratio of soluble A(1-42)/A(1-38) [and A(1-42)/A(1-40)] in autopsied brain extracts correlates with an earlier age-at-death in males (but not females) with a diagnosis of AD. These results suggest that A(1-38) is capable of physically counteracting, potentially in a sex-dependent manner, the neuropathological effects of the AD-relevant A(1-42).

Tangrodchanapong T et al. (2020) Front Pharmacol "Frondoside A Attenuates Amyloid- Proteotoxicity in Transgenic Caenorhabditis elegans by Suppressing Its Formation."

Tangrodchanapong T, Sobhon P, Meemon K

[Front Pharmacol, 2020]

Oligomeric assembly of Amyloid- (A) is the main toxic species that contribute to early cognitive impairment in Alzheimer's patients. Therefore, drugs that reduce the formation of A oligomers could halt the disease progression. In this study, by using transgenic <i>Caenorhabditis elegans</i> model of Alzheimer's disease, we investigated the effects of frondoside A, a well-known sea cucumber <i>Cucumaria frondosa</i> saponin with anti-cancer activity, on A aggregation and proteotoxicity. The results showed that frondoside A at a low concentration of 1 M significantly delayed the worm paralysis caused by A aggregation as compared with control group. In addition, the number of A plaque deposits in transgenic worm tissues was significantly decreased. Frondoside A was more effective in these activities than ginsenoside-Rg3, a comparable ginseng saponin. Immunoblot analysis revealed that the level of small oligomers as well as various high molecular weights of A species in the transgenic <i>C. elegans</i> were significantly reduced upon treatment with frondoside A, whereas the level of A monomers was not altered. This suggested that frondoside A may primarily reduce the level of small oligomeric forms, the most toxic species of A. Frondoside A also protected the worms from oxidative stress and rescued chemotaxis dysfunction in a transgenic strain whose neurons express A. Taken together, these data suggested that low dose of frondoside A could protect against A-induced toxicity by primarily suppressing the formation of A oligomers. Thus, the molecular mechanism of how frondoside A exerts its anti-A aggregation should be studied and elucidated in the future.

Viney ME et al. (2004) Naturwissenschaften "Is dauer pheromone of Caenorhabditis elegans really a pheromone?"

Viney ME, Franks NR

[Naturwissenschaften, 2004]

Animals respond to signals and cues in their environment. The difference between a signal (e.g. a pheromone) and a cue (e.g. a waste product) is that the information content of a signal is subject to natural selection, whereas that of a cue is not. The model free-living nematode Caenorhabditis elegans forms an alternative developmental morph (the dauer larva) in response to a so-called 'dauer pheromone', produced by all worms. We suggest that the production of 'dauer pheromone' has no fitness advantage for an individual worm and therefore we propose that 'dauer pheromone' is not a signal, but a cue. Thus, it should not be called a pheromone.

Schaeffer JM et al. (1990) J Antibiot (Tokyo) "Cochlioquinone A, a nematocidal agent which competes for specific [3H]ivermectin binding sites."

Williamson JM, Schaeffer JM, Bergstrom AR, Liesch JM, Goetz MA, Frazier EG

[J Antibiot (Tokyo), 1990]

Cochlioquinone A, isolated from the fungus Helminthosporium sativum, was found to have nematocidal activity. Cochlioquinone A is a competitive inhibitor of specific [3H]ivermectin binding suggesting that cochlioquinone A and ivermectin interact with the same membrane receptor.

Desta IT et al. (2016) J Lab Autom "Detecting and Trapping of a Single C. elegans Worm in a Microfluidic Chip for Automated Microplate Dispensing."

Giakoumidis N, Mustafa N, AlGharibeh N, Orozaliev A, Al-Sharif A, Song YA, Desta IT, Gunsalus KC

[J Lab Autom, 2016]

Microfluidic devices offer new technical possibilities for a precise manipulation of Caenorhabditis elegans due to the comparable length scale. C. elegans is a small, free-living nematode worm that is a popular model system for genetic, genomic, and high-throughput experimental studies of animal development and neurobiology. In this paper, we demonstrate a microfluidic system in polydimethylsiloxane (PDMS) for dispensing of a single C. elegans worm into a 96-well plate. It consists of two PDMS layers, a flow and a control layer. Using five microfluidic pneumatic valves in the control layer, a single worm is trapped upon optical detection with a pair of optical fibers integrated perpendicular to the constriction channel and then dispensed into a microplate well with a dispensing tip attached to a robotic handling system. Due to its simple design and facile fabrication, we expect that our microfluidic chip can be expanded to a multiplexed dispensation system of C. elegans worms for high-throughput drug screening.