Kaiser CM et al. (2012) Biophys J "Tracking UNC-45 chaperone-myosin interaction with a titin mechanical reporter."

Ma L, Oberhauser AF, Kaiser CM, Bujalowski PJ, Epstein HF, Anderson J

[Biophys J, 2012]

Myosins are molecular motors that convert chemical energy into mechanical work. Allosterically coupling ATP-binding, hydrolysis, and binding/dissociation to actin filaments requires precise and coordinated structural changes that are achieved by the structurally complex myosin motor domain. UNC-45, a member of the UNC-45/Cro1/She4p family of proteins, acts as a chaperone for myosin and is essential for proper folding and assembly of myosin into muscle thick filaments in vivo. The molecular mechanisms by which UNC-45 interacts with myosin to promote proper folding of the myosin head domain are not known. We have devised a novel approach, to our knowledge, to analyze the interaction of UNC-45 with the myosin motor domain at the single molecule level using atomic force microscopy. By chemically coupling a titin I27 polyprotein to the motor domain of myosin, we introduced a mechanical reporter. In addition, the polyprotein provided a specific attachment point and an unambiguous mechanical fingerprint, facilitating our atomic force microscopy measurements. This approach enabled us to study UNC-45-motor domain interactions. After mechanical unfolding, the motor domain interfered with refolding of the otherwise robust I27 modules, presumably by recruiting them into a misfolded state. In the presence of UNC-45, I27 folding was restored. Our single molecule approach enables the study of UNC-45 chaperone interactions with myosin and their consequences for motor domain folding and misfolding in mechanistic detail.

Kaiser M et al. (2011) Network "Evolution and development of brain networks: from Caenorhabditis elegans to Homo sapiens."

Varier S, Kaiser M

[Network, 2011]

Neural networks show a progressive increase in complexity during the time course of evolution. From diffuse nerve nets in Cnidaria to modular, hierarchical systems in macaque and humans, there is a gradual shift from simple processes involving a limited amount of tasks and modalities to complex functional and behavioral processing integrating different kinds of information from highly specialized tissue. However, studies in a range of species suggest that fundamental similarities, in spatial and topological features as well as in developmental mechanisms for network formation, are retained across evolution. 'Small-world' topology and highly connected regions (hubs) are prevalent across the evolutionary scale, ensuring efficient processing and resilience to internal (e.g. lesions) and external (e.g. environment) changes. Furthermore, in most species, even the establishment of hubs, long-range connections linking distant components, and a modular organization, relies on similar mechanisms. In conclusion, evolutionary divergence leads to greater complexity while following essential developmental constraints.

Kaiser M et al. (2009) Cereb Cortex "A simple rule for axon outgrowth and synaptic competition generates realistic connection lengths and filling fractions."

van Ooyen A, Hilgetag CC, Kaiser M

[Cereb Cortex, 2009]

Neural connectivity at the cellular and mesoscopic level appears very specific and is presumed to arise from highly specific developmental mechanisms. However, there are general shared features of connectivity in systems as different as the networks formed by individual neurons in Caenorhabditis elegans or in rat visual cortex and the mesoscopic circuitry of cortical areas in the mouse, macaque, and human brain. In all these systems, connection length distributions have very similar shapes, with an initial large peak and a long flat tail representing the admixture of long-distance connections to mostly short-distance connections. Furthermore, not all potentially possible synapses are formed, and only a fraction of axons (called filling fraction) establish synapses with spatially neighboring neurons. We explored what aspects of these connectivity patterns can be explained simply by random axonal outgrowth. We found that random axonal growth away from the soma can already reproduce the known distance distribution of connections. We also observed that experimentally observed filling fractions can be generated by competition for available space at the target neurons--a model markedly different from previous explanations. These findings may serve as a baseline model for the development of connectivity that can be further refined by more specific mechanisms.

Das L et al. (2018) Genomics "An integrated approach for identification of exon locations using recursive Gauss Newton tuned adaptive Kaiser window."

Nanda S, Das JK, Das L

[Genomics, 2018]

Identification of exon location in a DNA sequence has been considered as the most demanding and challenging research topic in the field of Bioinformatics. This work proposes a robust approach combining the Trigonometric mapping with Adaptive tuned Kaiser Windowing approach for locating the protein coding regions (EXONS) in a genetic sequence. For better convergence as well as improved accurateness, the side lobe height control parameter () of Kaiser Window in the proposed algorithm is made adaptive to track the changing dynamics of the genetic sequence. This yields better tracking potential of the anticipated Adaptive Kaiser algorithm as it uses the recursive Gauss Newton tuning which in turn utilizes the covariance of the error signal to tune the factor which has been shown through numerous simulation results under a variety of practical test conditions. A detailed comparative analysis with the existing mapping schemes, windowing techniques, and other signal processing methods like SVD, AN, DFT, STDFT, WT, and ST has also been included in the paper to focus on the strength and efficiency of the proposed approach. Moreover, some critical performance parameters have been computed using the proposed approach to investigate the effectiveness and robustness of the algorithm. In addition to this, the proposed approach has also been successfully applied on a number of benchmark gene sets like Musmusculus, Homosapiens, and C. elegans, etc., where the proposed approach revealed efficient prediction of exon location in contrast to the other existing mapping methods.

Kaiser M et al. (2006) PLoS Comput Biol "Nonoptimal component placement, but short processing paths, due to long-distance projections in neural systems."

Hilgetag CC, Kaiser M

[PLoS Comput Biol, 2006]

It has been suggested that neural systems across several scales of organization show optimal component placement, in which any spatial rearrangement of the components would lead to an increase of total wiring. Using extensive connectivity datasets for diverse neural networks combined with spatial coordinates for network nodes, we applied an optimization algorithm to the network layouts, in order to search for wire-saving component rearrangements. We found that optimized component rearrangements could substantially reduce total wiring length in all tested neural networks. Specifically, total wiring among 95 primate (Macaque) cortical areas could be decreased by 32%, and wiring of neuronal networks in the nematode Caenorhabditis elegans could be reduced by 48% on the global level, and by 49% for neurons within frontal ganglia. Wiring length reductions were possible due to the existence of long-distance projections in neural networks. We explored the role of these projections by comparing the original networks with minimally rewired networks of the same size, which possessed only the shortest possible connections. In the minimally rewired networks, the number of processing steps along the shortest paths between components was significantly increased compared to the original networks. Additional benchmark comparisons also indicated that neural networks are more similar to network layouts that minimize the length of processing paths, rather than wiring length. These findings suggest that neural systems are not exclusively optimized for minimal global wiring, but for a variety of factors including the minimization of processing steps.

Reinhardt F et al. (2024) Heliyon "Evolution of neuropeptide Y/RFamide-like receptors in nematodes."

Reinhardt F, Stadler PF, Kaiser A, Proemel S

[Heliyon, 2024]

The Neuropeptide Y/RFamide-like receptors belong to the Rhodopsin-like G protein-coupled receptors G protein-coupled receptors (GPCRs) and are involved in functions such as locomotion, feeding and reproduction. With 41 described receptors they form the best-studied group of neuropeptide GPCRs in <i>Caenorhabditis elegans</i>. In order to understand the expansion of the Neuropeptide Y/RFamide-like receptor family in nematodes, we started from the sequences of selected receptor paralogs in <i>C. elegans</i> as query and surveyed the corresponding orthologous sequences in another 159 representative nematode target genomes. To this end we employed a automated pipeline based on ExonMatchSolver, a tool that solves the paralog-to-contig assignment problem. Utilizing subclass-specific HMMs we were able to detect a total of 1557 Neuropeptide Y/RFamide-like receptor sequences (1100 NPRs, 375 FRPRs and 82 C09F12.3) in the 159 target nematode genomes investigated here. These sequences demonstrate a good conservation of the Neuropeptide Y/RFamide-like receptors across the Nematoda and highlight the diversification of the family in nematode evolution. No other genus shares all Neuropeptide Y/RFamide-like receptors with the genus <i>Caenorhabditis</i>. At the same time, we observe large numbers of clade specific duplications and losses of family members across the phylum Nematoda.

Gershkovich MM et al. (2019) Cell Commun Signal "Pharmacological and functional similarities of the human neuropeptide Y system in C. elegans challenges phylogenetic views on the FLP/NPR system."

Kaiser A, GroB VE, Promel S, Gershkovich MM

[Cell Commun Signal, 2019]

BACKGROUND: The neuropeptide Y system affects various processes, among others food intake, and is frequently discussed in the context of targeting obesity. Studies in model organisms are indispensable to enable molecular studies in a physiological context. Although the NPY system is evolutionarily conserved in all bilaterians, in the widely used model Caenorhabditis elegans there is controversy on the existence of NPY orthologous molecules. While the FMRFamide-like peptide (FLP)/Neuropeptide receptor-Resemblance (NPR) system in the nematode was initially suggested to be orthologous to the mammalian NPY system, later global phylogenetic studies indicate that FLP/NPR is protostome-specific. METHODS: We performed a comprehensive pharmacological study of the FLP/NPR system in transfected cells in vitro, and tested for functional substitution in C. elegans knockout strains. Further, we phenotypically compared different flp loss-of-function strains. Differences between groups were compared by ANOVA and post-hoc testing (Dunnett, Bonferroni). RESULTS: Our pharmacological analysis of the FLP/NPR system including formerly functionally uncharacterized NPY-like peptides from C. elegans demonstrates that G protein-coupling and ligand requirements for receptor activation are similar to the human NPY system. In vitro and in vivo analyses show cross-reactivity of NPY with the FLP/NPR system manifesting in the ability of the human GPCRs to functionally substitute FLP/NPR signaling in vivo. The high pharmacological/functional similarities enabled us to identify C. elegans FLP-14 as a key molecule in avoidance behavior. CONCLUSIONS: Our data demonstrate the pharmacological and functional similarities of human NPY and C. elegans NPR systems. This adds a novel perspective to current phylogenetic reconstructions of the neuropeptide Y system. NPY and NPR receptors are pharmacologically so similar that the human receptors can functionally compensate for the C. elegans ones, suggesting orthologous relationships. This is also underlined by the presence of NPY-like peptides and parallels in peptide requirements for receptor activation. Further, the results presented here highlight the potential of this knowledge for physiological as well as molecular studies on neuropeptide GPCRs such as the NPY system in the future.

Perez-Escudero A et al. (2007) Proc Natl Acad Sci U S A "Optimally wired subnetwork determines neuroanatomy of Caenorhabditis elegans."

de Polavieja GG, Perez-Escudero A

[Proc Natl Acad Sci U S A, 2007]

Wiring cost minimization has successfully explained many structures of nervous systems. However, in the nematode Caenorhabditis elegans, for which anatomical data are most detailed, wiring economy is thought to play only a partial role and alone has failed to account for the grouping of neurons into ganglia [Chen BL, Hall DH, Chklovskii DB (2006) Proc Natl Acad Sci USA 103:4723-4728; Kaiser M, Hilgetag CC (2006) PLoS Comput Biol 2:e95; Ahn Y-Y, Jeong H, Kim BJ (2006) Physica A 367:531-537]. Here, we test the hypothesis that optimally wired subnetworks can exist within nonoptimal networks, thus allowing wiring economy to give an improved prediction of spatial structure. We show in C. elegans that the small subnetwork of wires connecting sensory and motor neurons with sensors and muscles, comprising only 15% of connections, is close to optimal and alone predicts the main features of the spatial segregation of neurons into ganglia and encephalization. Moreover, a method to dissect networks into optimal and nonoptimal components is shown to find a large near-optimal subnetwork of 84% of neurons with a very low position error of 5.4%, and that explains clustering of neurons into ganglia and encephalization to fine detail. In general, we expect realistic networks not to be globally optimal in wire cost. We thus propose the strategy of using near-optimal subnetworks to understand neuroanatomical structure.

GroB VE et al. (2022) BMC Mol Cell Biol "NanoBRET in C. elegans illuminates functional receptor interactions in real time."

Schoneberg T, Kaiser A, GroB VE, Gershkovich MM, Promel S

[BMC Mol Cell Biol, 2022]

BACKGROUND: Protein-protein interactions form the basis of every organism and thus, investigating their dynamics, intracellular protein localization, trafficking and interactions of distinct proteins such as receptors and their ligand-binding are of general interest. Bioluminescence resonance energy transfer (BRET) is a powerful tool to investigate these aspects in vitro. Since in vitro approaches mostly neglect the more complex in vivo situation, we established BRET as an in vivo tool for studying protein interactions in the nematode C. elegans. RESULTS: We generated worms expressing NanoBRET sensors and elucidated the interaction of two ligand-G protein-coupled receptor (GPCR) pairs, the neuropeptide receptor NPR-11 and the Adhesion GPCR LAT-1. Furthermore, we adapted the enhanced bystander BRET technology to measure subcellular protein localization. Using this approach, we traced ligand-induced internalization of NPR-11 in vivo. CONCLUSIONS: Our results indicate that in vivo NanoBRET is a tool to investigate specific protein interactions and localization in a physiological setting in real time in the living organism C. elegans.

Albiez EJ et al. (1988) Trop Med Parasitol "Effects of high doses of diethylcarbamazine on adult Onchocerca volvulus examined by the collagenase technique and by histology."

Buttner DW, Kaiser A, Greene BM, Taylor HR, Albiez EJ, White AT, Walter G, Newland HS

[Trop Med Parasitol, 1988]

Thirty adult male nodule carriers from a hyperendemic onchocerciasis area in the Liberian rain forest were treated with high doses of diethylcarbamazine (30 mg/kg/d) over one week. Another ten patients received placebo tablets and served as a control. All detectable nodules were removed from half of the patients at two months and from the remaining patients at ten months after chemotherapy. The adult worms in the nodules were examined for pathological alterations by the collagenase technique including embryogram, and by histology. No macrofilaricidal effect was observed at either time, and no significant reduction of microfilariae in the uteri of the female worms or in the tissue of the nodules was seen. Two months after the therapy there was a significant increase of degenerated stretched intrauterine microfilariae but this effect was no longer observed after ten months. No pathological effect was seen on the intrauterine coiled microfilariae. On the contrary, their number had significantly increased after ten months which could mean a stimulation of the embryogenesis. No effect on spermatogenesis was observed. Both techniques, the collagenase digestion and the histological examination of the nodules, provided similar results to demonstrate that there was no marked long lasting effect on O. volvulus after a treatment with high doses of diethylcarbamazine.