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PubMed2025

Modular Photoswitchable Molecular Glues for Chemo-Optogenetic Control of Protein Function in Living Cells.

Optogenetic systems using photosensitive proteins and chemically induced dimerization/proximity (CID/CIP) approaches enabled by chemical dimerizers (also termed molecular glues), are powerful tools to elucidate the dynamics of biological systems and to dissect complex biological regulatory networks. Here, we report a versatile chemo-optogenetic system using modular, photoswitchable molecular glues (sMGs) that can undergo repeated cycles of optical control to switch protein function on and off. We use molecular dynamics (MD) simulations to rationally design the sMGs and further expand their scope by incorporating different photoswitches, resulting in sMGs with customizable properties. We demonstrate that this system can be used to reversibly control protein localization, organelle positioning, protein-fragment complementation as well as posttranslational protein levels by light with high spatiotemporal precision. This system enables sophisticated optical manipulation of cellular processes and thus opens up a new avenue for chemo-optogenetics.

Optogenetics↗

PubMed2025

A Versatile Disulfide-Containing Solid-Support Strategy for 3'-Modifiers in Oligonucleotides: Introducing Modular Tandem Oligonucleotide Synthesis.

Chemical modifications of oligonucleotides are routinely employed to enhance their functional properties. Amino-modifiers serve as versatile chemical handles for postsynthetic (bio)conjugation, nucleic acid immobilization on solid supports, and investigations into nonenzymatic genome replication relevant to the origins of life, to name a few. Here, we report a cost-effective, disulfide-containing solid-support linkage that enables the on-column synthesis of nucleic acids with 3'-amino or 3'-phosphate modifications. The orthogonality of this solid-support linker facilitates an on-column protecting group strategy, enabling the synthesis of DNA and RNA containing 3'-amino-2',3'-dideoxyribosides from commercial unprotected mononucleosides. Additionally, we present an on-column deprotection protocol for DNA and RNA, prior to cleavage from the solid support, eliminating the precipitation step typically required in conventional RNA workflows, leading to higher recovery for certain strands. Expanding on our previous work, we introduce a versatile modular tandem oligonucleotide synthesis (mTOS) approach, allowing selective release of downstream strands from the one directly bound to the solid-support via the disulfide-containing linker. Together, these advances in solid-support design and oligonucleotide synthesis unlock new opportunities in bioconjugation, biotechnology, and the study of prebiotic replication mechanisms, broadening the utility of chemically modified nucleic acids across research disciplines.

Disulfides↗

PubMed1987

A modular detector for flow cytometric multicolor fluorescence measurements.

A modular detector for measuring multicolor fluorescence from cells illuminated by single or multiple lasers has been developed for flow cytometers. Motion picture projector, camera, and CCTV/video lenses were evaluated for use in the detector by comparing their physical characteristics, image quality, and light collection efficiencies. A 25-mm focal length F/0.95 CCTV lens was selected, based on our criteria and test results. The detector was constructed out of square aluminum extrusion channels. A CCTV lens mounted on the outside of the first channel collected light emitted from cells and collimated it towards filters and secondary CCTV lenses located in each channel. The secondary lenses functioned as relay optics for directing and focusing light onto pinhole spatial filters for measurement by photomultipliers. The detector design allowed any number of channels to be connected together and the versatility for making simultaneous or sequential measurements. Measurements on lymphocytes labeled with four monoclonal antibodies conjugated to fluorescent dyes and measurements on viable tumor cells stained for DNA content and with three fluorescent-labeled antibodies were used to demonstrate the detector's capabilities.

Animals↗

PubMed1987

Chemical synthesis and in vivo hyperexpression of a modular gene coding for Escherichia coli translational initiation factor IF1.

An artificial gene encoding the Escherichia coli translational initiation factor IF1 was synthesized based on the primary structure (71 amino acid residues) of the protein. Codons for individual amino acids were selected on the basis of the preferred codon usage found in the structural genes for the initiation factor IF2 of E. coli and Bacillus stearothermophilus, both of which can be expressed at high levels in E. coli cells. We gave the IF1 gene a modular structure by introducing specific restriction enzyme sites into the sequence, resulting in units of three to ten codons. This was conceived to facilitate site-directed mutagenesis of the gene and thus to obtain IF1 with specific amino acid alterations at desired positions. The IF1 gene was assembled by shot-gun ligation of 9 synthetic oligodeoxyribonucleotides ranging in size from 31 to 65 nucleotides and cloned into an expression vector to place the gene under the control of an inducible promoter. Upon induction, E. coli cells harbouring the artificial gene were found to produce large amounts (greater than or equal to 60 mg/100 g cells) of a protein indistinguishable from natural IF1 in both chemical and biological properties.

Base Sequence↗

PubMed1985

Tibial plateau strength patterns in experimental modular knee replacement.

Nondestructive low-strain-rate compression tests were carried out on 12 human cadaver tibiae fitted with a metal modular resurfacing component on the medial or lateral condyle. The tests were done at 20 regularly spaced points on each plateau. The reproducibility of measurement was +/- 16% (95% tolerance limits). A statistically significant correlation was demonstrated between stiffness and ultimate force values obtained from the same points (r = 0.75, P less than 0.005). On the medial plateau the compressive stiffness of the system was maximal when load was applied to the center of the prosthesis, but declined sharply toward the medial and posterior margins. On the lateral plateau maximal stiffness values were obtained more posteriorly, and the stiffness gradients toward the periphery were less marked. Details of surgical technique and specific loading situations that may cause undesirable combinations of load and point of prosthetic component contact are discussed.

Biomechanical Phenomena↗

PubMed1986

A humeral modular prostheses for bone tumour surgery: a study of 56 cases.

Fifty six humeral prostheses were inserted from 1974 to 1984 for primary bone tumours of the shoulder. In 40 patients a proximal humeral resection was performed and in the remaining 16 cases a Tikhoff-Linberg procedure was employed. The length of humeral resection ranged from 9 cm to 24 cm. A detailed analysis of the oncological and functional results was made. The resection was well clear in 42 patients (75%), marginal in 12 (21.5%), and through tumour in 2 (3.5%). Eight local recurrences were noted. The functional results were satisfactory, the patients having a wide range of active rotation and being able to do sedentary work. A new modified humeral modular prosthesis was introduced in 1984 and is presented.

Adolescent↗

PubMed1983

A modular program for analysis of electrophysiological data on a laboratory minicomputer.

In the study of electrophysiological phenomena, the signals to be investigated are often reduced to sampled time series or point processes. Nowadays, the measuring equipment frequently includes one or more micro- and/or minicomputers which perform the data acquisition (including, e.g., A-D conversion and interval measurements) and the subsequent data processing and analysis. This paper describes the structured organization of data measurement and analysis of electrophysiological data performed by a modular software program implemented on a laboratory minicomputer. The program is used in our clinical laboratory by a number of research teams with different experimental objectives. The input data structure for the program has a standardized format, comprising multiplexed data channels preceded by a 256 entry parameter block containing general processing information and specific information concerning the analyses performed. The tasks carried out by the program are the calculation of distributions and correlations, digital filtering and estimation of spectra. The program can easily be extended by writing new software modules.

Computers↗

PubMed1992

The modular architecture of vertebrate collagens.

Collagens are typical mosaic proteins containing a number of shuffled domains. These domains have been classified by sequence similarity in order to characterize their structural and functional relationships to other proteins. This analysis provides an overview of homologies of collagen domains. It also reveals two new relationships: (i) a module common to type V, IX, XI, and XII collagens was found to be homologous to the heparin binding domain of thrombospondin; (ii) the modular architecture of a human type VII collagen fragment was identified. Its N-terminal globular domain contains fibronectin type III repeats located adjacent to a Von Willebrand factor type A module. The proposed structural similarities point to analogous subfunctions of the respective domains in otherwise distinct proteins.

Amino Acid Sequence↗

PubMed1992

Modularity of the slit protein. Characterization of a conserved carboxy-terminal sequence in secreted proteins and a motif implicated in extracellular protein interactions.

Since our characterization of the slit cDNA sequence, encoding a protein secreted by glial cells and involved in the formation of axonal pathways in Drosophila, we have discovered that the protein contains two additional sequence motifs that are highly conserved in a variety of proteins. A search of the GenPept database with the 73 amino acids at the carboxy terminus of slit revealed that this region contains significant similarity to a carboxy-terminal domain found in six other exported proteins. This observation has allowed us to define a new carboxy-terminal protein motif. In addition, comparisons with a 202 amino acid domain residing between epidermal growth factor (EGF) repeats in slit shows this region to be conserved in laminin, agrin and perlecan and, strikingly, also to lie between EGF repeats in both agrin and perlecan. Our analysis suggests this motif is involved in mediating interactions among extracellular proteins. Consistent with our previous characterization of the slit protein, both new motifs are found only in extracellular proteins. The identification of these two conserved motifs in slit reveals that the entire 1469 amino acids of the protein are made up of modular regions similar to those conserved in other extracellular proteins.

Amino Acid Sequence↗

PubMed1992

Description of a modular, low cost, eater meter for the study of feeding behavior and food preferences in fish.

The eater meter described in this paper is especially designed for fish studies. It consists of three parts: the detector, the feeder, and the interface between the detector and the feeder. The detector is a rod that closed a circuit (by contact or through a magnetic detector) when stuck by a fish, the feeder is electric and can be of any commercial model, and the interface is a simple electronic device, or a computer. Some preliminary results obtained with rainbow trout, Oncorhynchus mykiss, are also presented in order to illustrate the uses of this modular eater meter for fish.

Animals↗

PubMed1987

Flexible ureteropyeloscopy with modular, "disposable" endoscope.

A flexible modular ureteropyeloscope has been utilized in 36 patients. The flexible tips of this instrument can be replaced and have been available in sizes 6.0F, 8.5F, and 11.0F. The instrument was passed successfully into the ureter in 37 of 38 patients. The most frequent indications were surveillance for fragments after lithotripsy and for diagnosis of radiographic abnormalities in the upper tracts. The high success rate in these patients supports wider application of these techniques and indicates the potential for therapeutic procedures through flexible ureteroscopes.

Disposable Equipment↗

PubMed1990

The segment polarity gene armadillo encodes a functionally modular protein that is the Drosophila homolog of human plakoglobin.

The Drosophila segment polarity gene armadillo is required for pattern formation within embryonic segments and imaginal discs. We have found that armadillo is highly conserved during evolution; it is 63% identical to human plakoglobin, a protein found in adhesive junctions joining epithelial and other cells. We have examined arm protein localization in a number of larval tissues and found that arm protein accumulation within cells shares many features with the accumulation of plakoglobin. We have compared the phenotype and molecular lesions responsible for the different arm mutations. Surprisingly, severely truncated proteins retain some function; the degree of function is strictly correlated with the length of the truncated protein, suggesting that the internally repetitive arm protein is modular in function. We present a possible model for the cellular role of arm.

Alleles↗

PubMed1992

A modular numerical model of the cardiovascular system for studying and training in the field of cardiovascular physiopathology.

A modular numerical model of the cardiovascular system has been developed to reproduce the most important circulatory phenomena in terms of pressure and volume relationships. It is an easy tool to use, designed to be used with a friendly approach on any IBM or compatible personal computer: it offers a wide selection of graphical and numerical outputs and can be rearranged easily for a particular experiment. A set of subroutines related to different circulatory phenomena has been developed; they can be assembled easily together and communicate with each other by two variables. A full description of the existing subroutines is presented in this paper with three different application examples resulting from the rearrangement of the existing software modules: the first concerns the behaviour of the natural ventricle model itself and can be regarded as a ventricle stand-alone characterization test in terms of preload and afterload sensitivities, the second is related to the use of a pneumatic ventricle instead of the model of the natural ventricle, and the third is a full model of the cardiocirculatory system.

Cardiology↗

PubMedDate not supplied

Modular construction of nervous systems: a basic principle of design for invertebrates and vertebrates.

The modular construction of brain tissue is not solely a feature of vertebrate nervous tissue, but is characteristic of many invertebrate nervous systems as well. Modern vertebrate and invertebrate modules vary over several orders of magnitude in volume but vary less in diameter. Although the physiological and anatomical differences between the modules discussed herein are overpowering, their importance to nervous system functions are similar. Modules are the serial and parallel processing units that have allowed large-brained animals to evolve. Many invertebrate modules are discrete, hemispherical lobes, visible on the surface of the brain or nerve cord, whereas most mammalian modules are columnar or ellipsoidal tissue compartments that can only be visualized with specific anatomical methods. Lobes from the largest invertebrates can be more voluminous than any neocortical compartments, but these large lobes are usually not single modules. Large invertebrate lobes contain internal compartments that are single modules and of similar size to their vertebrate analogs. However, vertebrate cortical modules or columns, are far more numerous than the compartments in invertebrate brains and in several cases are known to be adjoined laterally into slabs of tissue that extend for several millimeters. Physiological data support the idea that neural modules are not just anatomical entities, but are active local circuits. The specific activities within each type of module will depend upon its neuronal components, both intrinsic and extrinsic, its functional roles and phylogenetic history. Many cellular and intercellular phenomena common to vertebrates and invertebrates underlie the development of modules. Neuronal and glial interactions and their interplay with the extracellular environment depend upon families of molecules with broad phyletic occurrences. The commonalities of growth mechanisms may to a large degree account for the widespread incidence of neuronal processing units. The strategy of enlarging a nervous system through the replication of the basic units is thought to be advantageous for several reasons. This plan allows nervous systems to economize on the branch sizes and lengths needed for interconnections, to ensure that appropriate targets are reached during development and to modulate specific circuits within a larger network.

Animals↗

PubMed1988

A simple modular tissue bath developed for 'in vitro' studies of the isolated spinal cord.

A tissue bath for studies of the mammalian spinal cord in vitro is described. The modular construction of the bath permits considerable flexibility for accommodating different tissue preparations. The individual components of the bath are easily constructed and the design permits multiple compartment baths to be simply formed. The design principle on which the bath is based may have much wider application than that described.

Animals↗

PubMed1985

tRNA-rRNA sequence homologies: evidence for an ancient modular format shared by tRNAs and rRNAs.

Homologies between tRNAs and rRNAs are identified in searches using various combinations of Escherichia coli, yeast, Halobacterium volcanii and bovine mitochondrial sequences. As in previously reported comparisons, the homologies are too frequent and long to be attributed to coincidence, and similar frequencies from inter- and intraspecies comparisons preclude evolutionary convergence as an explanation. In contrast to the earlier studies, patterns in the positioning of the homologies are now described. Graphing the positions of the homologies along orthogonal axes that represent numbers of bases in tRNA and rRNA shows recurring patterns in the alignments. Preferred spacings of integral multiples of 9 bases are found, suggesting a periodicity in the ancestral structure from which the tRNAs and rRNAs were derived. The periodicity also suggests persistence of a modular format in both classes of molecules that survived changes in sequence that occurred during evolution. A model is proposed for the generation of the ancestral molecule and the early evolution of the coding mechanism. Elongation by self-priming and self-templating gave a hairpin with a 9 base stem. Two additional cycles gave a 70-80 base tRNA-like structure. Additional cycles yielded a tandem repeat of this unit, roughly equivalent in size to the combined rRNAs of prokaryotes. The larger RNA would contain the information and materials for generating the smaller RNAs. It is proposed that multiple recombination among such molecules gave composite structures, presumed progenitors of today's t- and rRNAs. The distribution of the conserved domains among today's species argues for the existence of the ancestral molecule prior to divergence of lines leading to the various kingdoms. Their presence in the different nucleic acids suggests the existence of a nucleic acid with multiple functions prior to partitioning of these functions among the nucleic acids that exist today. The occurrence of overlaps, overlays and consensus alignments among the homologies provides the means for identifying contiguous and neighboring conserved regions and holds promise for the reconstruction of the sequence of an ancestral molecule.

Animals↗

PubMed1990

Modular organization of the lytic enzymes of Streptococcus pneumoniae and its bacteriophages.

The nucleotide sequences of genes cpl7 and cpl9 of the Streptococcus pneumoniae bacteriophages Cp-7 and Cp-9, encoding the muramidases CPL-7 and CPL-9, respectively, have been determined. The N-terminal domains of CPL-7 and CPL-9 were virtually identical to that previously reported for the CPL-1 muramidase. The C-terminal domain of the CPL-7 muramidase, however, was different from those of the host amidase and the phage Cp-1 and Cp-9 lysozymes. Whereas all enzymes studied are characterized by repeated sequences at their C termini, the repeat-unit lengths are 20 amino acids (aa) in CPL-1, CPL-9 and in the host amidase, but 48 aa in CPL-7. Six repeated sequences represent the C-terminal domains of CPL-1, CPL-9 and the host amidase, and 2.8 perfect tandem repetitions that of CPL-7. The peculiar characteristics of the structure of CPL-7 muramidase correlate with its biochemical and biological properties. Whereas CPL-1, CPL-9 and the pneumococcal amidase strictly depend on the presence of choline-containing cell walls for activity, CPL-7 is able to degrade cell walls containing either choline or ethanolamine. These results support the previously postulated role for the C-terminal domain of these lytic enzymes in substrate recognition and provide further experimental evidence supporting the notion that the proteins have evolved by an exchange of modular units.

Amino Acid Sequence↗

PubMed1990

A modular set of lacZ fusion vectors for studying gene expression in Caenorhabditis elegans.

We describe a series of plasmid vectors which contain modular features particularly useful for studying gene expression in eukaryotic systems. The vectors contain the Escherichia coli beta-galactosidase (beta Gal)-encoding region (the lacZ gene) flanked by unique polylinker segments on the 5' and 3' ends, and several combinations of a variety of modules: a selectable marker (an amber suppressor tRNA), a translational initiation region, a synthetic intron segment, the early polyadenylation signal from SV40, and 3' regions from two nematode genes. A segment encoding the nuclear localization peptide from the SV40 T antigen is incorporated into many of the constructs, leading to beta Gal accumulation in nuclei, which can facilitate identification of producing cells in complex tissues. To make functional beta Gal fusions to secreted proteins, we constructed plasmids with an alternate module encoding a synthetic transmembrane domain upstream from lacZ. This domain is designed to stop transfer of secreted proteins across the membrane during secretion, allowing the beta Gal domain of the fusion polypeptide to remain in the cytoplasm and thus function in enzymatic assays. We have used the vectors to analyze expression of several genes in the nematode Caenorhabditis elegans, and have demonstrated in these studies that lacZ can be expressed in a wide variety of different tissues and cell types. These vectors should be useful in studying gene expression both in C. elegans and in other experimental systems.

Amino Acid Sequence↗