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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↗
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↗
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↗
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↗
PubMed1989

A modular stopped-flow system for use in routine pharmaceutical analysis.

A modular stopped-flow system for routine pharmaceutical analysis is presented. It consists of an inexpensive stopped-flow module which is fitted to a spectrophotometer or spectrofluorimeter and controlled by a simple computer. The automatic technique developed with this system is suitable for the individual and simultaneous determination of various pharmaceuticals (anti-asthmatics, psychotropics, hormones, analgesics, anaesthetics and antiseptics) with satisfactory results.

Autoanalysis↗
PubMed1992

Interface corrosion of a modular head total hip prosthesis.

Wear and corrosion products released from metallic prosthetic joints can stimulate adverse reactions in the surrounding tissues that may eventually require revision of the prostheses. The authors report here a case of a modular total hip prosthesis removed after 35 months that showed evidence of corrosion and fretting at the Morse taper interface between the titanium alloy femoral stem and the cobalt-chromium ball.

Aged↗
PubMed1992

Late disassembly of a modular acetabular component. A case report.

Disassembly of metal-backed acetabular components used for total hip arthroplasty is becoming more common in both preassembled and modular designs. This complication is usually associated with a dislocation of the femoral component or other radiographic evidence of dissociation. A case of late disassembly of the acetabular component without dislocation or radiographic evidence is presented. The authors believe this complication should be considered, along with infection and aseptic loosening, in all cases of late development of pain following total hip arthroplasty.

Adult↗
PubMed1989

Modular design of synthetic protein mimics. Characterization of the helical conformation of a 13-residue peptide in crystals.

The incorporation of alpha-aminoisobutyryl (Aib) residues into peptide sequences facilitates helical folding. Aib-containing sequences have been chosen for the design of rigid helical segments in a modular approach to the construction of a synthetic protein mimic. The helical conformation of the synthetic peptide Boc-Aib-(Val-Ala-Leu-Aib)3-OMe in crystals is established by X-ray diffraction. The 13-residue apolar peptide adopts a helical form in the crystal with seven alpha-type hydrogen bonds in the middle and 3(10)-type hydrogen bonds at either end. The helices stack in columns, zigzag rather than linear, by means of direct NH...OC head to tail hydrogen bonds. Leucyl side chains are extended on one side of the helix and valyl side chains on the other side. Water molecules form hydrogen bonds with several backbone carbonyl oxygens that also participate in alpha-helix hydrogen bonds. There is no apparent distortion of the helix caused by hydration. The space group is P2(1)2(1)2(1), with a = 9.964 (3) A, b = 20.117 (3) A, c = 39.311 (6) A, Z = 4, and dx = 1.127 g/cm3 for C64H106N13O16.1.33H2O. The final agreement factor R was 0.089 for 3667 data observed greater than 3 sigma(F) with a resolution of 0.9 A.

Crystallization↗
PubMed1990

Recognizing words and pictures in sentence contexts: a test of lexical modularity.

Words or pictures completed sentence fragments to form coherent or incoherent sentences. Subjects made lexical decisions about words and object decisions about pictures. Modality was blocked in Experiment 1 and mixed in Experiment 2. In both experiments there were similar effects of context for words and pictures, contrary to the hypothesis that lexical priming produces the sentence context effect. Mixed conditions produced longer response latencies than blocked conditions but did not interact with the context effect. The finding of no interaction between the effect of context and the mixed-blocked manipulation, supports a version of lexical modularity in which context effects arise as a function of post-access integration processing.

Adult↗
PubMed1990

The Oxford modular cataract image analysis system.

A modular system of acquisition and analysis of Scheimpflug, retro-illumination and fluorescence images of the in vivo human crystalline lens is described. Image analysis is directed towards the following goals: Scheimpflug slit-images are analysed for: (1) The optical density of nuclear cataract present; (2) The dimensions of the lens and the lenticular zones; (3) The curvatures of the lens and lenticular zones. Retro-illumination images are analysed for: (1) The percentage area which is occupied by cataract; (2) A combined measure (weighted integral) describing both the amount of cataract present and its optical density. Lenticular auto-fluorescence images are analysed for the mean density (fluorescence) of the lens as a whole. A pilot study of the repeatability of the methods is presented.

Cataract↗