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PubMed2005

Viruses selectively upregulate Toll-like receptors in the central nervous system.

The resting CNS is an immunospecialized environment, devoid of most immune processes, although substantial inflammatory responses can be initiated. The innate immune mechanisms mediating recognition of CNS infections are unknown. This study provides a comprehensive analysis of Toll-like receptor (TLR) gene expression in the resting and virus-infected murine CNS. TLR transcripts were expressed in the resting CNS with strikingly high expression of TLR 3. Extraneural infection with neuroinvasive Semliki Forest virus resulted in CNS infection followed by rapid selective upregulation of TLR gene expression. Upregulation was independent of T-cell responses. Upregulation of TLR gene expression was also observed following rabies virus infection. TLR upregulation was appropriate to the pathogen and proportional to the virus load. Upregulation of TLR 3 and 9 was dependent upon the type-I interferon response and may act to increase the threshold of sensitivity to detect virus infection in cells surrounding virally infected cells.

Alphavirus Infections↗

PubMed2005

Dependence of the response of an amperometric biosensor formed in a micro flow channel on structural and conditional parameters.

Comprehensive analysis of the behavior of an amperometric biosensor incorporated in a micro flow channel was conducted by changing the structural and conditional parameters. The device used in the characterization consisted of a thin-film three-electrode system and a silicone rubber flow channel. An enzyme, glucose oxidase, was immobilized either at the bottom of the silicone rubber flow channel or on the electrode substrate. The flow rate, concentration, position of the immobilized enzyme, and channel height were changed, and the changes in the output current and the conversion efficiency were examined. When the flow rate and/or the channel height decreased, the output current and the conversion efficiency significantly increased. The conversion efficiency also increased by decreasing the concentration. The tendency of the flow dependence was reversed when the position of the immobilized enzyme was changed from the silicone rubber side to the electrode substrate. In addition, the influence of l-ascorbic acid was reduced by placing additional working electrodes in the upper stream. l-Ascorbic acid was eliminated more effectively as the flow rate decreased and the area of the working electrode for elimination increased.

Biosensing Techniques↗

PubMed2006

Homopolyvalent antibody-antigen interaction kinetic studies with use of a dual-polarization interferometric biosensor.

We used dual-polarization interferometry (DPI) to study the interaction kinetics between a 'homopolyvalent' antigen (Ag) and a monoclonal antibody (Ab). A model system, which uses a monoclonal Ab against a homopentameric Ag, C-reactive protein (CRP), is presented with principle and experiments for the study of the interactions between an Ab and an Ag that has multiple identical epitopes. This allows evaluation of the dissociation constant (K(D)) and of the binding stoichiometry by DPI based on measurements of phase changes of Ab-Ag complexes in the transverse magnetic (TM) and transverse electric (TE) polarization modes. The average experimental value of K(D) found by the DPI technique for anti-CRP Ab was shown to be in close agreement with the value obtained by an indirect competition-enzyme-linked immunosorbent assay (ELISA). Moreover, the total number of Ab combining sites on the DPI sensor chip was calculated, and the binding stoichiometry of the surface Ag-Ab complex was obtained. This study illustrates the advantages of the DPI method in biosensing in its capacity for simultaneous evaluation of the thickness and refractive index (density, mass) of adsorbed layers. This allowed a comprehensive analysis of affinity reactions between an Ab having two binding sites and a multi-sited Ag.

Antibodies, Monoclonal↗

PubMed2006

Digital diagnostics: Three-dimensional modelling.

Three-dimensional imaging techniques, such as computed tomograms (CT), structured light, and stereophotogrammetry, can be used to capture three-dimensional coordinate data, but comprehensive analysis is required to transform these techniques into powerful diagnostic tools. The object of this review is to highlight analytical functionality using software developed to study three-dimensional digital imaging and communications in medicine (DICOM) based digital data for diagnosis, planning of treatment, and evaluation of craniofacial changes. My specific aim was to apply three-dimensional software routines using geometric morphometrics or conventional measurements. These routines rely on robust algorithms to construct mean objects by manipulating the three-dimensional x, y, and z coordinates of all the objects' vertices. Conventional measurements and statistical tests can then be applied to the changes in the vertices, say, before and after treatment. Using graphical and geometric morphometric techniques such as finite-element analysis and principal components analysis, clinical craniofacial modelling can be used for the localisation and quantification of soft and hard tissue changes; diagnostic modelling can be undertaken for planning of treatment, and data-driven predictive modelling can be undertaken for the planning of many procedures based on the surgeon's own experience, patients, and resources. Three-dimensional modelling of digital data may therefore have added value for clinical diagnosis, and planning and assessment of treatment, including audit.

Algorithms↗

PubMed2006

Correction of the mineralization defect in hyp mice treated with protease inhibitors CA074 and pepstatin.

Increased expression of several osteoblastic proteases and MEPE (a bone matrix protein) occurs in X-linked hypophosphatemic rickets (hyp). This is associated with an increased release of a protease-resistant MEPE peptide (ASARM peptide), a potent inhibitor of mineralization. Cathepsin B cleaves MEPE releasing ASARM peptide and hyp osteoblast/osteocyte cells hypersecrete cathepsin D, an activator of cathepsin B. Our aims were to determine whether cathepsin inhibitors correct the mineralization defect in vivo and whether hyp-bone ASARM peptide levels are reduced after protease treatment. Normal littermates and hyp mice (n = 6) were injected intraperitoneally once a day for 4 weeks with pepstatin, CAO74 or vehicle. Animals were then sacrificed and bones plus serum removed for comprehensive analysis. All hyp mice groups (treated and untreated) remained hypophosphatemic with serum 1,25 vitamin D3 inappropriately normal. Serum PTH was significantly elevated in all hyp mice groups relative to normal mice (P = 0.0017). Untreated hyp mice had six-fold elevated levels of serum alkaline-phosphatase and two-fold elevated levels of ASARM peptides relative to normal mice (P < 0.001). In contrast, serum alkaline phosphatase and serum ASARM peptides were significantly reduced (normalized) in hyp mice treated with CA074 or pepstatin. Serum FGF23 levels remained high in all hyp animal groups (P < 0.0001). Hyp mice treated with protease inhibitors showed dramatic reductions in unmineralized osteoid (femurs) compared to control hyp mice (Goldner staining). Also, hyp animals treated with protease inhibitors showed marked and significant improvements in growth plate width (42%), osteoid thickness (40%) and cortical area (40%) (P < 0.002). The mineralization apposition rate, bone formation rate and mineralization surface were normalized by protease-treatment. High-resolution pQCT mineral histomorphometry measurements and uCT also confirmed a marked mineralization improvement. Finally, the growth plate and cortical bone of hyp femurs contained a massive accumulation of osteoblast-derived ASARM peptide(s) that was reduced in hyp animals treated with CA074 or pepstatin. This study confirms in vivo administration of cathepsin inhibitors improves bone mineralization in hyp mice. This may be due to a protease inhibitor mediated decrease in proteolytic degradation of the extracellular matrix and a reduced release of ASARM peptides (potent mineralization inhibitors).

Animals↗

PubMed2004

Sensorimotor-related discharge of simultaneously recorded, single neurons in the dorsal raphe nucleus of the awake, unrestrained rat.

Multi-channel, multi-neuron recording procedures were used to monitor simultaneously the spike train activity of single neurons (n=7-16 cells/animal) in the dorsal raphe (DR) nucleus of the awake, freely moving rat. Putative serotonergic and non-serotonergic neurons were distinguished from one another on the basis of established criteria, i.e. waveform shape and duration, firing pattern and firing frequency. As a group, presumed serotonergic neurons exhibited low tonic discharge rates, depressed firing after serotonin (5HT)-1a agonist administration, and, except for the transition from sleep to waking, a general insensitivity to specific sensory or motor events. By contrast, non-serotonergic cells in midline and lateral wing sub-regions of the nucleus displayed responses to a variety of sensorimotor events including locomotion, grooming, head movement, chewing, auditory stimuli, and whisker movement (both passive and active). However, within this latter group, the sensorimotor response repertoire of individual cells was not uniform. Likewise, non-5HT cells with diverse response profiles were identified in both medial and lateral sub-regions of the nucleus. Cells categorized as non-serotonergic also had varied responses to 5HT1a agonist administration. These results emphasize the diverse input/output relationships of individual DR neurons and underscore the need for a more comprehensive analysis of such properties under waking conditions in order to obtain a better understanding of the role of the DR nucleus in brain function.

Acoustic Stimulation↗

PubMed2006

Mast cells accumulate in the anogenital region of somatosensory thalamic nuclei during estrus in female mice.

Mast cells are located in the mammalian thalamus where their numbers are sensitive to reproductive hormones. To evaluate whether differences between sexes and over the estrus cycle influence the nuclear distribution of mast cells in mice, we mounted a comprehensive analysis of their distribution in males compared to females and in females over the estrus cycle. Compared to males, mast cells were more numerous in the lateral intralaminar and posterior nuclei of females during estrus and in the ventral posterolateral (VPL) and medial geniculate nuclei during proestrus. During estrus, mast cells were especially concentrated in those regions within the VPL and posterior thalamic nuclei that receive somatosensory information from the anogenital region. Treatment of ovariectomized mice with estrogen increased the number and the percent of mast cells that were degranulated compared to that after ovariectomy alone, an effect that was most apparent in the lateral intralaminar, VPL and posterior nuclei. In estrogen-primed, ovariectomized females, progesterone delivered 5 h before tissue collection counteracted the effects of estrogen. Cromolyn, a mast cell stabilizer, injected centrally 1 h prior to and 24 h after estrogen in ovariectomized mice, prevented the increase in number of mast cells in the whole thalamus and in the intralaminar, VPL and posterior nuclei. This suggests that estrogen induces hyperplasia by a mechanism that involves mast cell degranulation. Based on the discrete anatomical location of mast cells in areas of somatosensory nuclei that receive anogenital input together with the temporal correspondence of these cells with estrus, mast cells are well situated to influence sensory input in females during mating.

Analysis of Variance↗

PubMed2005

Application of microarray-based technology to neuroblastoma.

In the past decade, microarray technology has become a major tool for high-throughput comprehensive analysis of gene expression, genotyping and re-sequencing applications. High-throughput microarrays are used for expression profiling analyses with the aims of gene or pathway discovery, tumor subclassification or relapse risk assessment. The introduction of microarray CGH provides a powerful tool to precisely detect and quantify genomic aberrations and map these directly onto the human genome. This review summarizes the current status of the application of microarray technology to neuroblastoma research.

Humans↗

PubMed2026

Antibody-drug conjugates against multidrug-resistant cancers: Biomarker-guided patient selection, payload engineering, linker chemistry, and bystander effects.

Antibody-drug conjugates (ADCs) are one of the most significant advancements in modern cancer therapeutics. Combining the target selectivity of monoclonal antibodies with the cytotoxic potential of payloads, ADCs effectively kill cancer cells and offer hope to patients with even refractory cancer types. Beyond simply increasing the number of therapeutic options available for cancer patients, ADCs have become a powerful frontline agent in overcoming multidrug resistance (MDR). As one of the most challenging obstacles to effective cancer care, MDR is mediated by ATP-binding cassette (ABC) transporter-mediated drug efflux, target-based mutations, and dysregulated apoptosis. The clinical success of ADCs specifically engineered to overcome MDR, including in heterogeneous tumors and cancer cells that exhibit bypass signaling, is well established. This is especially evident with trastuzumab deruxtecan (T-DXd) in HER2-low, HER2-positive, and HER2-mutant cancers; sacituzumab govitecan (SG) in TROP2-expressing triple-negative breast cancer (TNBC) and urothelial carcinoma; and enfortumab vedotin in Nectin-4-positive bladder cancer. By overcoming MDR, ADCs have enabled more effective treatment algorithms across multiple malignancies. Most importantly, the clinical application of ADCs has become inextricably linked to cancer genomics. HER2 testing has evolved from a two-tiered system to a continuous spectrum including HER2-ultralow, HER2-low, HER2-positive, and ERBB2-mutant categories. Each of these categories exhibits different eligibility guidelines for ADC patient selection. As cancer cells continue to evolve and develop resistance to even ADCs through mutations and variants, researchers and clinicians have used pharmacogenomics to predict ADC response and resistance. To define the genomic architecture of ADC-resistant tumor subpopulations, single-cell transcriptomic studies and liquid biopsy approaches are being used to enable real-time examination of the tumor genome during ADC therapy, thereby optimizing treatment and circumventing resistance driven by emerging mutations and variants. This review provides a comprehensive analysis of the molecular structure of ADCs, the pharmacological principles underlying their potent cytotoxic activity against MDR cancer cells, the genomic and transcriptomic biomarkers that guide ADC patient selection, and the emerging resistance mechanisms that will shape the next generation of promising ADC development.

Humans↗

PubMed2005

Animal models for arrhythmias.

The complex pathophysiology of human arrhythmias has proven difficult to model. Direct correlations between the traditional arrhythmia mechanisms, including abnormal excitability, conduction, or repolarization and underlying molecular or cellular biology are poorly defined, as the primary etiologies of many human arrhythmias remain unknown. Since the causes of several arrhythmic syndromes have been identified, genetic models reproducing the mechanisms of these arrhythmias have become feasible. Initial murine modeling has revealed that in many cases the pathophysiology of the respective human disease is more complex than had been suspected. Insights from human genetic studies and animal models strongly suggest that the primary molecular defects may contribute at many stages in the causal chain leading to arrhythmia. The comprehensive analysis of each arrhythmia will require knowledge not only of the membrane effects of the primary defects, but also downstream intracellular signals, the developmental results of these perturbations, and the integration of compensatory responses and environmental factors. Precise modeling will require not only the mutation of specific residues in known disease genes, but also the systematic study of each of the many steps in arrhythmogenesis. Ultimately, such models will enable unbiased screens for disease mechanisms and novel therapies.

Animals↗

PubMed2006

Quality management and volume-related outcomes in the cardiac catheterization laboratory.

The assessment of quality in the cardiac catheterization laboratory is a complex, ongoing process that requires a comprehensive analysis of the multiple elements of quality. Although clinical outcomes are a reflection of the quality process, they derive from a complex interaction of clinical, technical, and process-of-care components. Procedural volume is associated but not equated with clinical outcomes, although the magnitude of this association depends on numerous covariates, most notably the diminishing rate of adverse outcomes over time.

Cardiac Catheterization↗

PubMed2025

One thousand SARS-CoV-2 antibody structures reveal convergent binding and near-universal immune escape.

Understanding antibody recognition and adaptation to viral evolution is central to vaccine and therapeutic development. Over 1,100 SARS-CoV-2 antibody structures have been resolved, marking the largest structural biology effort for a single pathogen. We present a comprehensive analysis of this landmark dataset to investigate the principles of antibody recognition and immune escape. Human immunoglobulins and camelid single-chain antibodies dominate, collectively mapping 99% of the receptor-binding domain. Despite remarkable sequence and conformational diversity, antibodies exhibit convergence in their paratope structures, revealing evolutionary constraints in epitope selection. Analyses reveal near-universal immune escape of antibodies, including all clinical monoclonals, by advanced variants such as KP3.1.1. On average, over one-third of antibody epitope residues are mutated. These findings support pervasive immune escape, underscoring the need to effectively leverage multi-epitope-targeting strategies to achieve durable immunity. To support community accessibility, we developed an interactive web server for visualization and analysis of antibody-antigen complexes and mutational data.

SARS-CoV-2↗

PubMed2004

Rpd3p relocation mediates a transcriptional response to rapamycin in yeast.

Treating yeast cells with rapamycin, a small molecule that inhibits the TOR proteins, leads to the repression of many genes. Consistent with prior studies, we find that RPD3, which encodes a histone deacetylase (HDAC), is required for repression upon rapamycin treatment. To elucidate the mechanism underlying RPD3-mediated repression, we screened all promoters in yeast for occupancy by Rpd3p before and after treatment with rapamycin. We find that Rpd3p binds to the promoters of rapamycin-repressible genes only following treatment. These data conflict with a previously proposed model suggesting that Rpd3p is constitutively bound to rapamycin-repressible genes and becomes active only after a stimulus such as treatment with rapamycin. Rather, the comprehensive analysis presented here strongly supports a model in which recruitment of Rpd3p to gene promoters is a regulated step in the control of gene repression.

Down-Regulation↗

PubMed2004

Comprehensive two-dimensional separations of complex mixtures using reversed-phase reversed-phase liquid chromatography.

A comprehensive two-dimensional reversed-phase reversed-phase liquid chromatographic system for the separation of a complex mixture of oligostyrenes was developed using results from a previous theoretical assessment of the informational similarity, percent synentropy, orthogonality and peak capacity of hypothetically coupled systems. The degree of sample attribute order in the first separation dimension was also used in the development of the experimental two-dimensional system. A C18(methanol)/CCZ(acetonitrile) two-dimensional system was chosen for the comprehensive analysis of the oligostyrene mixtures because this system had the lowest solute crowding, highest orthogonality and was observed to have order with respect to a sample attribute in the first separation dimension. The separations achieved were in full agreement with the results from information theory and (a geometric approach to) factor analysis assessments. High sampling rates in the first liquid chromatographic dimension were shown to be impossible or inefficient when the peak capacity and separation time of the second dimension was high or when the aim of the exercise was to isolate individual sample constituents in high yield.

Chromatography, Liquid↗

PubMed2005

Proteomic LC-MS systems using nanoscale liquid chromatography with tandem mass spectrometry.

Current nano-scale liquid chromatography-tandem mass spectrometry (nanoLC-MS/MS) approaches in proteome research are reviewed from an analytical perspective. For comprehensive analysis of cellular proteins, analytical methods with higher resolution, sensitivity, and wider dynamic range are required. Miniaturized LC coupled with tandem mass spectrometry is currently one of the most versatile techniques. In this review, the current status of nanoLC-MS/MS systems as well as data management systems is addressed. In addition, the future prospects for complete proteomics are discussed.

Chromatography, Liquid↗

PubMed2026

Comprehensive identification of carboxylic acids by using bromine isotope-based chemical isotope labelling and structure-guided molecular network.

Carboxylic acids (CAs) are important contributors to the flavor quality of sauce-flavor Chinese Baijiu, yet their comprehensive analysis remains challenging due to poor ionization efficiency, weak chromatographic retention, and limited annotation capability. Herein, we developed a workflow for the high-coverage discovery and annotation of CAs in Baijiu by coupling chemical isotope labeling-liquid chromatography-mass spectrometry with a structure-guided molecular network strategy (SGMNS). A bromine-containing derivatization reagent, 1-(3-aminopropyl)-3-bromoquinolin-1-ium bromide (APBQ), was designed and synthesized to exploit the natural isotope distribution of bromine and characteristic MS/MS fragmentation behavior. Following APBQ derivatization, the target CAs showed superior chromatographic retention and favorable analytical performance. Based on isotopic peak pairing in MS1 and diagnostic fragment validation in MS2, 372 potential CA derivatives were discovered from pooled Baijiu samples and 355 of them were validated by diagnostic fragments in MS2 spectra. To address the scarcity of derivatized spectral libraries, SGMNS was employed for annotation using a background network constructed from APBQ-labeled candidates derived from the Expanded Chinese Baijiu Compound Database. The developed method was further applied to profile Baijiu samples, revealing pronounced differences in CA composition across the seven fermentation rounds. Notably, rounds 3 to 5 exhibited the largest numbers of differential CAs. This study provided an effective analytical strategy for large-scale CA profiling, offering new insight into the chemical basis of flavor formation during multi-round fermentation of sauce-flavor Baijiu.

Isotope Labeling↗

PubMed2004

The study of control methods for the robotic testing system for human musculoskeletal joints.

Biomechanical testing of human musculoskeletal joints not only requires qualified testing machines and devices, but also needs an excellent control method to obtain better experimental results. In this paper, we take the human functional spinal unit (FSU) as an example to study how to improve the performance of the robotic testing system. First, the mechanical characteristics of the FSU are described and the simplified model (a rigid body-spring system) for the specimen is given. Because the location of the center of rotation (COR) of the specimen affects the performance of the system, so a comprehensive analysis on the location of the COR is carried out. Furthermore, the performance of the robotic testing system can be also improved through the improvement of the control methods. Two control methods have been proposed, one is the improved hybrid control and the other is fuzzy logic control (FLC).

Fuzzy Logic↗

PubMed2004

Pursuit of the muscular ideal: Physical and psychological consequences and putative risk factors.

Developing a lean muscular figure for the purposes of sports and/or appearance has become a central issue for males. Concern has been raised because the desire to develop such a body build may lead to the adoption of numerous health-threatening behaviors. Consequently, this review presents a comprehensive analysis of the physical and psychological consequences that result from the use of steroids (legal and illegal), ephedrine, and deleterious dieting strategies specific to males. Putative risk factors for these behaviors will be identified, and the clinical disorder associated with the extreme abuse of these behaviors, muscle dysmorphia, will be examined.

Anabolic Agents↗