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Antidiuretic action of chlorpropamide in mammalian kidney, considering intrarenal infusions effect on urinary concentration, free water clearance, glomerular filtration and sodium excretion
The FSH secretion-inhibiting action of inhibin in vitro under basal conditions and also in the presence of LH-RH is suppressed by the addition of MIX, a phosphodiesterase inhibitor. In the presence of LH-RH, inhibin reduces significantly the intracellular level of cAMP in isolated pituitary cells. In contrast, the simultaneous addition of MIX and inhibin raises the cAMP level, and this stimulation is comparable to the increase observed when MIX is added alone. These observations suggest that one mode of action of inhibin could be mediated by a reduction in cAMP within the pituitary gonadotropic cell.
Thiamin pyrophosphate (TPP)-dependent enzymes are a divergent family of TPP and metal ion binding proteins that perform a wide range of functions with the common decarboxylation steps of a -(O=)C-C(OH)- fragment of alpha-ketoacids and alpha- hydroxyaldehydes. To determine how structure and catalytic action are conserved in the context of large sequence differences existing within this family of enzymes, we have carried out an analysis of TPP-dependent enzymes of known structures. The common structure of TPP-dependent enzymes is formed at the interface of four alpha/beta domains from at least two subunits, which provide for two metal and TPP-binding sites. Residues around these catalytic sites are conserved for functional purpose, while those further away from TPP are conserved for structural reasons. Together they provide a network of contacts required for flip-flop catalytic action within TPP-dependent enzymes. Thus our analysis defines a TPP-action motif that is proposed for annotating TPP-dependent enzymes for advancing functional proteomics.
Photoillumination effect on growth rate of Chlorella vulgaris, discussing action spectrum and mechanism of light requirement for heterotrophic growth
Antibiotics that operate via multiple mechanisms of action are a promising strategy to combat growing resistance. Previous studies have shown that dual action antifolates formed from a pyrroloquinazolinediamine core can inhibit the growth of bacterial pathogens without developing resistance. Here, in this work, we expand the scope of dual action antifolates by repurposing the 2,4-diamino-1,6-dihydro-1,3,5-triazine (DADHT) cycloguanil scaffold to a variety of derivatives designed to inhibit dihydrofolate reductase (DHFR) and disrupt bacterial membranes. Dual mechanism DADHTs have activity against a variety of target pathogens, including Mycobacterium tuberculosis, Mycobacterium abscessus, and Pseudomonas aeruginosa, among other ESKAPEE organisms. Through X-ray crystallography, we confirmed engagement of the Escherichia coli DHFR target and found that some DADHTs stabilize a previously unobserved conformation of the enzyme but, broadly, bind in the occluded conformation. Using in vitro inhibition of purified E. coli and Staphylococcus aureus DHFR and disruption of E. coli membranes, we determined that alkyl substitution of dihydrotriazine at the 6-position best optimizes the DADHT's two mechanisms of action. By employing both mechanisms, the DADHT spectrum of activity was extended beyond the scope of traditional antifolates. Finally, we are optimistic that the dual mechanism approach, particularly through the action of antifolates, offers a unique means of combating hard-to-treat bacterial infections.
Switch mechanism limits the stroke of the piston by stopping the piston motor drive. This allows retention of a fluid sample in an automated wet-chemical analysis system.
Introduction Bispecific antibodies (BsAbs) are a class of antibody therapeutics engineered in various molecular formats to bind two distinct antigens and potentially mediate multiple biological effects. These molecular formats are tailored to mediate specific mechanisms of action and possess unique physicochemical and biological properties that are necessary to assure product quality. In ovarian cancer (OC), both EGFR- and VEGF-A-mediated signaling pathways are often upregulated and cooperate to promote tumor growth and angiogenesis. Thus, inhibiting of EGFR- and VEGF-A pathways with a BsAb may provide synergistic anti-tumor activity. Methods Using publicly available sequences and applying immunoglobulin domain crossover (CrossMab) and knobs-into-holes (KIH) technologies, we generated a BsAb to simultaneously bind EGFR and VEGF-A (designated as anti-EGFR/VEGF-A BsAb). This BsAb served as a model for physiochemical and biological characterization of quality attributes that would be critical for the BsAb’s mechanisms of action. Our goal was to gain fundamental insights into BsAbs designed to target a receptor with one arm and a soluble ligand with the other, to support bioassay development and inform quality control strategies. Results Our data demonstrated that the CrossMab/KIH platform successfully produced a correctly assembled BsAb during cell culture. Characterization confirmed that the anti-EGFR/VEGF-A BsAb bound both EGFR and VEGF-A with comparable activity and affinity to the respective parental monoclonal antibodies. Functionally, the BsAb disrupted both EGF/EGFR and VEGF-A/VEGFR2 signaling pathways in OC and human umbilical vein endothelial cell (HUVEC) models. Furthermore, the BsAb effectively blocked angiogenic signaling driven by VEGF-A secreted from OC cells in a paracrine manner. Discussion Based on the combinatorial mechanism of action and our characterization findings, we concluded that two or more bioassays may be needed to accurately assess the activity of both arms of this type of BsAb.
Progress in immunology continues to grow exponentially every year. New applications of this knowledge are being developed for a broad range of clinical conditions. Conversely, the study of primary and secondary immunodeficiencies is helping to elucidate the intricate mechanisms of the immune system. We have selected a few of the most significant contributions to the fields of basic and clinical immunology published between October 2001 and October 2002. Our choice of topics in basic immunology included the description of T-bet as a determinant factor for T(H)1 differentiation, the role of the activation-induced cytosine deaminase gene in B-cell development, the characterization of CD4(+)CD25(+) regulatory T cells, and the use of dynamic imaging to study MHC class II transport and T-cell and dendritic cell membrane interactions. Articles related to clinical immunology that were selected for review include the description of immunodeficiency caused by caspase 8 deficiency; a case series report on X-linked agammaglobulinemia; the mechanism of action, efficacy, and complications of intravenous immunoglobulin; mechanisms of autoimmunity diseases; and advances in HIV pathogenesis and vaccine development. We also reviewed two articles that explore the possible alterations of the immune system caused by spaceflights, a new field with increasing importance as human space expeditions become a reality in the 21st century.
The development of quantitative structure-activity relationship (QSAR) is essential for reducing the chemical hazards of new weapon systems. The current collaboration between HEST (toxicology research and testing), MLPJ (computational chemistry) and PRS (computational chemistry, new propellant synthesis) is focusing R&D efforts on basic research goals that will rapidly transition to useful products for propellant development. Computational methods are being investigated that will assist in forecasting cellular toxicological end-points. Models developed from these chemical structure-toxicity relationships are useful for the prediction of the toxicological endpoints of new related compounds. Research is focusing on the evaluation tools to be used for the discovery of such relationships and the development of models of the mechanisms of action. Combinations of computational chemistry techniques, in vitro toxicity methods, and statistical correlations, will be employed to develop and explore potential predictive relationships; results for series of molecular systems that demonstrate the viability of this approach are reported. A number of hydrazine salts have been synthesized for evaluation. Computational chemistry methods are being used to elucidate the mechanism of action of these salts. Toxicity endpoints such as viability (LDH) and changes in enzyme activity (glutahoione peroxidase and catalase) are being experimentally measured as indicators of cellular damage. Extrapolation from computational/in vitro studies to human toxicity, is the ultimate goal. The product of this program will be a predictive tool to assist in the development of new, less toxic propellants.
The pathogen Mycobacterium abscessus (Mab) can cause severe and difficult-to-treat chronic lung infections. Despite the rising incidence and clinical concern of Mab infections, treatment options are limited and often ineffective. Treatment is complicated by Mab’s ability to persist in a nonreplicating, drug-resistant state. Several β-lactam antibiotics are potently bactericidal against Mab but are underutilized because their molecular mechanisms of action against Mab are incompletely understood. In the current study, we used β-lactam-derived activity-based probes and chemoproteomics to report the first comprehensive list of Mab enzymes targeted by β-lactams. We compared β-lactam targets across two Mab subspecies in actively replicating and nonreplicating cultures, using a new carbon starvation model of persistence. We identified 17 targets that were active in every condition tested, seven of which were previously unknown to bind β-lactams. Lastly, we characterized the β-lactamase activity and β-lactam inhibition profiles of nine Mab enzymes, demonstrating that imipenem inhibits these targets more effectively than cefoxitin. These findings demonstrate β-lactam target engagement in persistent Mab and provide clarity on the mechanisms of action of clinically relevant β-lactams in Mab, crucial steps toward fully realizing their potential for treating infections caused by this opportunistic pathogen.
Context/Background: Astronauts use pharmaceuticals during spaceflight to manage acute and chronic pain, but use of analgesics will have drawbacks for exploration-class missions because the shelf life of these medications is limited, resupply will be curtailed, astronauts may develop tolerance and/or addiction to these medications, and side effects can include impairment of cognitive abilities. Electromagnetic devices have been developed that treat pain terrestrially by affecting neuromodulation–dubbed “electroceuticals”, these devices have varied mechanisms of action that either stimulate or suppress neural activity in the central nervous system or peripheral nerves. Objective/Purpose: The available literature was reviewed and FDA-approved pain treatments (both pharmacological and non-pharmacological), as well as those currently under development, were assessed for their suitability for use in exploration class spaceflight missions. Data Sources: Due to the COVID-19 pandemic and the resulting closure of libraries, data sources were restricted to those available digitally. Online database searches included PubMed, U.S. Patent and Trademark Office, federal grant award databases (National Aeronautics and Space Administration (NASA), Department of Defense (DoD), National Institutes of Health (NIH)), and general internet searches. More than 1,600 records were reviewed in this effort. Study Selection/Eligibility Criteria: Targeted searches included different aspects of pain management. Priority was given to review studies, to cover as much of the available literature as possible in this limited effort. Study Appraisal and Synthesis Methods/Data Extraction and Data Synthesis: The titles of the studies and the awards that were obtained by searching online databases were reviewed and further information was sought for the relevant titles. Abstracts or award summaries were generally available online; for journal abstracts, full text articles were either available online or were requested via interlibrary loan. Results: An overwhelming majority of the literature focuses on the treatment of chronic rather than acute pain because it is assumed that acute pain only rarely fails to resolve and instead transitions into chronic pain when the central nervous system becomes hypersensitized. The available electromagnetic devices marketed for pain treatment have varying levels of invasiveness, use different mechanisms of action, and have demonstrated varying efficacy when evaluated scientifically. A truly noninvasive, highly efficient device is desired for use during spaceflight. One portable, self-contained, FDA-approved device was identified that, from preliminarily assessment, best met these criteria; the device noninvasively applies pulsed shortwave therapy (PSWT) to modify pain signals from peripheral nerves, however, the device has limited battery life and the effects are relatively non-selective in type of neural signal modified. Limitations: This current effort, although extensive, did not identify a comprehensive list of all alternatives for pain treatment. Once the pandemic limitations are lifted, a longer, more thorough effort may find additional options. Conclusions/Implications: The ideal electromagnetic pain treatment device for use on exploration-class spaceflight missions does not yet exist, but it may be available soon. It is not feasible for NASA to develop medical devices due to the schedule constraints for pending exploration-class missions, but adapting a promising device that is already FDA-approved might be an option. Monitoring research that is ongoing at other federal agencies is recommended, and further review of the candidate PSWT device identified in this current effort may be warranted.
CONTEXT/BACKGROUND Astronauts use pharmaceuticals during spaceflight to manage acute and chronic pain, but use of analgesics will have drawbacks for exploration-class missions because the shelf life of these medications is limited, resupply will be curtailed, astronauts may develop tolerance and/or addiction to these medications, and side effects can include impairment of cognitive abilities. Electromagnetic devices have been developed that treat pain terrestrially by affecting neuromodulation–dubbed “electroceuticals”, these devices have varied mechanisms of action that either stimulate or suppress neural activity in the central nervous system or peripheral nerves. OBJECTIVE/PURPOSE The available literature was reviewed and FDA-approved pain treatments (both pharmacological and non-pharmacological), as well as those currently under development, were assessed for their suitability for use in exploration class spaceflight missions. DATA SOURCES Due to the COVID-19 pandemic and the resulting closure of libraries, data sources were restricted to those available digitally. Online database searches included PubMed, U.S. Patent and Trademark Office, federal grant award databases (National Aeronautics and Space Administration (NASA), Department of Defense (DoD), National Institutes of Health (NIH)), and general internet searches. More than 1,600 records were reviewed in this effort. STUDY SELECTION/ELIGIBILITY CRITERIA Targeted searches included different aspects of pain management. Priority was given to review studies, to cover as much of the available literature as possible in this limited effort. STUDY APPRAISAL AND SYNTHESIS METHODS/DATA EXTRACTION AND DATA SYNTHESIS The titles of the studies and the awards that were obtained by searching online databases were reviewed and further information was sought for the relevant titles. Abstracts or award summaries were generally available online; for journal abstracts, full text articles were either available online or were requested via interlibrary loan. RESULTS An overwhelming majority of the literature focuses on the treatment of chronic rather than acute pain because it is assumed that acute pain only rarely fails to resolve and instead transitions into chronic pain when the central nervous system becomes hypersensitized. The available electromagnetic devices marketed for pain treatment have varying levels of invasiveness, use different mechanisms of action, and have demonstrated varying efficacy when evaluated scientifically. A truly noninvasive, highly efficient device is desired for use during spaceflight. One portable, self-contained, FDA-approved device was identified that, from preliminarily assessment, best met these criteria; the device noninvasively applies pulsed shortwave therapy (PSWT) to modify pain signals from peripheral nerves, however, the device has limited battery life and the effects are relatively non-selective in type of neural signal modified. LIMITATIONS This current effort, although extensive, did not identify a comprehensive list of all alternatives for pain treatment. Once the pandemic limitations are lifted, a longer, more thorough effort may find additional options. CONCLUSIONS/IMPLICATIONS The ideal electromagnetic pain treatment device for use on exploration-class spaceflight missions does not yet exist, but it may be available soon. It is not feasible for NASA to develop medical devices due to the schedule constraints for pending exploration-class missions, but adapting a promising device that is already FDA-approved might be an option. Monitoring research that is ongoing at other federal agencies is recommended, and further review of the candidate PSWT device identified in this current effort may be warranted.
The metabolism of winter rye seedlings (Secale cereale, L. cv. Winter) cultured in 99.6% D2O was investigated. Compared with water grown seedlings, the protein content was much lower in the D2O cultured seedlings and the incorporation of H(3)-leucine and H(3)-phenylalanine into medium to high molecular weight proteins was partially blocked. The synthesis of the enzyme peroxidase was also reduced in the D2O plants. Seedlings cultured in D2O incorporate H(3)-thymidine into DNA, but do not take up H(3)-uridine. These results suggest that some of the toxic effects of D2O culture on higher plants can be attributed to a partial block of protein synthesis.
Single drive actuator operates novel mechanism that expands, attaches to object, and withdraws to latch object firmly to another part. Packaging is extremely simple and compact, and eliminates need for machined parts or close tolerances.
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Double-swivel toggle mechanism releases large, heavy objects reliably. Double-swiveling action of mechanism ensures it clears restraining pins upon release. Pins retain toggle and its load. If pin fails to withdraw at designated time for releasing payload, toggle swivels about its upper ball, and ring swivels about lower ball so ring flange clears failed pin. Double-swivel action ensures disengagement even it two pins fail to withdraw.
For a variety of medical and scientific reasons, human bones can be exposed to a wide range of ionizing radiation levels. In vivo radiation therapy (0.05 kGy) is used in cancer treatment, and ex vivo irradiation (25-35 kGy) is used to sterilize bone allografts. Ionizing radiation in these applications has been shown to increase risk of fracture, decrease bone quality and degrade collagen integrity. Past studies have investigated the deleterious effects of radiation on cortical or trabecular bone specimens individually, but to date no studies have examined whole bones containing both cortical and trabecular tissue. Furthermore, a clear relationship between the dose and the mechanical and biochemical response of bone's extracellular matrix has yet to be established for doses ranging from cancer therapy to allograft sterilization (0.05-35 kGy). To gain insight into these issues, we conducted an ex vivo radiation study to investigate non-cellular (i.e. matrix) effects of ionizing radiation dose on vertebral whole bone mechanical properties, over a range of radiation doses (0.05-35 kGy), with a focus on any radiation-induced changes in collagen. With underlying mechanisms of action in mind, we hypothesized that any induced reductions in mechanical properties would be associated with changes in collagen integrity. METHODS: 20-week old female mice were euthanized and the lumbar spine was dissected using IACUC approved protocols. The lumbar vertebrae (L1- S1) were extracted from the spine via cuts through adjacent intervertebral discs, and the endplates, posterior processes, surrounding musculature, and soft tissues were removed (approx. 1.5mm diameter, approx. 2mm height). Specimens were randomly assigned to one of five groups for ex vivo radiation exposure: x-ray irradiation at 0.05, 1, 17, or 35 kGy, or a 0 kGy control. Following irradiation, the vertebrae were imaged using microcomputed tomography (micro-CT) and then subjected to either monotonic compressive loading to failure or uniform cyclic compressive loading. During cyclic testing, samples were loaded in force control to a force level that corresponded to a strain of 0.46%, as determined in advance by a linearly elastic micro-CT-based finite element analysis for each specimen. Tests were stopped at imminent fracture, defined as a rapid increase in strain. The main outcome for the monotonic test was the strength (maximum force); for cyclic testing it was the fatigue life (log of the number of cycles of loading at imminent failure). A fluorometric assay was used on the S1 vertebrae to measure the number of non-enzymatic collagen crosslinks[4]. A one-way ANOVA was performed on mechanical properties and collagen crosslinks; means were compared with controls using Dunnett's method, with a Tukey-Kramer post-hoc analysis when significance was found (p < or = 0.05). RESULTS: Compared to the unirradiated control group, the concentration of non-enzymatic collagen crosslinks was significantly increased for all irradiated groups (p < 0.0001), and being higher by at least 50% (Figure 1a). By contrast, the radiation effects on the collagen were only evident at the higher doses. For irradiation exposures of 17 kGy or more, strength decreased substantially as the radiation level was increased, but no effect was evident below 17 kGy (Figure 1b). There was no significant change in the stiffness or maximum displacement for any radiation dose (p>0.05). The finite element analysis prescribed force level for cyclic loading exceeded the measured (monotonic) strength of the 17 and 35 kGy irradiated groups (mean +/- SD, 20.6 +/- 5.6 N; 13.2 +/- 3.7 N, respectively) and therefore these groups were eliminated from the fatigue study. The fatigue life for the 0.05 and 1 kGy groups were similar to each other and were not statistically significantly different from the control group (Figure 1c).
It has been postulated that alpha 2-adrenergic receptors play a modulatory role in the regulation of blood pressure. Activation of alpha 2-receptors located in the central nervous system results in inhibition of sympathetic tone and decrease of blood pressure. This indeed may be the mechanism of action of central sympatholytic antihypertensives such as alpha-methyldopa. Presynaptic alpha 2-receptors also are found in adrenergic nerve terminals. These receptors act as a negative feedback mechanism by inhibiting the release of norepinephrine. The relevance of alpha 2-adrenergic receptors for blood pressure regulation can be explored with yohimbine, a selective antagonist of these receptors. Yohimbine increases blood pressure in resting normal volunteers. This effect is associated with an increase in both sympathetic nerve activity, reflecting an increase in central sympathetic outflow, and in norepinephrine spillover, reflecting potentiation of the release of norepinephrine from adrenergic nerve terminals. These actions, therefore, underscore the importance of alpha 2-adrenergic receptors for blood pressure regulation even under resting conditions. Patients with autonomic failure, even those with severe sympathetic deprivation, are hypersensitive to the pressor effects of yohimbine. This increased responsiveness can be explained by sensitization of adrenergic receptors, analogous to denervation supersensitivity, and by the lack of autonomic reflexes that would normally buffer any increase in blood pressure. Preliminary studies suggest that the effectiveness of yohimbine in autonomic failure can be enhanced with monoamine oxidase inhibitors. Used in combination, yohimbine increases norepinephrine release, whereas monoamine oxidase inhibitors inhibit its degradation. Therefore, yohimbine is not only a useful tool in the study of blood pressure regulation, but may offer a therapeutic option in autonomic dysfunction.