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Results for “ADAM Proteins”

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At least 19 recordsLinked to original sources
PubMed2026

Platelet triggering receptor expressed on myeloid cells-like transcript 1 regulation in healthy donors and patients at risk of bleeding and thrombosis.

BACKGROUND: Triggering receptor expressed on myeloid cells-like transcript 1 (TLT-1), a platelet-specific &#x3b1;-granule protein, is implicated in hemostasis, but its regulation remains unclear. Platelet dysfunction contributes to trauma-induced coagulopathy (TIC) and thrombotic complications in trauma or mechanical circulatory support (MCS); however, underlying mechanisms remain poorly understood. OBJECTIVES: This study investigated the molecular mechanisms underlying soluble TLT (sTLT)-1 release and its role as a biomarker of platelet dysfunction in patients with severe trauma or receiving MCS. METHODS: TLT-1 dynamics on platelets exposed to glycoprotein (GP)VI ligand, coagulation, or shear stress in vitro were evaluated by ELISA and immunoblotting. sTLT-1 was measured in plasma from trauma or MCS-treated patients and healthy donors. Associations with TIC, injury severity, and mortality were assessed. RESULTS: Proteolysis of TLT-1 to release a 10- to 17-kDa fragment was metalloproteinase dependent and blocked by ADAM10 and ADAM17 inhibition. Unlike GPVI, platelet TLT-1 exposure increased following PAR-1 activation. sTLT-1 was elevated in trauma patients compared with controls and correlated with TIC (P < .05) and injury severity (P < .01). Receiver-operating characteristic analysis demonstrated discriminatory performance for TIC (area under the curve, 0.78; P = .011), with a Youden cutoff of 1.180 ng/mL yielding 89% sensitivity and 73% specificity. Platelet TLT-1 was basally expressed, mobilized 2.5-fold with activation, and shed in response to GPVI ligation and plasma recalcification. Shear-exposed platelets and plasma from MCS-treated patients exhibited elevated sTLT-1 levels. CONCLUSION: Unlike GPVI, TLT-1 increased on activated platelets and was regulated by ADAM10 and ADAM17. TLT-1 release is triggered by shear stress, GPVI ligands or activated factor X. Plasma sTLT-1 was associated with trauma severity and TIC.

Humans↗
PubMed2026

Hypoxia reprograms VEGF signaling to differentially control ADAMTS2 and ADAMTS3 expression in endothelial cells.

ADAMTS2/-3, key metalloproteinases involved in collagen processing and extracellular matrix dynamics, remain insufficiently characterized in terms of their transcriptional regulation under hypoxic and pro-angiogenic conditions. In this study, we demonstrate that VEGF&#x2081;&#x2086;&#x2085; robustly enhances ADAMTS2/-3 expression in endothelial cells, with hypoxia providing a striking amplification of this response. Bioinformatic analyses revealed that hypoxia and VEGF induced HIF-mediated and time-varying expression responses in ADAMTS2/-3. Using HUVECs exposed to CoCl&#x2082;-induced hypoxia, VEGF stimulation led to substantial increases in ADAMTS2 (approximately 19-fold at 3&#x202f;h) and ADAMTS3 (approximately 46-fold at 3&#x202f;h) mRNA levels, accompanied by concordant protein upregulation. Promoter-reporter assays revealed strong VEGF responsiveness in defined ADAMTS2 (-658/+112) and ADAMTS3 (-131/+40; -1340/+40) promoter fragments, particularly under hypoxic conditions. Pharmacological inhibition showed that JNK, MAPK/ERK, p38, and PI3K pathways each contributed partially to VEGF-mediated transcription, indicating multi-pathway convergence rather than single-pathway dependency. This finding is consistent with RNA-seq analyses showing that VEGF-related signaling is extensively re-regulated under hypoxic conditions. Extension of these analyses to MG-63 and SAOS-2 cell lines revealed modest but consistent VEGF-induced upregulation, supporting a tissue-independent regulatory axis. Collectively, these findings position ADAMTS2/-3 as potent hypoxia- and VEGF-responsive genes, uncovering their integration into HIF-1&#x3b1;-dependent transcriptional networks and VEGF-activated signaling cascades. This work highlights the relevance of ADAMTS2/-3 in angiogenesis-associated extracellular matrix remodeling and identifies them as promising biomarkers and potential therapeutic targets in hypoxia-driven vascular pathology.

Humans↗
PubMed2024

A fast comparative genome browser for diverse bacteria and archaea.

Genome sequencing has revealed an incredible diversity of bacteria and archaea, but there are no fast and convenient tools for browsing across these genomes. It is cumbersome to view the prevalence of homologs for a protein of interest, or the gene neighborhoods of those homologs, across the diversity of the prokaryotes. We developed a web-based tool, fast.genomics, that uses two strategies to support fast browsing across the diversity of prokaryotes. First, the database of genomes is split up. The main database contains one representative from each of the 6,377 genera that have a high-quality genome, and additional databases for each taxonomic order contain up to 10 representatives of each species. Second, homologs of proteins of interest are identified quickly by using accelerated searches, usually in a few seconds. Once homologs are identified, fast.genomics can quickly show their prevalence across taxa, view their neighboring genes, or compare the prevalence of two different proteins. Fast.genomics is available at https://fast.genomics.lbl.gov.

Archaea↗
PubMed2025

Genetic haplotypes in VWA8, OSBPL6, and ADAMTS9-AS2 are associated with immune-related adverse effects in ICI-treated patients with cancer.

BACKGROUND: Immune-related adverse events (irAEs) remain largely unpredictable, potentially affecting multiple organ systems and occurring at almost any point during and even occasionally after immune checkpoint inhibitor (ICI) treatment. To identify populations at risk for these immune-mediated toxicities, we analyzed genetic characteristics and immune markers associated with clinically significant irAEs. METHODS: We carried out a genome-wide association study on 373 white patients receiving ICI treatment. We identified single nucleotide polymorphisms associated with irAEs. Blood cytokine profiling and peripheral blood mononuclear cell RNA sequencing were performed at pretreatment baseline and 6-8 weeks after ICI initiation. Findings were validated in two external cohorts. RESULTS: We identified genetic haplotypes in VWA8 (Von Willebrand Factor A Domain Containing 8), OSBPL6 (Oxysterol Binding Protein Like 6), and ADAMTS9-AS2 (ADAM Metallopeptidase With Thrombospondin Type 1 Motif 9 Antisense RNA 2) associated with grade &#x2265;2 irAEs. Patients carrying risk haplotypes for one or more genes exhibited significantly greater rates of grade &#x2265;2 (OR 3.02; 95%&#x2009;CI 1.83 to 5.02; p<0.001), grade &#x2265;3 (OR 3.59; 95%&#x2009;CI 1.93 to 6.64; p<0.001), and multiple type irAE (OR 2.60; 95%&#x2009;CI 1.53 to 4.39; p<0.001). Serum CCL3 levels were significantly elevated in individuals carrying risk haplotypes (p=0.03). Gene expression analysis demonstrated activated autoimmune and inflammatory pathways in the genetic risk group. CONCLUSIONS: Novel polymorphisms in VWA8, OSBPL6, and ADAMTS9-AS2 may impact immune pathways, promote inflammation, potentiate autoimmune phenotypes, and convey risk of irAE in ICI-treated patients.

Humans↗
PubMed1978

[A new method for testing the quality of food protein for maintenance metabolism. 1. Investigations into the amount of 15N excreted via the urine of 15N-labelled young rats fed various proteins].

Over a period of 7 days, 38 experimental rats were fed a casein diet with a supplementation of 6.6 mg 15N-excess (15N') in the form of ammonium acetate. From the 5th experimental day, groups of 4 or 5 rats each were fed, over 5 days, different protein carriers to meet the meintenance requirement (115 kcal/kg body weight 0.75). The 15N-excretion via the urine, in terms of % of N absorbed from the food protein, served as yardstick of protein quality under maintenance conditions. The least 15N-excretion rates were reciprocally relativated for this maximum value (reciprocal 15N excretion biological value). The least 15N-excretion values from the 2nd to the 5th experimental days allowed to establish the following order for protein quality under maintenance conditions: fish meal, casein, wheat, whole egg, soybean (assayprotein), yeast peas, gelatin. The very good quality of the wheat protein for the maintenance state is seen in relation with the high content of glutamic acid (33.5 g/16 g N) and aspartic acid (5.7 g/16 gN). The found lysine content of the wheat protein (3.1 g/16 g N) proved sufficient for maintenance conditions.

Animals↗
PubMed1978

The disposition and metabolism of flurbiprofen in several species including man.

Flurbiprofen was rapidly absorbed in all species studied. 2. Half-lives of elimination measured 0 to 12 h after a single dose were: mouse 3.4 h, rat 2.5 h, dog 10.1 h, baboon 3.1 h and man 3.9 h. A second phase of elimination was seen in the dog. Flurbiprofen accumulated in the circulation of the dog on repeated dosing. 3. After dosing with [14C]flurbiprofen, tissue levels of radioactivity in dog and baboon were similar to that in plasma. In the rat, levels were slightly elevated in liver, kidney, large intestine and thyroid after repeated dosing. 4. The dog excreted equal amounts of radioactivity in urine and faeces. In other species renal excretion was the more important route. 5. Six metabolites have been detected, the most important being: 2-(2-fluoro-4'-hydroxy-4-biphenylyl)propionic acid (metabolite 1), 2-(i-fluoro-3',4'-dihydroxy-4-biphenylyl)propionic acid (metabolite 2) and 2-(2-fluoro-3'-hydroxy-4'-methoxy-4-biphenylyl)propionic acid (metabolite 3). The proportions of the metabolites and the extents of their conjugation varied among the species. 6. Metabolites were detected in the circulation of rat, mouse and baboon but not in dog and man. 7. Flurbiprofen did not affect the hepatic drug-metabolizing enzyme system of rat. 8. Flurbiprofen was extensively bound to serum protein of rat, dog, baboon and man.

Adolescent↗
PubMed2025

Pooled PPIseq: Screening the SARS-CoV-2 and human interface with a scalable multiplexed protein-protein interaction assay platform.

Protein-Protein Interactions (PPIs) are a key interface between virus and host, and these interactions are important to both viral reprogramming of the host and to host restriction of viral infection. In particular, viral-host PPI networks can be used to further our understanding of the molecular mechanisms of tissue specificity, host range, and virulence. At higher scales, viral-host PPI screening could also be used to screen for small-molecule antivirals that interfere with essential viral-host interactions, or to explore how the PPI networks between interacting viral and host genomes co-evolve. Current high-throughput PPI assays have screened entire viral-host PPI networks. However, these studies are time consuming, often require specialized equipment, and are difficult to further scale. Here, we develop methods that make larger-scale viral-host PPI screening more accessible. This approach combines the mDHFR split-tag reporter with the iSeq2 interaction-barcoding system to permit massively-multiplexed PPI quantification by simple pooled engineering of barcoded constructs, integration of these constructs into budding yeast, and fitness measurements by pooled cell competitions and barcode-sequencing. We applied this method to screen for PPIs between SARS-CoV-2 proteins and human proteins, screening in triplicate >180,000 ORF-ORF combinations represented by >1,000,000 barcoded lineages. Our results complement previous screens by identifying 74 putative PPIs, including interactions between ORF7A with the taste receptors TAS2R41 and TAS2R7, and between NSP4 with the transmembrane KDELR2 and KDELR3. We show that this PPI screening method is highly scalable, enabling larger studies aimed at generating a broad understanding of how viral effector proteins converge on cellular targets to effect replication.

Humans↗
PubMed2023

Targeting Borrelia burgdorferi HtpG with a berserker molecule, a strategy for anti-microbial development.

Conventional antimicrobial discovery relies on targeting essential enzymes in pathogenic organisms, contributing to a paucity of new antibiotics to address resistant strains. Here, by targeting a non-essential enzyme, Borrelia burgdorferi HtpG, to deliver lethal payloads, we expand what can be considered druggable within any pathogen. We synthesized HS-291, an HtpG inhibitor tethered to the photoactive toxin verteporfin. Reactive oxygen species, generated by light, enables HS-291 to sterilize Borrelia cultures by causing oxidation of HtpG, and a discrete subset of proteins in proximity to the chaperone. This caused irreversible nucleoid collapse and membrane blebbing. Tethering verteporfin to the HtpG inhibitor was essential, since free verteporfin was not retained by Borrelia in contrast to HS-291. For this reason, we liken HS-291 to a berserker, wreaking havoc upon the pathogen's biology once selectively absorbed and activated. This strategy expands the druggable pathogenic genome and offsets antibiotic resistance by targeting non-essential proteins.

Borrelia burgdorferi↗
PubMed2025

p53 enhances DNA repair and suppresses cytoplasmic chromatin fragments and inflammation in senescent cells.

Genomic instability and inflammation are distinct hallmarks of aging, but the connection between them is poorly understood. Here we report a mechanism directly linking genomic instability and inflammation in senescent cells through a mitochondria-regulated molecular circuit involving p53 and cytoplasmic chromatin fragments (CCF) that are enriched for DNA damage signaling marker &#x3b3;H2A.X. We show that p53 suppresses CCF accumulation and its downstream inflammatory phenotype. p53 activation suppresses CCF formation linked to enhanced DNA repair and genome integrity. Activation of p53 in aged mice by pharmacological inhibition of MDM2 reverses transcriptomic signatures of aging and age-associated accumulation of monocytes and macrophages in liver. Mitochondrial ablation in senescent cells suppresses CCF formation and activates p53 in an ATM-dependent manner, suggesting that mitochondria-dependent formation of &#x3b3;H2A.X&#x2009;+&#x2009;CCF dampens nuclear DNA damage signaling and p53 activity. These data provide evidence for a mitochondria-regulated p53 signaling circuit in senescent cells that controls DNA repair, genome integrity, and senescence- and age-associated inflammation, with relevance to therapeutic targeting of age-associated disease.

Animals↗
PubMed1979

Studies on horseradish peroxidase in dimethyl sulphoxide/water mixtures. The activation of hydrogen peroxide and the binding of fluoride.

We studied the variation in spectra and in reactivity towards H2O2 of solutions of horseradish peroxidase in dimethyl sulphoxide/water mixtures, obtained by diluting stock solutions of the enzyme in either water or dimethyl sulphoxide, and assayed the enzyme activity and studied the binding of F- by the peroxidase in 65% (v/v) dimethyl sulphoxide. A broadly similar pattern of changes is observed whether one starts from water or from dimethyl sulphoxide; the changes are essentially reversible, though hysteresis is observed. When the dimethyl sulphoxide content of the solvent mixture is increased, the peroxidase retains its ability to activate H2O2 up to 74% (v/v) dimethyl sulphoxide. The peroxidase in 65% (v/v) dimethyl sulphoxide binds F- together with a proton (or the equivalent loss of HO-), as already established for aqueous solutions. We point out that the occurrence in such solutions of both the ability to activate H2O2 and the inability to bind F- without taking up H+ or losing HO- supports the proposed mechanism for activating H202, whereby the protein binds the substrate in the form of the much more reactive HO2-.

Fluorides↗
PubMed1975

Renal mitochondrial glutamine metabolism and dietary potassium and protein content.

Renal mitochondrial glutamine metabolism and dietary potassium and protein content. Glutamine distribution, glutamate accumulation, phosphate-dependent glutaminase (PDG) concentrations and intact mitochondrial ammonia production were studied in renal mitochondria from rats fed low, normal and high potassium diets and in mitochondria from rats fed high or low protein diets. The rats given a low potassium diet were potassium-depleted by 10 to 20% but in none of the groups were there any abnormalities of extracellular acid-base status. Glutamine was present in the outer space of mitochondria but could not be depleted in the matrix space in any group. In both the potassium-depleted and the high protein animals, we found increased matrix -14-C-uptake of glutamine (as -14-C-glutamate), increased intact mitochondrial ammonia production and increased concentrations of PDG. In the K+-depleted group there was a decreased matrix -14C-uptake when -14C-gamma-ketoglutarate of -14C-glutamate was present in the medium. Potassium loading produced no change in mitochondrial glutamine metabolism. Protein loading (compared with protein depletion) and potassium depletion induce an increased uptake of glutamine into the renal mitochondrial matrix space which leads to its increased deamidation. This adaption may explain the increased renal ammonia production seen in these situations when compared to their respective controls.

Ammonia↗
PubMed1978

The cerebrospinal fluid in visna, a slow viral disease of sheep.

The temporal development of the CSF abnormalities was examined in visna, a chronic neurological disease caused by a persistent viral infection of sheep. Two types of changes were observed. During the first 30 to 40 days there was an intense mononuclear pleocytosis associated with high protein and proportionately elevated IgG. Later, there was a persistent slight pleocytosis associated with mildly elevated protein which had an increased proportion of IgG and antivisna antibody. These later cellular and protein changes are similar to those found in a number of chronic neurological diseases of man.

Animals↗
PubMed1979

Enrichment of albumin and IgG in the airway secretions of dogs breathing ozone.

A study was undertaken of the acute effect of the inhalation of ozone (1.0-1.5 ppm) on the concentration of proteins in the airway secretions harvested from the trachea of intact anesthetized dogs. Secretions were first collected during a control day during which room air was breathed. The dogs breathed ozone (1.0-1.5 ppm) on a second day. This protocol permitted each dog to serve as its own control. During the inhalation of ozone the concentration of total aqueous-soluble proteins, as well as of albumin and IgG were not significantly effected. However, when expressed as a percentage of total protein, both albumin and IgG were significantly enriched in the secretions. The quantitative changes of certain proteins in airway secretions may be an important reflection of the pulmonary response to ozone.

Administration, Intranasal↗
PubMed2025

Laboratory Evolution Reveals Transcriptional Mechanisms Underlying Thermal Adaptation of Escherichia coli.

Adaptive laboratory evolution is able to generate microbial strains, which exhibit extreme phenotypes, revealing fundamental biological adaptation mechanisms. Here, we use adaptive laboratory evolution to evolve Escherichia coli strains that grow at temperatures as high as 45.3 &#xb0;C, a temperature lethal to wild-type cells. The strains adopted a hypermutator phenotype and employed multiple systems-level adaptations that made global analysis of the DNA mutations difficult. Given the challenge at the genomic level, we were motivated to uncover high-temperature tolerance adaptation mechanisms at the transcriptomic level. We employed independently modulated gene set (iModulon) analysis to reveal five transcriptional mechanisms underlying growth at high temperatures. These mechanisms were connected to acquired mutations, changes in transcriptome composition, sensory inputs, phenotypes, and protein structures. They are as follows: (i) downregulation of general stress responses while upregulating the specific heat stress responses, (ii) upregulation of flagellar basal bodies without upregulating motility and upregulation fimbriae, (iii) shift toward anaerobic metabolism, (iv) shift in regulation of iron uptake away from siderophore production, and (v) upregulation of yjfIJKL, a novel heat tolerance operon whose structures we predicted with AlphaFold. iModulons associated with these five mechanisms explain nearly half of all variance in the gene expression in the adapted strains. These thermotolerance strategies reveal that optimal coordination of known stress responses and metabolism can be achieved with a small number of regulatory mutations and may suggest a new role for large protein export systems. Adaptive laboratory evolution with transcriptomic characterization is a productive approach for elucidating and interpreting adaptation to otherwise lethal stresses.

Escherichia coli↗
PubMed2026

The proteomic profile of leisure time physical activity across two decades: implications for future cardiovascular risk and mortality.

AIMS: We aimed to (i) investigate associations between leisure time physical activity level cumulated over 20 years and multiple plasma proteins and (ii) explore if proteins significantly associated with physical activity are also associated with risk of imminent myocardial infarction (MI), long-term MI, and mortality. METHODS AND RESULTS: In the cohort Uppsala Longitudinal Study of Adult Men, leisure time physical activity was self-reported at Ages 50, 60, and 70. At Age 70, 720 plasma proteins were analysed in 782 participants with up to 19.3 years of follow-up for MI and 26.3 years follow-up for mortality. In the nested case-cohort study Markers of Imminent Myocardial Infarction, plasma proteins were measured in disease-free individuals from six European cohorts. Cases (n = 420) were those with acute MI within 6 months of a blood draw, with up to four cohort representatives per case (n = 1598). A higher level of leisure time physical activity level was inversely associated with 12 plasma proteins after adjusting for age, education, smoking, and established cardiovascular risk factors (Bonferroni-corrected P < 0.000069). Of these 12 proteins, interleukin-6 was associated with increased incidence of imminent MI [hazard ratio, HR 1.22; 95% confidence interval, CI (1.09-1.37)], tumour necrosis factor receptor superfamily member 11A was associated with increased long-term MI incidence [HR 1.22 (1.01-1.48)] and 11 proteins were associated with increased mortality [HR 1.14-1.30 (1.01-1.42)]. CONCLUSION: These findings confirm and extend our understanding of how physical activity could assert its beneficial effect on cardiovascular health through proteins involved with modulating inflammatory, immune, and metabolic pathways. Further research is needed to explore the causal mechanisms behind these associations. LAY SUMMARY: In this study, we aimed to investigate (i) whether leisure time physical activity level cumulated over 20 years is associated with 720 plasma proteins and (ii) if proteins that are significantly associated with leisure time physical activity level across 20 years in Part 1 are also associated with imminent and long-term risk of myocardial infarction (MI) and mortality.Higher physical activity level over 20 years was inversely associated with 12 plasma proteins involved in inflammatory, immune, and metabolic processes. Several plasma proteins were in turn associated with MI and mortality.Findings confirm and extend our understanding how physical activity could assert its beneficial effect on cardiovascular health via the circulating plasma proteins.

Humans↗
PubMed1978

The action of human high density lipoprotein on cholesterol crystals. Part 2. Biochemical observations.

Electron microscopy of the reaction product between human pooled high density lipoprotein (HDL) and cholesterol shows that characteristic liposome macromicellar bodies are formed. These bodies vary in size between 30 and 1200 nm. In comparison with HDL, they contain markedly more cholesterol, but less protein and phospholipid. Their phospholipid pattern shows enrichment with sphingomyelin and phosphatidyl serine in comparison with HDL.

Cholesterol↗