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At least 19 recordsLinked to original sources
PubMed1979

Depth of nontarget processing in an attention task.

Two studies examined the effect of the sensory discriminability of targets from nontargets on depth of nontarget processing. Subjects shadowed target words that were binaurally presented with coincident nontarget words. Targets and nontargets were spoken in the same male voice under low sensory discriminability and in male and female voices, respectively under high sensory discriminability. Across the two studies, depth of nontarget processing was assessed in three ways: extent to which shadowing accuracy was disrupted by a semantic overlap between targets and nontargets, expenditure of capacity (reaction time to subsidiary light signals), and nontarget recall. All three possible measures of depth of nontarget processing decreased as sensory discriminability increased. The data support the assumption of multiple-loci theories of attention that nontargets can be perceptually inhibited; they contraindicate the assumption of late-selection theories that perceptual processing is automatic and irrepressible.

Attention↗
PubMed1979

Effect of estrogen on ovalbumin gene expression in differentiated nontarget tissues.

By use of cloned DNA fragments as probes, low levels of ovalbumin RNA sequences (structural and intervening sequences) were detected in nuclear RNA extracts of nontarget tissues, such as liver, spleen, brain, and heart of chicks. The expression of the ovalbumin gene sequences was hormone dependent. In estrogen-stimulated chicks, a low level of ovalbumin RNA sequences, ranging from 0.2 to 0.7 molecule per cell, was present in nontarget tissues while less than 0.01 molecule per cell could be found in the same tissues of unstimulated chicks. A significant amount of the ovalbumin mRNA sequences was also found in polysomes of liver and brain. The ovalbumin mRNA sequences could be translated into proteins which were only localized in a few cells among the entire population of liver cells as determined by an immunocytochemical assay. These results suggest that there are some cells in liver, spleen, heart, and brain which can respond to hormone stimulation and produce ovalbumin mRNA and its translational product.

Animals↗
PubMed1979

Information processing in a binary classification task.

Three choice-reaction time studies were conducted to investigate whether information processing is exhaustive or self-terminating, serial or parallel, and N-dependent or N-independent. A total of 54 subjects were required to make key-pressing responses to one, two, or three digits presented in a circular display; one key was pressed if the display contained one or more target digits and another key was pressed if the display contained only nontarget digits. The first two studies utilized within-subjects designs in which the displays were constructed from only one target and one nontarget item (Study 1) or from three target and seven nontarget items (Study 2). The third study used a between-subjects design in which different groups of subjects responded to one-, two-, or three-element displays. In general, the results indicate that CRTs increased as the total number of display elements increased and decreased as the number of target elements (or the ratio of target to nontarget items) increased for a given display size. When only target elements were presented, CRT was independent of the number of elements displayed, and when only one target was presented, CRT increased as total number of elements increased. Theses combined results are interpreted as support for the inference that information processing in visual search tasks tends to be self-terminating, serial, and N-dependent (of limited capacity).

Adult↗
PubMed2025

Molecular Biomarker Testing Patterns and Turnaround Time in US Patients With Advanced Non-Small Cell Lung Cancer.

BACKGROUND: Patients with advanced non-small cell lung cancer (aNSCLC) are recommended to undergo molecular testing for targetable genomic alterations. However, as high-throughput methods are increasingly used, long test turnaround time (TAT) may lead to lower receipt of appropriate targeted therapy. Guidelines recommend a 2-week TAT for ALK and EGFR testing, 2 prevalent pathogenic alterations with highly effective targeted therapies. PATIENTS AND METHODS: Using an electronic health record-derived, deidentified database, we conducted a retrospective cohort study of patients with aNSCLC diagnosed between 2011 and 2023 who received testing for ≥1 of 8 molecular markers. We assessed the number of biomarkers tested per patient, testing modality, and TAT (defined as the interval between specimen collection and result date) over time. We also evaluated patients with ALK/EGFR-altered aNSCLC who initiated early nontargeted treatment prior to test result availability, examining associations with TAT and clinical outcomes. RESULTS: The study sample comprised 33,945 patients, with a mean age of 68.2 years; 49.4% were female, 58.3% were White, and 83.4% reported a history of smoking. From 2011 to 2023, the mean number of biomarkers tested per patient (range, 2.0-6.8) and the use of next-generation sequencing (NGS) increased, whereas the mean TAT converged to 3 weeks. Fewer than half of the patients with ALK/EGFR-altered aNSCLC had a TAT of ≤2 weeks, and 1 in 8 initiated early nontargeted treatment. Longer TAT was associated with early nontargeted treatment when analyzed as both a continuous variable (odds ratio, 1.83 per week) and a binary variable (TAT >2 vs ≤2 weeks; odds ratio, 6.02). Early treatment was associated with worse median progression-free survival (9 vs 11 months) in patients with ALK/EGFR-altered aNSCLC. CONCLUSIONS: Biomarker testing and NGS use have increased over time in US patients with aNSCLC. TAT has plateaued and remains longer than recommended in consensus guidelines. Longer TAT was associated with early nontargeted therapy in patients with ALK+/EGFR+ aNSCLC, leading to suboptimal first-line treatment and poorer clinical outcomes.

Humans↗
PubMed1975

An analysis of the binding of the chick oviduct progesterone-receptor to chromatin.

The binding of progesterone-receptor complexes to chromatin from target and nontarget tissues was studied in vitro. Chromatin from both target and nontarget tissues responds in a similar manner to saly and cofactors and has the same K(D) (approx. 3.10(-9) M) for the progesterone-receptor complex. The only observed difference in the binding of the progesterone-receptor complex to target and nontarget chromatins is the difference in total number of acceptor sites. oviduct chromatin has approx. 1300 sites/pg DNA, spleen chromatin has approx. 840 sites/pg DNA, and erythrocyte chromatin has about 330 sites/pg DNA. The K(D) and number of acceptor sites for progesterone-receptor complex binding to oviduct chromatin remains the same even after extensive purification of the progesterone-receptor complex. Activation of cytosol labeled with [3H]progesterone by preincubation at 25 degrees C, analogous to that required for maximal nuclear binding, occurs if the binding studies to chromatin are performed in 0.025 M salt. The absence of an observable temperature effect when the studies are performed at 0.15 M salt is due to the activation of the receptor by salt. The dissociation of the progesterone-receptor complex from chromatin exhibits a single dissociation rate and the initial event is the appearance of free progesterone rather than a progesterone-receptor complex. Lastly, the treatment of chromatin with an antibody prepared against either single-stranded DNA or double-stranded DNA does not alter the extent of binding of the progesterone-receptor complex. Similarly, pretreatment of chromatin with a single-stranded nuclease does not inhibit the capacity of chromatin to bind the hormone-receptor complex.

Animals↗
PubMed1975

Progesterone-binding components of chick oviduct. IX. The kinetics of nuclear binding.

A cell-free system was used to study the kinetics of progesterone-receptor interaction with purified nuclei prepared from estrogen-primed chick oviducts. The binding process was a saturable phenomenon in both target and nontarget tissues. More nuclear acceptor sites were available to target tissue (similar to 9000 sites per oviduct nucleus) than in nontarget tissues (similar to 1000 to 3000 sites per nucleus), but the binding constant was essentially the same (Kd similar to 10-8 M). A second much smaller class of higher affinity sites (Kd similar to 10-11M) may exist. Its presence was detected by Scatchard plot nonlinearity at very low concentrations of added receptor-hormone complex (similar to 10-10 to 10-12M). The current study focused on the prevalent class of acceptor sites which was more readily detectable. Receptor binding to these sites was highly sensitive to salt. More sites were exposed at 25 degrees than at 0 degrees. Binding to these sites was inhibited in a nonselective fashion by the addition of protein. Although receptors may be activated by temperature or conditions of high ionic strength, these conditions could not capacitate more than 30 to 40% of the progesterone-receptor proteins for binding. Rate studies suggested that temperature plays a minimal role in nuclear uptake of activated receptors. Such a finding is consistent with a diffusion-limited uptake process.

Ammonium Sulfate↗
PubMed2026

Attribution of PM2.5-Induced Transcriptomic Perturbation to Toxic Components.

Ambient fine particulate matter (PM2.5) is a chemically complex mixture whose health impacts are not fully captured by particle mass. Here, we developed an interpretable chemotranscriptomic framework to attribute PM2.5-induced molecular perturbations to toxicity-relevant components. PM2.5 collected from urban roadside and coastal environments was separated into whole, extractable, and unextractable fractions, characterized by LC/GC × GC-HRMS-based nontarget analysis and inductively coupled plasma mass spectrometry (ICP-MS), and evaluated using cytotoxicity testing and transcriptomic profiling in human bronchial epithelial cells. Urban PM2.5 exhibited greater cytotoxic potency per unit mass than coastal PM2.5, with extractable fractions accounting for most cytotoxic and pathway-level responses. Transcriptomics revealed distinct site-specific modes of action: urban PM2.5 preferentially induced oxidative stress, xenobiotic metabolism, and cell cycle suppression, consistent with acute, nonapoptotic injury, whereas coastal PM2.5 elicited weaker cytotoxicity but stronger interferon-mediated immune and apoptosis-related signaling. Integrating chemical abundance with pathway activity using random forest regression, SHAP interpretation, and mechanistic corroboration reduced 5,033 detected features to 444 pathway-linked candidate drivers. Fewer than 5% of features explained ∼95% of cumulative model contribution. Standard-confirmed contributors included plasticizer-related compounds, aromatic and heteroaromatic combustion products, and copper for urban PM2.5 and secondary/aged organics and nickel for coastal PM2.5. These findings support mechanism-informed prioritization of hazardous PM2.5 components beyond mass-based assessment.

Particulate Matter↗
PubMed2024

Value of a secretomic approach for distinguishing patients with COVID-19 viral pneumonia among patients with respiratory distress admitted to intensive care unit.

In intensive care units, COVID-19 viral pneumonia patients (VPP) present symptoms similar to those of other patients with Nonviral infection (NV-ICU). To better manage VPP, it is therefore interesting to better understand the molecular pathophysiology of viral pneumonia and to search for biomarkers that may clarify the diagnosis. The secretome being a set of proteins secreted by cells in response to stimuli represents an opportunity to discover new biomarkers. The objective of this study is to identify the secretomic signatures of VPP with those of NV-ICU. Plasma samples and clinical data from NV-ICU (n = 104), VPP (n = 30) or healthy donors (HD, n = 20) were collected at Nantes Hospital (France) upon admission. Samples were enriched for the low-abundant proteins and analyzed using nontarget mass spectrometry. Specifically deregulated proteins (DEP) in VPP versus NV-ICU were selected. Combinations of 2 to 4 DEPs were established. The differences in secretome profiles of the VPP and NV-ICU groups were highlighted. Forty-one DEPs were specifically identified in VPP compared to NV-ICU. We describe five of the best combinations of 3 proteins (complement component C9, Ficolin-3, Galectin-3-binding protein, Fibrinogen alpha, gamma and beta chain, Proteoglycan 4, Coagulation factor IX and Cdc42 effector protein 4) that show a characteristic receptor function curve with an area under the curve of 95.0%. This study identifies five combinations of candidate biomarkers in VPP compared to NV-ICU that may help distinguish the underlying causal molecular alterations.

Humans↗
PubMed2026

Dnmt3b and Dnmt3l knockdown reduces blastocyst development in early mouse embryos.

A one-cell embryo called a zygote develops into a blastocyst through several successive cell divisions and lineage specification, this process is called early embryo development. Both embryonic genome activation (EGA) and the first lineage specification during early embryonic development depend on tightly coordinated epigenomic organization. Regulation of the epigenome is primarily governed by DNA methylation mediated through DNA methyltransferase (Dnmt) enzymes. Dnmt1 is responsible for the maintenance of methylation during cellular division, while Dnmt3a/Dnmt3b enzymes play a role in the establishment of de novo methylation particularly during gametogenesis and early embryo development. Despite its lack of catalytic activity, Dnmt3l functions as a cofactor enhancing Dnmt3a/3b activity. Dnmt3b deficiency results in global hypomethylation and ultimately embryonic lethality. In this study, we aim to elucidate the effect of Dnmt3b and Dnmt3l silencing on early embryo development. For this purpose, our experimental groups were established using an in vitro mouse embryo development model: control, Dnmt3b small interfering RNA (siRNA), Dnmt3l siRNA, and a nontargeting siRNA group. Following gene silencing at the one-cell stage, embryonic developmental competence, the expression pattern of nonsilenced Dnmt enzymes, global DNA methylation levels, and transcriptome profiles were analyzed at the blastocyst stage. Dnmt3b/3l silencing resulted in decreased global DNA methylation and Dnmt1/3a expression, and reduced blastocyst rate. Differentially expressed genes included those involved in X-chromosome inactivation (Xist), transcriptional regulation (Rn7sk), translation (Eef1a1, Eef2), trophoblast development (Hsd3b1), compaction (Gja1), and oxidative phosphorylation (CYTB, COX1, mt-Rnr1). Our findings indicate that siRNA-mediated knockdown of Dnmt3b and Dnmt3l is associated with reduced blastocyst development, impaired embryo quality, and alterations in DNA methylation-related processes during early embryonic development.

Animals↗
PubMed1975

Physiologic significance of 17beta-estradiol binding in the rabbit Fallopian tube.

Rabbit Fallopian tube contractility was recorded in vitro during perfusion with either Locke's solution or that solution containing CN-55, 945-27 (CN; or CI-628), a nonsteroidal estrogen antagonist (Endocrinology 79: 153, 1966). Contractility was inhibited and 17beta-estradiol (E2) displaced from both its cytoplasmic (8S) and nuclear (4S) receptors in the presence of the above agent. These effects result from a direct interaction between CN and the E2-receptor complexes. Two types of evidence show the specificity of the foregoing responses: (1) nonspecific binding of E2 to serum proteins was unaffected by the antagonist and (2) CN had no effect on contractility of a nontarget tissue, i.e., rabbit ileum. In addition, Fallopian tube contractions induced by strong electrical stimulation of K-depolarized tissues (i.e., in the absence of normal ionic gradients) were inhibited by CN and a decrease in the binding capacities of 8S and 4S receptors was again observed. Thus, antagonism of specific E2 binding inhibits the contractile mechanism at a level other than the cell membrane. These observations, and additional findings concerning the reversibility of CN action, indicate that E2 binding is essential for contractility of the rabbit Fallopian tube.

Animals↗
PubMed2026

Proteome-level evidence that tebuconazole, both alone and in interaction with thiacloprid, affects epigenetic events in bumblebee heads.

Tebuconazole, a widely used ergosterol biosynthesis-inhibiting fungicide, can affect nontargets, especially when combined with insecticides. We employed label-free quantitative proteomics to investigate the effects of long-term exposure to sublethal concentrations (100 μg/L) of tebuconazole, either by itself or alongside the neonicotinoid thiacloprid (100 μg/L), on the heads of Bombus terrestris workers. A Bayesian factor power analysis revealed that the experiment produced conclusive proteomic results. Tebuconazole treatment revealed eleven differentially abundant proteins, which increased elevenfold with thiacloprid. The proteins that changed in the same direction in both treatments suggest the occurrence of epigenetic events because they are involved in histone trimethylation (H3K4me3), pre-mRNA processing, and folate (vitamin B9) metabolism. Following co-exposure, the abundance of histone H2A.V and its associated proteins was affected. Two important detoxification-related proteins, CYP6BE1 and CYP6AQ1 (honey bee homologs), were identified, as well as proteins that suggest hormonal and neurotoxic effects. Overall, this study suggests that tebuconazole affects key epigenetic processes in bumblebee heads at the proteome level, though this was not confirmed at the biological level or through orthogonal methods. The tested chemicals were previously found to affect trimethylations, but not H3K4me3. We suggest analyzing the different trimethylations, their interplay, and associated hallmarks, such as folate levels. SIGNIFICANCE: The effects of pesticides and their combinations on organisms can be unexpected until they are examined using modern, complex methods. High-throughput proteomics can provide data on important biochemical processes affected by pesticides, offering a different perspective to that at the expression level. Despite their low acute toxicity, a group of fungicides that inhibit (ergo)sterol biosynthesis (EBI or SBI) are considered dangerous to pollinators, including bumblebees. This is due to the increasing toxicity of insecticides through the inhibition of cytochrome P450 detoxification enzymes. We found that tebuconazole had a similar effect on epigenetic events when used alone or in combination with the insecticide thiacloprid. Key proteins suggest that H3K4 histone trimethylation (H3K4me3) was impacted. To our knowledge, this expands the existing evidence suggesting that tebuconazole/triazole fungicides affect histone trimethylation H3K27me3. Since literature shows that thiacloprid affects H3K9me3, it is possible that thiacloprid and tebuconazole interact in these epigenetic events that affect each other. Overall, our results suggest that tebuconazole affects proteins involved in histone trimethylation, pre-mRNA processing, and folate metabolism. These are all hallmarks of epigenetic processes and were further extended by the co-exposure of tebuconazole and thiacloprid to more differently abundant proteins. Additionally, the results provide data on cytochrome P450s of the CYP6 family, which act as detoxifying proteins, as well as proteins that indicate hormonal and neurotoxic effects in bumblebee heads. Finally, the results of the Bayesian power analysis confirmed the meaningfulness of the proteomic data analyzed in this study. If the new findings obtained at the proteome level are verified by different methods, the full extent of the side effects of tebuconazole can be revealed.

Animals↗
PubMed2025

Optical Genome Mapping Is a Powerful Diagnostic Tool in Non-Hodgkin Lymphoma.

Non-Hodgkin lymphoma (NHL) is a diverse and heterogeneous group of hematological malignancies. These lymphomas arise from the clonal proliferation of either B/T or natural killer lymphocytes, and their correct classification relies partly on identifying characteristic structural variants and copy number alterations. Current standard-of-care technologies for detecting these genomic features, chromosome banding analysis (CBA) and fluorescent in situ hybridization (FISH), are labor intensive and have specific limitations. CBA has low resolution and relies on viable cell culture, whereas the targeted approach of FISH does not provide the whole genome view required for comprehensive disease characterization. This highlights the need for higher-resolution nontargeted genomic methods. Previous studies have evaluated optical genome mapping (OGM) as a whole genome alternative for cytogenomic characterization in NHL diagnostics but were restricted in number and to cases with peripheral blood and/or bone marrow invasion. Here, we selected a comprehensive cohort of 110 NHL cases (79 B-NHL and 31 T-NHL/natural killer-NHL) derived from different types of tissue biopsies, all with established histopathological diagnoses. Seventy-eight samples were genomically well characterized at diagnosis by CBA and FISH. The remaining 32 cases were included because of previous CBA failure, although FISH data were available for 20 cases. OGM provided informative results in 94% of the cohort, with a high concordance rate of 97.6% compared with CBA/FISH in detecting clinically relevant aberrations. The 2 variants that were missed were both present at the detection threshold of OGM. In contrast, OGM successfully resolved 26 samples with previous CBA failure and detected 3 additional disease-defining events, resulting in diagnostic reclassification of 1 patient. Finally, OGM identified novel recurrent aberrations that warrant further investigation into their pathogenetic implications. To conclude, OGM robustly detects clinically relevant structural variants and copy number alterations and presents a promising alternative to CBA and FISH in routine diagnostic evaluation of NHL.

Humans↗
PubMed1979

Prolactin receptors in the ovary.

The binding of prolactin (PRL) to the plasma membranes of bovine and human ovaries was investigated using both homologous and heterologous 125I-prolactin. Saturation and Scatchard analysis demonstrated that human prolactin binds to human ovarian membranes with a Kd of 2 x 10(-10) M; to bovine ovarian membranes with a Kd of 1.9 x 10(-10) M; and to bovine corpora lutea membranes with a Kd of 1.9 x 10(-10) M. The concentrations of binding sites in bovine and human ovaries were 2.9 x 10(-15) moles/mg of protein and 2.0 x 10(-15) moles/mg of protein, respectively. The number of bindings sites in the bovine corpora lutea was 1.5 x 15(-15) moles/mg of protein. Specificity studies with bovine PRL, ovine PRL, human luteinizing hormone, human follicle-stimulating hormone, and bovine growth hormone showed this binding to be specific. Comparison of binding of PRL to membranes of other target and nontarget tissues suggests that the ovary is one of the primary target tissues. These data suggest that prolactin plays a role in the ovarian cycle.

Animals↗
PubMed2026

GPNMB-directed CAR T cell therapy against MiT/TFE-family fusion-driven solid tumors.

Chimeric antigen receptor (CAR) T cell therapy for solid tumors is constrained by the scarcity of safe, uniformly expressed cell-surface targets. Here we identify glycoprotein NMB (GPNMB)-an MiT/TFE-family fusion-driven protein-as being highly, homogeneously and stably expressed in primary and relapsed alveolar soft-part sarcoma (ASPS) and translocation renal cell carcinoma. We develop a GPNMB-directed CAR T cell product, GCAR1, which demonstrates potent activity against patient-matched cells, organoids and xenograft models. Post hoc interim analysis of a first-in-human open-label, individual-participant trial ( NCT07104682 ) for a participant with relapsed/refractory, metastatic ASPS showed that GCAR1 induces stable disease for up to 3 months, accompanied by resolution of many nontarget lesions (primary endpoint), and is well tolerated. GCAR1 T cells expand in peripheral blood as a polyclonal population and remain detectable for 1 month. Spatial transcriptomics identified immunosuppressive niches in a treatment-resistant lesion and immune checkpoint blockade synergized with GCAR1 in a xenograft model. Altogether, our data provide a proof of concept for treating GPNMB-expressing solid tumors with GCAR1 and more broadly targeting surface antigens driven by oncogenic gene fusions with CAR T cell therapies.

Animals↗
PubMed2026

VIPR RNA-guided DNA recognition by noncontiguous geometric triplex formation.

Viral interference programmable repeat (VIPR) systems use a noncontiguous code for RNA-guided transcriptional silencing. How the Vipr protein and a VIPR RNA (vrRNA) comprising alternating GGY and NN segments achieve precise DNA targeting is unknown. Here, we present 21 cryo-electron microscopy structures that help explain the mechanism of target engagement. Vipr protomers oligomerize along the vrRNA to form a right-handed helical filament, sequestering each GGY motif and positioning the adjacent NN bases for target base pairing. DNA binding, in which every third nucleotide is skipped, results in a gapped vrRNA-DNA hybrid helix that encircles the nontarget DNA strand to form a geometric triplex. These findings suggest that triplex-mediated target-strand handoff could enable noncontiguous and programmable RNA-guided DNA recognition in VIPR systems.

DNA↗