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At least 19 recordsLinked to original sources

PubMed2026

African swine fever virus A151R protein antagonizes the antiviral activity of barrier-to-autointegration factor (BAF) by targeting its dsDNA-binding activity.

Barrier-to-autointegration factor (BAF) is a ubiquitous double-stranded DNA-binding protein that compacts DNA and can restrict poxvirus replication in the cytoplasm. BAF antiviral DNA-binding activity is tightly regulated by dynamic phosphorylation mediated by viral and cellular enzymes. For example, vaccinia virus counteracts BAF by encoding the B1 kinase, which phosphorylates BAF and abrogates its DNA-binding activity. Some DNA viruses, such as African swine fever virus (ASFV), undergo cytoplasmic replication but appear to lack a B1-like kinase. Interestingly, ASFV encodes A151R, a viral protein recently found to stably interact with BAF. Here, we demonstrate that A151R is capable of counteracting the antiviral properties of BAF. Structural modeling indicates that A151R is not a protein kinase and does not phosphorylate BAF but instead directly targets its double-stranded DNA-binding interface. This interaction enhances genome replication and progeny production of a B1-deficient virus. Mechanistically, A151R markedly impairs BAF DNA binding and disrupts its dimerization, a key requirement for high-affinity DNA association. Importantly, disruption of the A151R-BAF interaction abolishes these effects and restores BAF antiviral function. In addition, expression of the unphosphorylatable BAF mutant, which normally exhibits strong chromatin association, was redistributed to the cytoplasm in the presence of A151R, further supporting phosphorylation-independent regulation of BAF-DNA association. In conclusion, our findings support a previously unrecognized mechanism by which ASFV A151R disables BAF antiviral activity by obscuring its DNA-binding interface and inhibiting DNA binding in a phosphorylation-independent manner.IMPORTANCEDNA viruses replicating in the cytoplasm must overcome host intrinsic defenses to ensure productive replication, yet the mechanisms underlying their antagonism of the DNA-binding antiviral factor BAF remain incompletely understood. Here, we identify African swine fever virus (ASFV) A151R as a novel viral regulator that disables BAF by targeting its double-stranded DNA-binding interface rather than altering its phosphorylation state. We demonstrate that A151R impairs BAF DNA binding, disrupts its dimerization, and promotes viral DNA accumulation and progeny production in a BAF-dependent manner. Importantly, this activity requires A151R-BAF interaction and is independent of BAF phosphorylation status. Our findings reveal a previously unrecognized strategy employed by ASFV to neutralize host DNA-binding restriction factors and expand the molecular framework of BAF-mediated antiviral defense.

A151R↗

PubMed2025

Gene Specific Pathogenicity Predictor for Chromatin-Remodeling BAF Complex-Associated Neurodevelopmental Disorders.

Advancements in whole genome sequencing have increased the number of variants of uncertain significance (VUS) identified in patient genomes. This has created a diagnostic bottleneck for genetic counselors tasked with sifting through these variants and determining those most likely to be causative for a patient's clinical presentation. Machine learning (ML) tools can aid in identifying pathogenic variants from VUS, but there is a need for gene-specific algorithms that predict pathogenic variants with high accuracy. To address this need, we present a workflow for developing gene-specific, ensemble-learning ML tools, that leverage outputs from other algorithms, locations of variants within the gene, and evolutionary conservation data to make a prediction of pathogenicity. Variants in SMARCA2 and SMARCA4 that are associated with rare neurodevelopmental diseases were used to screen 15 ML algorithms. A random forest learner was tuned to yield a final accuracy of 0.93 on holdout data. Generalizing this predictor to other BAF complex proteins resulted in a sharp decline in performance. We trained a final predictor for all genes in the study to create a predictor that identifies pathogenic variants in these BAF subunits with an accuracy of 0.91 on holdout data. This predictor specific to BAF complex proteins performs with higher accuracy and AUROC than any other predictor. The decline in performance when generalized to other proteins emphasizes the need for the gene-specific calibration of predictors. Our workflow for the development of such models provides a quick, computationally inexpensive route for improving the ML tools available to genetic counselors.

Journal Article↗

PubMed1976

Phase I studies with Baker's Antifol (BAF) (NSC 139105).

Phase I studies were conducted in 58 adult cancer patients with Baker's Antifol (BAF), a new active-site directed inhibitor of dihydrofolate reductase. Dose escalation ranged from 10 to 250 mg/m2/day X 5 days and courses of treatment were repeated every 2-3 weeks. Biologic effects were observed mostly at doses greater than 100 mg/m2/day X 5 days. The patients developed myelosuppression during 19% of the trials. Other types of toxicity were dermatitis in 12 to 30% and stomatitis in 7 to 38% of the trials. Toxicity was directly related to the impairment of the patient's liver function. Two partial responses (in a patient with adenocarcinoma of the lung and a patient with transitional cell carcinoma of the bladder) occurred. BAF is an active new chemotherapeutic agent which deserves further clinical trials in patients with various malignancies.

Adolescent↗

PubMed1978

Sequential chemoimmunotherapy of colorectal cancer: evaluation of methotrexate, Baker's Antifol and levamisole.

Fifty-two untreated patients with colorectal cancer were randomized to receive 5-fluorouracil (5-FU) alternating either with methotrexate (MTX) or Baker's Antifol (BAF) with or without the immunostimulant, levamisole (Program I). Fifty-five patients who had received prior treatment were randomized to receive methyl-CCNU (Me) with MTX or BAF (Program II). Fifteen of these patients had failed to respond to initial therapy with 5-FU plus MTX or BAF and subsequently received Me plus the alternate antifol. Overall response rate for each of programs I and II was 10%. The responses were 1/11 with 5-FU-MTX plus levamisole, 2/12 with 5-FU-MTX, 1/8 with 5-FU-BAF plus levamisole, 0/8 with 5-FU-BAF, 2/20 with Me-MTX and 2/21 with Me-BAF. The median survival times (MST) for patients receiving Programs I and II were 10 and 5 months, respectively. The MST for all patients receiving MTX was significantly longer than that of patients receiving BAF Survival was not influenced by levamisole administration. Both chemotherapy programs were well tolerated. The sequential administration of 4 active agents failed to improve the results of treatment of colorectal cancer.

Adolescent↗

PubMed1978

Clinical, toxicological, and pharmacological studies of combination chemotherapy of adenocarcinoma with adriamycin and Baker's antifolate.

Ten patients with disseminated adenocarcinoma were treated with combination chemotherapy employing Adriamycin and Baker's Antifolate (BAF). There were seven patients with lung adenocarcinoma, two of whom achieved partial remission while the remaining five had their disease stabilized. Drug toxicity to the bone marrow, gastrointestinal mucosa, and skin was dose-limiting and was greater than the known toxicities of the individual drugs. Pharmacological studies of both drugs were performed on five patients to determine whether abnormal pharmacokinetics could explain this collateral toxicity. Adriamycin plasma concentrations and disappearance seemed to be unaffected by BAF. However, BAF levels were prolonged, apparently due to an Adriamycin effect on the plasma elimination of BAF, resulting in a prolonged exposure of sensitive tissues and organs to BAF. Consequently, when BAF and Adriamycin are used in combination, appropriate dose and schedule changes must be made to avoid any potentially serious side effects.

Adenocarcinoma↗

PubMed2026

SWI/SNF Alterations Define a Chromatin-Dependent Subtype of Urothelial Carcinoma.

PURPOSE: SWI/SNF (BAF) chromatin remodeling complex alterations are common in urothelial carcinoma, yet no biomarker-directed therapeutic strategies have been established for this population. We investigated whether BAF alterations delineate a biologically distinct, therapeutically actionable urothelial carcinoma subtype. EXPERIMENTAL DESIGN: We performed integrative genomic and transcriptomic analyses of 792 urothelial carcinoma tumors from the Oncology Research Information Exchange Network (ORIEN) and validated findings in the TCGA-BLCA cohort. Mechanistic studies incorporated RNA sequencing and ATAC-seq following histone deacetylase (HDAC) inhibition. Functional dependencies were assessed using patient-derived xenograft organoids and cell line models. Clinical relevance was explored in a biomarker-enriched investigator-initiated trial. RESULTS: Approximately half of urothelial carcinoma tumors exhibited BAF alterations, defining a previously unrecognized chromatin-altered molecular subtype characterized by activation of proliferative programs, loss of lineage identity, and altered metabolic signaling. This subtype was enriched for transcriptomic programs associated with HDAC inhibitor sensitivity and depleted of HDAC inhibitor resistance signatures. Mechanistically, HDAC inhibition induced widespread chromatin remodeling with reduced accessibility at AP-1 and TEAD-associated regions, and downregulation of E2F- and MYC-driven transcriptional networks. Functional studies confirmed enhanced HDAC inhibition sensitivity in ARID1A -mutated cell lines and a patient-derived organoid model. Early clinical observations demonstrated a durable responder treated with HDAC inhibitors and immunotherapy. CONCLUSIONS: BAF alterations define a chromatin-dependent tumor state in urothelial carcinoma that is selectively vulnerable to HDAC inhibition. Integrating genomic, epigenomic, functional, and early clinical evidence, these findings provide a rationale for biomarker-enriched clinical trials and HDAC inhibitor-based combination strategies in urothelial carcinoma.

Journal Article↗

PubMed1979

Comparison of the plaque-stimulating and thymocyte-stimulating activities derived from human monocytes.

Human monocytes have been reported to release factors that can elicit distinct responses from a number of different target cells. In this report, it is shown that most of the thymocyte-stimulating activity in supernatants of endotoxin-stimulated monocytes can be separated from the plaque-stimulating factor (BAF) by gel filtration and isoelectric focusing; however, since these activities could not be entirely resolved, the question was addressed whether the plaque-stimulating activity of BAF depends upon the stimulation of T-cells. Several critical experiments are reported which fail to support this hypothesis. On the other hand, these experiments led to the observation that the response to BAF depends on both an IgM-positive B-cell and a G10-adherent, plastic nonadherent, IgM-negative, irradiation-insensitive cell found in nude splenocytes. Finally, the possibility is discussed that this factor may be responsible for many of the physiological sequelae of infection.

Animals↗

PubMed1992

[Differences of regional blood flow after stellate ganglion block with local anesthetic and that after stellate ganglion resection using ultrasonic Doppler flowmeter].

Ten mongrel dogs were divided into two groups; stellate ganglion block (SGB, n = 5) group and stellate ganglion resection (SGR, n = 5) group. Anesthesia was induced with pentobarbital 25 mg.kg-1. The animals were mechanically ventilated to maintain a constant PaCO2 (35-40 mmHg). Left common carotid arterial flow (CCAF), left external carotid arterial flow (ECAF), left vertebral arterial flow (VAF) and left brachial arterial flow (BAF) were measured using an ultrasonic transit time flowmeter. Internal carotid arterial flow (ICAF) was calculated by subtracting ECAF from CCAF. After thoracotomy, the first SGB with 0.5% mepivacaine 1.5 ml or SGR was performed. Ninety minutes after the first SGB, the second SGB was performed. The data were taken for 180 minutes after the first SGB or SGR. In SGB, CCAF and BAF increased significantly for the duration of action of local anesthetic. But VAF and ICAF increased significantly for a short time after the block. In SGR, CCAF, BAF and ICAF increased significantly during the experiment. But VAF showed a transitory increase immediately after the resection. The authors conclude that sympathetic ganglion block with local anesthetic should be performed repeatedly when increase of blood flow in blood vessels with strong autoregulation from the brain is anticipated.

Animals↗

PubMed1979

Purification and properties of human B cell-activating factor.

Human monocytes, when appropriately stimulated in vitro, release into the culture medium a factor (BAF) that stimulates the IgM response of T-depleted murine splenocytes to heterologous erythrocytes. The behavior of this factor on gel filtration, isoelectric focusing, ion exchange chromatography, and isopycnic centrifugation was studied. BAF appears to be a molecule of 15,000 daltons, pI 6.5, 1.33 g/ml with low solubility at low ionic strength. It is stable to acid, mild heating, and long-term storage. Activity is lost in alkali or by boiling. Papain may reduce BAF activity slightly, whereas trypsin and chymotrypsin have no significant effect. These properties are similar to those of other monokines reported to have a similar m.w.

Animals↗

PubMed1977

Chemoimmunotherapy of metastatic large bowel cancer: nonspecific stimulation with BCG and levamisole.

The administration of two chemoimmunotherapy programs to 103 consecutive patients with metastatic colorectal cancer resulted in improved survival for patients who achieved either objective tumor regressions or disease stabilization for more than 8 weeks. Objective tumor regression was observed in 47% of patients treated with the Ftorafur-methyl-CCNU-methotrexate-Bacillus Calmette-Guerin (FTOR-MeM-BCG) program and in 34% of patients treated with the 5-fluorouracil-methotrexate-Baker's antifol (FU-M-BAF) +/- Levamisole program. The combinated median duration of survival for patients who achieved objective tumor regression and disease stabilization with FTOR-MeM-BCG was 13 months compared with 6 months for patients who had progression of disease (p = 0.001). The corresponding values for patients treated with FU-M-BAF +/- levamisole were 11 months and seven months, respectively (p = 0.001). While the role of BCG immunotherapy in these results remains speculative, the administration of levamisole immunotherapy did not appear to have influenced results significantly. Patients who presented at diagnosis with Dukes A, B and C lesions, and therefore had longer disease-free intervals, responded more frequently to chemoimmunotherapy and survived longer than patients who presented at diagnosis with Dukes D lesions. Similarly, greater antitumor effect was observed in patients with lower pretreatment plasma CEA levels evaluation of these pretreatment characteristics may have insignificant implications for the design of future clinical trials.

BCG Vaccine↗

PubMed1992

Distinct downstream signaling mechanism between erythropoietin receptor and interleukin-2 receptor.

Erythropoietin receptor (EPOR) and interleukin-2 receptor beta chain (IL-2R beta) belong to the same cytokine receptor superfamily and have highly conserved sequences in their intracellular signaling domain. However, common downstream signaling pathways of these receptors have not been demonstrated. In the present study, we introduced and expressed the murine EPOR in murine IL-2-, IL-3- and IL-5-dependent cell lines and analyzed their growth response to EPO. We found that the expression of EPOR induced EPO dependence in IL-3-dependent BAF-B03 and IL-5-dependent Y16 cells but not in IL-2-dependent CTLL-2 cells, although the EPOR-expressing CTLL-2 cell lines could bind and internalize EPO as efficiently as the BAF-B03-derived cell lines. Additional expression of AIC2B, a common signal transducer for IL-3R, IL-5R and GM-CSFR, made no difference to the EPO responsiveness of the EPOR-expressing CTLL-2 cell lines. These results suggest that the cellular components required for the transduction of EPOR signal and IL-2R signal are at least partially different, and this difference cannot be explained solely by the absence of AIC2B.

Animals↗

PubMed1992

Absolute quantitation of gallium-67 citrate accumulation in the lungs and its importance for the evaluation of disease activity in pulmonary sarcoidosis.

Our modification of a method for the absolute quantification of gallium-67 uptake in lungs with a scintillation camera and computer is described. The uptake of 67Ga in lungs, expressed in percentage of administered radioactivity, was determined by the transmission-emission method. We proved theoretically and experimentally that a 67Ga planar source could be replaced with a 57Co planar source. The performance of lung perfusion scans allows a more accurate delineation of the regions of interest on gallium scans. The method was applied to control subjects (n = 27) and to patients (n = 114) suffering from biopsy-proven pulmonary sarcoidosis (28 with inactive and 86 with active disease). The obtained results were compared with chest X-ray findings, the percentage of lymphocytes in the bronchoalveolar fluid (BAF-ly%), and serum angiotensin-converting enzyme (SACE) values. The method seems suitable for the assessment of disease activity in sarcoidosis. It is more accurate in detecting parenchymal involvement in lung sarcoidosis than the commonly used X-ray criteria. No correlation was found between 67Ga uptake and the BAF-ly% and SACE values.

Bronchoalveolar Lavage Fluid↗

PubMed1992

Reevaluation of dioxin bioconcentration and bioaccumulation factors for regulatory purposes.

Bioconcentration factors (BCF) or bioaccumulation factors (BAF) reported for 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD or dioxin) in aquatic environments encompass a wide range of values, from less than 1000 to 189,000 l/kg. These values are based on concentrations of TCDD in various environmental media including water, sediment, or food. Under the Federal Water Pollution Control Act and its enabling regulations (40 CFR 100-140, 400-470), point source discharge limits are established so that the nominal receiving water concentration will not exceed the water quality criterion. To be consistent with this regulatory process, the water quality criterion should also be calculated using an accumulation factor that is based on a nominal water concentration. The regulatory process for developing a water quality criterion for TCDD requires the selection of a BAF that describes the relationship between the source to be regulated and the fish tissue concentration.

Animals↗

PubMed1992

Ozone depletion and its effects on human populations.

Concern about the ozone-depleting potential of man-made chemicals has led the United Nations to control their usage. Under the present arrangements, fully halogenated chlorofluorocarbons, halons and carbon tetrachloride will be phased out by the year 2000, and methylchloroform by the year 2005. Even so, atmospheric chlorine is expected to rise to seven times its natural level, so further ozone losses and greater ultraviolet B (UVB) exposure can be expected over heavily populated areas of the globe. Calculating changes in skin cancer incidence is a two-stage process which must take account of the increase in biologically effective UVB that results from an ozone loss of 1% (optical amplification factor, OAF) and the percentage increase in skin cancer incidence that results from a 1% increase in annual UV dose (biological amplification factor, BAF). Epidemiological data provide a BAF value of approximately 1.7 for basal cell carcinoma and 3.0 for squamous cell carcinoma. The absorption spectrum of ozone and the increased carcinogenic impact of UV radiation around 300 nm results in a value for OAF of approximately 1.6%; thus a 10% loss of ozone, if sufficiently sustained, would eventually increase the incidence of basal and squamous cell carcinomas by almost 30% and 50%, respectively. Dermatologists, therefore, need to look carefully at the environment in order to safeguard the health of future generations.

Air Pollution↗

PubMed1979

The problem of interaction of shigella with epithelial cells.

A review and analysis of data on the investigation of factors concerning the initial events of interaction of Shigella with epithelial cells: attachment of penetration are presented. In the experiments with 3H-labeled bacteria it was shown that although common pili confer adhesive properties to bacteria but the penetration of Shigella into the cell is not increased. It was stated that LPS of Shigella O antigen plays an important role not only in interaction with cellular and humoral factors of the macroorganism defence but also in an initial stage of attachment of bacteria to the membrane of epithelial cells. However LPS of O antigen does not provide the penetration of the agent into the cell. In filtrates of virulent strains of Shigella flexneri, in contrast to those of smooth mutants and hybrids, lacking penetration ability, a biologically active factor (BAF) of protein or lipoprotein nature which reduced the LD50 of virulent and avirulent bacteria in infection of chicken embryos on chorioallantoic membrane, decreases ID50 and complicates the course of the infectious process in conjunctival infection of guinea pigs with virulent Shigella strain was revealed. S. flexneri transductant with a restored ability to induce kerato-conjunctivitis restored an ability to produce the BAF as well. Comparison of these data with the findings of other investigators was carried out. Perspectives of interpretation of penetration mechanism of Shigella into epithelial cells are discussed.

Antigens, Bacterial↗

PubMed1977

Phase II trial of Baker's antifol in metastatic sarcoma.

Iv Baker's antifol (BAF) (250 mg/m2/day X 3 consecutive days) was administered to 34 patients with metastatic sarcoma. All patients had received extensive prior therapy including prior chemotherapy and had progressive disease at the start of the study. Liver and renal functions were normal in all patients. Of 29 patients evaluable for response, 25 demonstrated progressive disease and four had stable disease for periods of from 1 to 6 months. No objective responses were observed. The other five patients died from 3 to 12 days after initiation of therapy. Toxicity included myelosuppression of significant degree in nine patients, gastrointestinal effects of nausea and vomiting in seven, stomatitis in three, and dermatitis in four. Most toxicity was mild to moderate, although one drug-related death due to marked myelosuppression was seen. In conclusion, BAF is considered to be insignificantly active in the secondary treatment of metastatic sarcomas at the dose and schedule studied.

Antineoplastic Agents↗

PubMed2026

Biomonitoring of industrial heavy metal pollution via enzymatic and metabolic responses in desert ants (Cataglyphis savignyi) and beetles (Tentyrum sp) as bioindicators.

The current work seeks to evaluate the effectiveness of Cataglyphis saviginyi and Tentyrum sp as indicators of pollution in the city's main industrial regions by analyzing their enzymatic activity and primary metabolites. Soil samples were collected at each site under investigation to analyze soil characteristics and heavy metal content. C. saviginyi and Tentyrum sp were collected across four consecutive seasons (2023-2024) to investigate enzymatic (GPT, GOT, ALP, ACP, LDH) and metabolic (lipid, protein, carbohydrate) biomarkers. The physicochemical properties of the soil differed substantially between the industrial areas and the control site. Soil heavy metal buildup was highest at industrial sites (1 and 4) compared to the control site, with the order being Zn > Cr > Cd > Cu. Heavy metal pollution indices were determined. Increased industrial activity from metal industries, ceramics, and chemical painting companies defines this area, as seen by the high Cdeg, mCd, PI, and PLI values derived for industrial sites 1 and 4. While C. saviginyi and Tentyrum sp deconcentrated and released Cr, Cd, and Zn into the soil via the biological accumulation factor (BAF), Cu acted as a macro-concentrator. Compared with the control site, industrial environments were shown to increase levels of GPT, GOT, LDH, ACP, protein, and carbohydrates in C. saviginyi. However, lipid and ALP activity was suppressed. at industrial sites, Tentyrum sp carbohydrate content was higher than at control sites, but GPT, GOT, ALP, ACP, LDH, protein, and lipid activities were all suppressed. Consequently, enzymatic and metabolic biomarkers proved to be sensitive indicators for assessing industrial heavy metal pollution in desert ecosystems.

Animals↗

PubMed2026

CRISPR-Enabled functional genomics in hPSCs-derived neural models for autism spectrum disorder.

Autism Spectrum Disorder (ASD) is a genetically heterogeneous neurodevelopmental condition in which hundreds of individually rare risk variants converge on a small number of shared biological pathways, including synaptic scaffolding, chromatin remodeling, excitation-inhibition balance, and cellular energy metabolism. Translating this genetic heterogeneity into mechanistic insight requires experimental systems capable of interrogating individual gene functions in human-relevant neural contexts at scale. CRISPR-enabled functional genomics in human pluripotent stem cell (hPSC)-derived neural models, spanning neural progenitors, cortical and inhibitory neurons, astrocytes, microglia, and brain organoids, provides precisely this capability. By integrating pooled perturbation screens with multimodal readouts including single-cell and spatial transcriptomics, chromatin accessibility profiling, proximity labeling proteomics, multi-electrode array electrophysiology, and metabolic flux analysis, these platforms enable systematic, causal mapping of ASD gene function at system resolution. Early applications have already revealed convergent mechanisms: BAF complex disruption expands the ventral progenitor pool and biases its fate toward oligodendrocyte and interneuron lineages; ADNP loss impairs microglial synaptic pruning through altered endocytic trafficking; and mTOR pathway dysregulation in PTEN- and TSC2-perturbed models links genetic risk directly to metabolic and mitochondrial dysfunction. Computational frameworks including MIMOSCA and SCEPTRE enable causal network reconstruction and pseudotime inference from these datasets, moving the field from gene lists toward pathway-level models of ASD pathobiology. Translational applications leverage isogenic iPSC panels and variant-level base and prime editing to stratify ASD variants by functional impact, informing gene therapy design for haploinsufficient targets such as CHD8 and SCN2A via AAV or antisense oligonucleotide delivery. Remaining challenges, including model developmental immaturity, batch variability, and the difficulty of modeling polygenic risk, are addressed by a roadmap integrating spatial perturbomics, AI-driven causal inference, and population-scale standardized biobanks. This review synthesizes the current state of CRISPR-based functional genomics in human stem cell neural models as a coherent experimental framework for converting ASD genetic associations into mechanistic understanding and therapeutic opportunity.

Humans↗