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Brain perivascular macrophages regulate endothelial cell function via a cMAF-dependent transcriptional program in mouse and human.

Brain perivascular macrophages maintain brain physiology, yet their transcriptional regulators and functions in health and disease remain unclear. Using single-cell multi-omics and functional experiments, we identify cellular musculoaponeurotic fibrosarcoma oncogene (cMAF) as a key transcription factor for brain perivascular macrophages, and conditional deletion of cMAF disrupts their phenotype in vivo. Functionally, cMAF drives insulin-like growth factor-1 (IGF1) expression in perivascular macrophages, enabling communication with endothelial cells. Consistently, cMAF deletion in perivascular macrophages causes transcriptional alterations in cerebral arteries, affecting vascular functions. Notably, cMAF emerges as the main transcription factor for human perivascular macrophages, suggesting conservation of this transcriptional module. During Alzheimer's disease (AD), human perivascular macrophages upregulate cMAF and IGF1 to enhance communication with vascular cells, and this response is abrogated in APOE4 carriers. Lastly, we explore an uncharacterized polymorphism in cMAF, providing evidence that the cMAF program is protective against AD. Targeting cMAF in perivascular macrophages may offer new therapeutic strategies for neurodegenerative and cerebrovascular diseases.

APOE4↗

TH2 cytokine-associated transcription factors in atopic and nonatopic asthma: evidence for differential signal transducer and activator of transcription 6 expression.

BACKGROUND: The expression of IL-4 and IL-5 is increased in patients with atopic asthma compared with control subjects and correlates with indices of pulmonary function. In nonatopic asthma the expression of IL-4, unlike IL-5, fails to correlate with pulmonary function, and compared with their atopic counterparts, these patients have fewer cells expressing IL-4 receptor (IL-4R). As such, a deficiency in the IL-4 signaling pathway may be implicated in nonatopic asthma. The transcription factors GATA-3 and cMAF mediate IL-4 and IL-5 synthesis, whereas signal transducer and activator of transcription 6 (STAT-6) is critical for IL-4R signaling. OBJECTIVE: This study examines the expression profile of these transcription factors in asthma, according to atopic status. METHODS: With immunocytochemistry, the expression of GATA-3, cMAF, and STAT-6 protein was determined in sections of bronchial biopsy specimens from patients with atopic asthma (n = 7), patients with nonatopic asthma (n = 8), and control subjects (n = 8). RESULTS: Higher numbers of cells expressing GATA-3 and cMAF were observed in patients with atopic and those with nonatopic asthma than in control subjects and patients with tuberculosis (P <.001). There were also more STAT-6-immunoreactive cells in patients with atopic and those with nonatopic asthma than in control subjects (P <.0001, P <.05). Notably, however, fewer cells expressing STAT-6 protein were observed in nonatopic versus atopic asthma (P <.0001). CONCLUSIONS: These results demonstrate the upregulation of GATA-3 and cMAF in both variants of asthma and indicate that reduced IL-4R signaling, because of lower STAT-6 expression, may be a feature of nonatopic asthma.

Adult↗

Spontaneous calcific emboli from calcific mitral annulus fibrosus.

Clinically important complications resulting from calcific mitral annulus fibrosus (CMAF) are unusual. They include mitral regurgitation, mitral stenosis, and complete heart block. In one patient with massive CMAF associated with multiple systemic calcific emboli originating from the mitral valve, the emboli were the cause of multiple brain infarcts and a clinical course of unexplained neurological deterioration. We believe that this is the first report of such a complication occurring with CMAF.

Brain↗

A switch from MafB to MafA expression accompanies differentiation to pancreatic beta-cells.

Major insulin gene transcription factors, such as PDX-1 or NeuroD1, have equally important roles in pancreatic development and the differentiation of pancreatic endocrine cells. Previously, we identified and cloned another critical insulin gene transcription factor MafA (RIPE3b1) and reported that other Maf factors were expressed in pancreatic endocrine cells. Maf factors are important regulators of cellular differentiation; to understand their role in differentiation of pancreatic endocrine cells, we analyzed the expression pattern of large-Maf factors in the pancreas of embryonic and adult mice. Ectopically expressed large-Maf factors, MafA, MafB, or cMaf, induced expression from insulin and glucagon reporter constructs, demonstrating a redundancy in their function. Yet in adult pancreas, cMaf was expressed in both alpha- and beta-cells, and MafA and MafB showed selective expression in the beta- and alpha-cells, respectively. Interestingly, during embryonic development, a significant proportion of MafB-expressing cells also expressed insulin. In embryos, MafB is expressed before MafA, and our results suggest that the differentiation of beta-cells proceeds through a MafB+ MafA- Ins+ intermediate cell to MafB- MafA+ Ins+ cells. Furthermore, the MafB to MafA transition follows induction of PDX-1 expression (Pdx-1(high)) in MafB+ Ins+ cells. We suggest that MafB may have a dual role in regulating embryonic differentiation of both beta- and alpha-cells while MafA may regulate replication/survival and function of beta-cells after birth. Thus, this redundancy in the function and expression of the large-Maf factors may explain the normal islet morphology observed in the MafA knockout mice at birth.

Animals↗

Effectiveness of in-room air filtration and dilution ventilation for tuberculosis infection control.

Tuberculosis (TB) is a public health problem that may pose substantial risks to health care workers and others. TB infection occurs by inhalation of airborne bacteria emitted by persons with active disease. We experimentally evaluated the effectiveness of in-room air filtration systems, specifically portable air filters (PAFs) and ceiling-mounted air filters (CMAFs), in conjunction with dilution ventilation, for controlling TB exposure in high-risk settings. For each experiment, a test aerosol was continuously generated and released into a full-sized room. With the in-room air filter and room ventilation system operating, time-averaged airborne particle concentrations were measured at several points. The effectiveness of in-room air filtration plus ventilation was determined by comparing particle concentrations with and without device operation. The four PAFs and three CMAFs we evaluated reduced room-average particle concentrations, typically by 30% to 90%, relative to a baseline scenario with two air-changes per hour of ventilation (outside air) only. Increasing the rate of air flow recirculating through the filter and/or air flow from the ventilation did not always increase effectiveness. Concentrations were generally higher near the emission source than elsewhere in the room. Both the air flow configuration of the filter and its placement within the room were important, influencing room air flow patterns and the spatial distribution of concentrations. Air filters containing efficient, but non-high efficiency particulate air (HEPA) filter media were as effective as air filters containing HEPA filter media.

Filtration↗

Cell-type-restricted binding of the transcription factor NFAT to a distal IL-4 enhancer in vivo.

By DNase I hypersensitivity analysis, we have identified an inducible, cyclosporin A-sensitive enhancer located 3' of the interleukin-4 (IL-4) gene. The enhancer binds the Th2-specific transcription factor GATA3 in vivo but is not perceptibly influenced by the absence of a second Th2-specific factor, cMaf. The antigen-inducible transcription factor NFAT1 binds the IL-4 enhancer and the IL-4 promoter only in stimulated Th2 cells; conversely, NFAT1 binds to the interferon (IFN)-gamma promoter only in stimulated Th1 cells. Our results support a model whereby transcription factors such as NFAT1, which are nonselectively induced in antigen-stimulated T cells, gain access to cytokine regulatory regions only in the appropriate subset of differentiated T cells in vivo. This restricted access enables antigen-dependent and subset-specific transcription of cytokine genes.

3' Untranslated Regions↗

Ectopic Pax6 expression disturbs lens fiber cell differentiation.

PURPOSE: Pax6 is a transcription factor necessary for the specification and subsequent formation of the ocular lens. It is expressed in all lens cells at early stages of development. After lens formation, Pax6 expression is maintained in the lens epithelium, whereas its level abruptly decreases in differentiated fiber cells. This study is to test the hypothesis that normal fiber cell differentiation would be perturbed by sustained Pax6 expression. METHODS: Transgenic mice expressing the canonical form of mouse Pax6 were created under the control of a modified mouse alphaA-crystallin promoter. The phenotypic changes in the transgenic lens were analyzed by light and electron microscopy. The effect of ectopic Pax6 expression on the lens fiber cells was investigated by in situ hybridization, immunohistochemical staining, real-time reverse transcriptase-polymerase chain reaction (RT-PCR), and two-dimensional (2-D) gel electrophoresis. RESULTS: Transgenic mice from seven different lines all had cataracts with severity that correlated with the transgene expression level in lens fiber cells. In severely affected lines, a lumen was present between the apical surfaces of the epithelial and fiber cells, suggesting that secondary fiber cell elongation is incomplete. Electron microscopy analysis showed that the ball-and-socket interdigitations between neighboring fiber cells were underdeveloped or attenuated in the transgenic lens. Most interesting, elevated levels of Pax6 in fiber cells reduced the protein levels of transcription factor cMaf, which is known to be essential in fiber cell differentiation. Furthermore, the total amount of lens proteins was 60% less than normal in the Pax6 transgenic lens. Among the crystallins examined, the relative ratio of intact betaB1-crystallin protein to total lens protein was significantly reduced. Real-time reverse transcriptase PCR showed that the ratio of betaB1-crystallin transcript levels to total mRNA levels were reduced by 87%. CONCLUSIONS: The data demonstrate that high levels of Pax6 expression disrupt normal fiber cell differentiation and maturation.

Animals↗

[New chemotherapeutic method for the treatment of tracheal and bronchial cancers--nebulization chemotherapy].

A new chemotherapeutic method for the treatment of tracheal and bronchial tree cancers, and of lung cancer with invasion to the bronchial tree has been developed. It is named Nebulization Chemotherapy or NC therapy. This method is based on vaporizing the anti-cancer drug (5-Fluorouracil, 5-FU) solution with a supersonic nebulizer, and inhaling the vaporized anticancer drug trans-orally through the bronchial tree. Patients were divided into two groups. The first group, where NC therapy was the main method of treatment used, included 6 patients. Of these, 4 (2CR and 2PR) showed a good anti-cancer response to the treatment. The other was a group receiving combination treatment with our CMAF protocol (cis-platinum, mitomycin C, adriamycin and 5-FU) and NC therapy. This group included 6 patients, 5 of whom (2CR, 2PR and 1MR) showed a remarkable anti-tumor response. Side-effects to the bronchial tree, pulmonary parenchyma or other systemic toxicity have not been noted so far after NC therapy. However, a few patients showed glottitis. Only trace amounts of circulating 5-FU were detected in serial serum samples.

Adenocarcinoma↗