Increase in CFC-11 emissions from eastern China based on atmospheric observations.

The recovery of the stratospheric ozone layer relies on the continued decline in the atmospheric concentrations of ozone-depleting gases such as chlorofluorocarbons1. The atmospheric concentration of trichlorofluoromethane (CFC-11), the second-most abundant chlorofluorocarbon, has declined substantially since the mid-1990s2. A recently reported slowdown in the decline of the atmospheric concentration of CFC-11 after 2012, however, suggests that global emissions have increased3,4. A concurrent increase in CFC-11 emissions from eastern Asia contributes to the global emission increase, but the location and magnitude of this regional source are unknown3. Here, using high-frequency atmospheric observations from Gosan, South Korea, and Hateruma, Japan, together with global monitoring data and atmospheric chemical transport model simulations, we investigate regional CFC-11 emissions from eastern Asia. We show that emissions from eastern mainland China are 7.0 ± 3.0 (±1 standard deviation) gigagrams per year higher in 2014-2017 than in 2008-2012, and that the increase in emissions arises primarily around the northeastern provinces of Shandong and Hebei. This increase accounts for a substantial fraction (at least 40 to 60 per cent) of the global rise in CFC-11 emissions. We find no evidence for a significant increase in CFC-11 emissions from any other eastern Asian countries or other regions of the world where there are available data for the detection of regional emissions. The attribution of any remaining fraction of the global CFC-11 emission rise to other regions is limited by the sparsity of long-term measurements of sufficient frequency near potentially emissive regions. Several considerations suggest that the increase in CFC-11 emissions from eastern mainland China is likely to be the result of new production and use, which is inconsistent with the Montreal Protocol agreement to phase out global chlorofluorocarbon production by 2010.

Comprehensive Evaluation of (+)-Usnic Acid-induced Cardiotoxicity in Rats by Sequential Cross-omics Analysis.

Two-week administration of (+)-usnic acid (UA) induces mitochondrial swelling of cardiomyocytes, and toxicogenomic analysis of the heart revealed upregulation of oxidative stress, amino acid limitation, and endoplasmic reticulum stress-related genes in rats. To analyze the pathogenesis, UA was orally administrated to rats for 1, 4, 7, and 14 days, and sequential histopathological, genomic, and metabolomic analyses were performed on the heart, liver, and plasma. As a result, mitochondrial swelling of cardiomyocytes was observed on day 15 preceded by genomic upregulation on days 5 and 8. Of the focused gene groups, amino acid limitation-related genes represented by Mthfd2 showed numerically higher values or upregulation from day 5, which was sustained through the experimental period. On the contrary, oxidative stress-related genes were upregulated temporally on day 5. In metabolomic analysis, amino acids such as taurocholate and their metabolites fluctuated in concert with the upregulation of amino acid limitation-related genes in the heart, liver, and plasma. Moreover, accumulations of bile acids were manifested in all the tested tissues, while no histopathological change was seen in the liver. Increased bile acids might have an indirect effect on the myocardium; however, more detailed analysis is required. In conclusion, amino acid limitation was suggested as the pivotal toxic trigger of UA-induced cardiotoxicity.

Multiannual top-down estimate of HFC-23 emissions in East Asia.

Trifluoromethane (CHF3, HFC-23), with a 100-year global warming potential (GWP) of 12400, is regulated under the Kyoto Protocol. HFC-23 emissions in East Asia, especially in China, are currently thought to represent the majority of global HFC-23 emissions. This study provides both a bottom-up emission inventory and the multiannual top-down estimate of HFC-23 emissions in East Asia during 2007-2012. The new bottom-up inventory yields improved simulated HFC-23 mixing ratios compared to previous bottom-up inventories. The top-down estimate uses inverse modeling to further improve the model-measurement agreement. Results show that China contributed 94-98% of all HFC-23 emissions in East Asia. Annual a posteriori emissions from China were around 6.3 Gg/yr during the period 2007-2010 after which they increased to 7.1 ± 0.7 Gg/yr in 2011 and 8.8 ± 0.8 Gg/yr in 2012. For the first time, this study also provides a top-down estimate of HFC-23/HCFC-22 (chlorodifluoromethane, CHClF2) coproduction ratios in non-CDM (Clean Development Mechanism) HCFC-22 production plants as well as in all HCFC-22 production plants in China.

Identification of Toyocamycin, an agent cytotoxic for multiple myeloma cells, as a potent inhibitor of ER stress-induced XBP1 mRNA splicing.

The IRE1α-XBP1 pathway, a key component of the endoplasmic reticulum (ER) stress response, is considered to be a critical regulator for survival of multiple myeloma (MM) cells. Therefore, the availability of small-molecule inhibitors targeting this pathway would offer a new chemotherapeutic strategy for MM. Here, we screened small-molecule inhibitors of ER stress-induced XBP1 activation, and identified toyocamycin from a culture broth of an Actinomycete strain. Toyocamycin was shown to suppress thapsigargin-, tunicamycin- and 2-deoxyglucose-induced XBP1 mRNA splicing in HeLa cells without affecting activating transcription factor 6 (ATF6) and PKR-like ER kinase (PERK) activation. Furthermore, although toyocamycin was unable to inhibit IRE1α phosphorylation, it prevented IRE1α-induced XBP1 mRNA cleavage in vitro. Thus, toyocamycin is an inhibitor of IRE1α-induced XBP1 mRNA cleavage. Toyocamycin inhibited not only ER stress-induced but also constitutive activation of XBP1 expression in MM lines as well as primary samples from patients. It showed synergistic effects with bortezomib, and induced apoptosis of MM cells including bortezomib-resistant cells at nanomolar levels in a dose-dependent manner. It also inhibited growth of xenografts in an in vivo model of human MM. Taken together, our results suggest toyocamycin as a lead compound for developing anti-MM therapy and XBP1 as an appropriate molecular target for anti-MM therapy.

Mixed germ cell tumor with embryonal carcinoma, choriocarcinoma, and epithelioid trophoblastic tumor in the ovary of a cynomolgus monkey.

A seven-year-old female cynomolgus monkey had a mass in the left ovary with metastasis to the lung and the right ovary. The mass of these organs showed three different characteristics, and its immunohistochemical profiles were consistent with embryonal carcinoma (EC), choriocarcinoma (CC), and epithelioid trophoblastic tumor (ETT). The EC was characterized with sheets and glandlike structures with large pleomorphic, single-nucleated epithelial cells that were immunohistochemically positive for α-fetoprotein, octamer-4, and CD30, and with multinucleated giant cells resembling syncytiotrophoblasts. The CC also represented biphasic proliferation of the cytotrophoblast positive for cytokeratin 7 (CK7), which showed negative immunoreactivity for all three of the above antibodies, and it was syncytiotrophoblast positive for human chorionic gonadotropin. The ETT showed numerous floating cells in an abundant eosinophilic extracellular matrix with vacuolated or eosinophilic cytoplasm and was immunohistochemically positive for CK7, p63, and α-inhibin, which features nodule or cordlike structures. Collectively, this neoplasm was identified as a mixed germ cell tumor with EC, CC, and ETT. To our knowledge, this is the first report of EC in nonhuman primates as a component of mixed germ cell tumor.

Pathogenesis of Kawasaki disease.

Kawasaki disease (KD) most frequently affects infants and young children under 5 years of age. This disease is considered a kind of systemic vasculitis syndrome, and primarily invades the medium-sized muscular arteries, including coronary arteries. Diagnosis of KD is based on characteristic clinical signs and symptoms, which are classified as principal clinical findings and other clinical and laboratory findings. Even though the aetiology of KD is unknown, epidemiological data suggest that some kinds of infectious agents are involved in the onset of KD. In addition, the data indicate that host genetics underlie the disease's pathogenesis. Histologically, coronary arteritis begins 6-8 days after the onset of KD, and leads immediately to inflammation of all layers of the artery. The inflammation spreads completely around the artery; as a result, structural components of the artery undergo intense damage; the artery then begins to dilate. Inflammatory cell infiltration continues until about the 25th day of the disease, after which the inflammatory cells gradually decrease in number. KD arteritis is characterized by granulomatous inflammation that consists of severe accumulation of monocytes/macrophages. Aberrant activation of monocytes/macrophages is thought to be involved in the formation of vascular lesions. The lesions in all the arteries are relatively synchronous as they evolve from acute to chronic injury. There is no fibrinoid necrosis nor any mixture of acute inflammatory lesions and scarring lesions, which are characteristics in polyarteritis nodosa in KD.

Histopathological features of murine systemic vasculitis caused by Candida albicans extract--an animal model of Kawasaki disease.

OBJECTIVE AND DESIGN: We examined the histopathological features of systemic vasculitis caused in mice by injection of a Candida albicans ( C. albicans) extract and investigated the principal genetic roles in the development of vasculitis. MATERIALS AND METHODS: C. albicans extract was injected intraperitoneally for five consecutive days in the 1st and 5th weeks to CD-1, C57BL/6N, C3H/HeN, BALB/cAnN, DBA/2N and CBA/JN mice. At week 8, mice were killed, and histological examination was performed by light microscopy. RESULTS: Arteritis had developed in 66% of CD-1 mice. The extramural coronary arteries and aortic root close to the orifice of coronary arteries were most frequently involved. Histologically, the characteristic feature of the arteritis was proliferative and granulomatous inflammation accompanied by numerous macrophages, lymphocytes, plasma cells and neutrophils. Fibrocellular intimal thickening with destruction of the internal elastic lamina and media was also observed. Five mouse strains after injection of C. albicans extract were clearly classified into a resistant group (CBA/JN, DBA/2N and BALB/cAnN mice) and a sensitive group (C3H/HeN and C57BL/6N mice). The inbred mouse strains which showed the same histocompatibility-2 (H-2) haplotype exhibited a different susceptibility to development of vasculitis. CONCLUSION: This arteritis murine model shows unique histological features that have not been observed in other animal vasculitis models and it most closely resembles Kawasaki disease in humans. The genetic control of susceptibility to induction of vasculitis by the C. albicans extract is dependent to the mouse strains, but is not linked to the H-2 loci.

New polymorphisms of haematopoietic prostaglandin D synthase and human prostanoid DP receptor genes.

BACKGROUND: Prostaglandin D2 (PGD2), a major cyclo-oxygenase metabolite of arachidonic acid in mast cells, induces bronchoconstriction in the human lung. It has been reported that mice lacking PGD receptor fail to develop the bronchial hyper-responsiveness upon ovalbumin challenge, suggesting that PGD2 functions as a mediator of allergic asthma. OBJECTIVE: To determine if there are any mutations associated with the development of asthma in the haematopoietic prostaglandin D synthase (H-PGDS) gene and the human prostanoid DP receptor (PTGDR) gene. METHODS AND RESULTS: We screened the 5'flanking and coding regions of the H-PGDS gene and the PTGDR gene by direct sequence. We identified one variant in intron 2 (IVS2 + 11 A > C) and one variant in intron 3 (IVS3 + 13T > C) of the H-PGDS gene, and two variants in the 5'flanking region of the PTGDR gene (-197T > C and -2C > T). The IVS3 + 13T > C and -197T > C variants were rare, appearing only once in 48 subjects. transmission disequilibrium test (TDT) analysis of 144 asthmatic families revealed that the IVS2 + 11 A allele of the H-PGDS gene was significantly transmitted preferentially to asthma-affected children (P = 0.0056), but no association was observed between -2C/T polymorphism of the PTGDR gene and asthma (P > 0.05). CONCLUSION: Our results suggest that the IVS2 + 11A/C allele may be involved in the development of asthma in the Japanese population.

A genome-wide linkage analysis of orchard grass-sensitive childhood seasonal allergic rhinitis in Japanese families.

Seasonal allergic rhinitis (SAR) is an inflammatory disease of the nose and eyes that follows sensitization to air-born pollens. We conducted a genome-wide linkage screening of 48 Japanese families (188 members) with orchard grass (OG)-sensitive SAR children (67 affected sib-pairs) in a farming community in central Japan where OG was planted for apple farming and OG pollen is a major cause of SAR. We used the GENEHUNTER program to performed nonparametric multipoint linkage analysis for OG-sensitive SAR as a qualitative trait and for log total serum IgE levels and OG-RAST IgE levels as quantitative traits. Genotyping data of 400 microsatellite markers suggested linkage of SAR to chromosomes 1p36.2, 4q13.3, and 9q34.3 (P < 0.001), linkage of serum total IgE levels to 3p24.1, 5q33.1, 12p13.1, and 12q24.2 (P < 0.001), and linkage of OG-RAST IgE levels to 4p16.1, 11q14.3, and 16p12.3 (P < 0.001). Weak evidence for linkage of SAR to 5q33.1 was also observed (P = 0.01). All these regions, with the exception of 9q34.3, have been previously reported to be linked to asthma and/or atopy. These data suggest that, although loci linked to SAR are likely to be common to asthma, a strong contribution by specific gene(s) to OG-sensitive SAR is unlikely.

Identification of missense mutation in the IL12B gene: lack of association between IL12B polymorphisms and asthma and allergic rhinitis in the Japanese population.

Interleukin-12 (IL-12) is a macrophage-derived cytokine that modulates T lymphocyte responses and can suppress allergic inflammation. In a genome-wide screen, we found strong evidence for linkage of atopic asthma with marker D5S1352, located close to IL12B, with a maximum lod score of 4.34. We screened for mutation in IL12B and found three novel (-4475-4insG, Glu186Asp and Ser226Asn) variants and one previously reported (1188A>C) variant in IL12B, and conducted transmission disequilibrium tests in families identified through children with atopic asthma or allergic rhinitis. Frequencies of the Asn226 and 1188C alleles in the parents were 0.04 and 0.5, respectively. Preferential transmission of either the Ser226/Asn226 or 1188A/C allele to asthma-affected or rhinitis-affected children was not observed (P > 0.1) and was not associated significantly with total serum IgE level (P > 0.1). Our results indicate that polymorphisms in IL12B are not likely to be associated with the development of atopy-related phenotypes.

Haplotypes of the 5' region of the IL-4 gene and SNPs in the intergene sequence between the IL-4 and IL-13 genes are associated with atopic asthma.

IL-4 and IL-13 are important in IgE synthesis and allergic inflammation. Therefore, genes encoding IL-4 and IL-13 are candidates for predisposition to asthma and atopy. A recent study in the YAC transgenic mouse has revealed that one of the conserved noncoding sequences (CNS-1) between IL-4 and IL-13 influences the expression of IL-4, IL-5, and IL-13, suggesting that CNS-1 acts as a coordinate regulator of these genes. This investigation screened for mutations in the 13-kb region between IL-4 and IL-13, which includes the human equivalent of the murine CNS-1. Four single nucleotide polymorphisms (SNPs) were found in the region between IL-4 and IL-13 (IL-4-IL-13SNP1, IL-4-IL-13SNP2, IL-4-IL-13SNP3, and IL-4-IL-13SNP4). There was no mutation in the human CNS-1. We genotyped these and other previously reported polymorphisms in IL-4 and IL-13 using asthmatic families, and examined association by transmission disequilibrium test. Two-locus haplotype analysis revealed that haplotypes composed of the IL-4 RP2del, IL-4 +33T, or IL-4 -589T alleles and either IL-4-IL-13SNP3G or IL-4-IL-13SNP4C are transmitted significantly to asthma-affected children (p = 0.002). This data suggests that haplotypes composed of the 5' region polymorphisms in the IL-4 gene and SNPs in the intergene sequence between IL-4 and IL-13 influence the development of asthma.

Pinonaldehyde and some other organics in rain and snow in central Japan.

Solvent-extractable organic compounds in the rain and snow collected at local cities in the mountainous region in central Japan, were analyzed by GC/MS and GC. Pinonaldehyde (2,2-dimethyl-3-acetyl-cyclobutyl-ethanal), an atmospheric reaction product of alpha-pinene, was detected in the rain and snow for the first time, and n-alkanes (C17-C33), fatty acids (C8-C23), and benzoic acid were also detected as major organic components. Concentrations of pinonaldehyde, C17-C33 n-alkanes, C8-C11 fatty acids, C12-C23 fatty acids and benzoic acid ranged between <0.02-13, 0.10-35, 0.55-5.7, 4.2-19 and <0.02-6.0 microg/l, respectively. Their composition showed some difference in summer and winter. In summer, fatty acids and benzoic acid were more abundant, while pinonaldehyde and n-alkanes were much less. Higher photochemical reactivity and higher bioactivity in summer could explain these seasonal changes except for pinonaldehyde, which would suffer from further oxidation in the atmosphere after its photochemical production from alpha-pinene. Predominance of pinonaldehyde and C12-C23 fatty acids in the rain and snow showed a remarkable contrast to n-alkanes in aerosol phase, which were the most abundant components. It indicated that oxygenated products from biogenic compounds might be important as cloud condensation nuclei in forest areas.

Depth profiles of volatile halogenated hydrocarbons in seawater in the Bay of Bengal.

Measurements were made of bromocarbons (CHBr3 and CH2Br2), iodocarbons (CH2I2 and CH2ClI), and dimethylsulfide (DMS, CH3SCH3) in seawater collected from the Bay of Bengal under tropical stratified conditions. These compounds showed different depth profiles, characteristic of each group. CH2I2 and CH2ClI showed very similar depth profiles to chlorophyll-a, suggesting their production by phytoplankton followed by rapid decay in seawater. The CH2I2 maximum at a depth a little below the CH2ClI maximum was consistent with its more significant photolytic decay. The bromocarbons were less localized in their distributions than were the iodocarbons, suggesting their longer residence time in seawater after their release from phytoplankton. Both of these profiles were different from the pattern of DMS, which had its maxima above the chlorophyll-a maximum layer near the surface.

Association between a new polymorphism in the activation-induced cytidine deaminase gene and atopic asthma and the regulation of total serum IgE levels.

BACKGROUND: Activation-induced cytidine deaminase (AICDA) is a recently identified RNA-editing deaminase that plays an important role in class-switching. Defects in AICDA result in a hyper-IgM phenotype and lack of IgG, IgA, and IgE in both human beings and mice. OBJECTIVE: The aim of this study was to determine whether the AICDA gene is related to regulation of total serum IgE and development of atopic asthma. METHODS: We screened for polymorphisms in the 5;-flanking and coding regions of the AICDA gene in subjects with atopic asthma and analyzed the effect of these polymorphisms on the development of atopic asthma and on total serum IgE levels in Japanese asthmatic families. RESULTS: We identified 3 novel polymorphisms (5923A/G, 7888C/T, and 8578A/C) and 1 rare variant (Arg25Cys) in the AICDA gene. Transmission disequilibrium testing showed that the 7888C allele was transmitted preferentially to asthma-affected children (P =.007). Mean log [total serum IgE] levels of parents with the 7888C/7888C, 7888C/7888T, and 7888T/7888T genotypes were 2.12, 1.99, and 1.77, respectively, and a significant association was observed between the genotypes (P =.02). In RT-PCR experiments, we found 2 novel splice variants of AICDA, one lacking all of exon 4 (variant 1; 367 base pairs) and the other lacking the first 30 base pairs of exon 4 (variant 2; 453 base pairs). These variants were not associated with the 7888C/T polymorphism. CONCLUSION: The 7888C/T polymorphism might be associated with the pathogenesis of atopic asthma and the regulation of total serum IgE levels.

HoxA and HoxB cluster genes subdivide the digestive tract into morphological domains during chick development.

The digestive tract exhibits region-specific morphology and cytodifferentiation along the anteroposterior axis. We analyzed the spatial expression patterns of Hox genes belonging to the HoxA and HoxB cluster (Hoxa-4 approximately a-9, Hoxb-5 approximately b-9) in the developing chick digestive tract. The expression domains of these Hox genes correlated with morphological subdivision of the digestive tract along the anteroposterior axis.

Histomorphometric characteristics and cellular kinetics of colorectal polyps with epithelial serrated proliferation adjacent to carcinoma.

Four cases of colorectal polyps with epithelial serrated proliferation (CP-ESP) with malignant transformation were studied. In CP-ESP adjacent to carcinoma, if the nuclear size in the surface layer was significantly smaller than those in the bottom and the middle layers of the crypts, the specimen was defined as zone formation positive. If there was no significant difference among the layers, the specimen was defined as zone formation negative. Cell kinetics were evaluated using Ki-67 immunostaining. The CP-ESP regions of cases 1 and 2 showed zone formation with inferior and lateral glandular branching, and were qualitatively hyperplastic on cell kinetics. Cases 3 and 4 showed inferior and lateral glandular branching with no zone formation, and were kinetically neoplastic (adenoma). The histogenesis of hyperplastic polyps with atypia (cases 1 and 2) involves the hyperplastic polyp-carcinoma sequence. In contrast, the development of tubulovillous adenoma or serrated adenoma (cases 3 and 4) may involve the tubulovillous adenoma-carcinoma or serrated adenoma-carcinoma sequence.

Effect of adsorption of bovine serum albumin on liposomal membrane characteristics.

The effect of adsorption of bovine serum albumin (BSA) on the membrane characteristics of liposomes at pH 7.4 was examined in terms of zeta potential, micropolarity, microfluidity and permeability of liposomal bilayer membranes, where negatively charged L-alpha-dipalmitoylphosphatidylglycerol (DPPG)/L-alpha-dipalmitoylphosphatidylcholine (DPPC), negatively charged dicetylphosphate (DCP)/DPPC and positively charged stearylamine (SA)/DPPC mixed liposomes were used. BSA with negative charges adsorbed on negatively charged DPPG/DPPC mixed liposomes but did not adsorb on negatively charged DCP/DPPC and positively charged SA/DPPC mixed liposomes. Furthermore, the adsorption amount of BSA on the mixed DPPG/DPPC liposomes increased with increasing the mole fraction of DPPG in spite of a possible electrostatic repulsion between BSA and DPPG. Thus, the adsorption of BSA on liposomes was likely to be related to the hydrophobic interaction between BSA and liposomes. The microfluidity of liposomal bilayer membranes near the bilayer center decreased by the adsorption of BSA, while the permeability of liposomal bilayer membranes increased by the adsorption of BSA on liposomes. These results are considered to be due to that the adsorption of BSA brings about a phase separation in liposomes and that a temporary gap is consequently formed in the liposomal bilayer membranes, thereby the permeability of liposomal bilayer membranes increases by the adsorption of BSA.

Mutation screening of interferon regulatory factor 1 gene (IRF-1) as a candidate gene for atopy/asthma.

BACKGROUND: IL-4 gene cluster on chromosome 5 contains several candidate genes for atopy and asthma. Several independent studies have shown evidence for linkage between the markers flanking IL-4 gene cluster and asthma and/or asthma-related traits. Interferon regulatory factor 1 (IRF-1) is located approximately 300 kb telomeric to IL-4 and recent study reveals that IRF-1 deficiency results in an elevated production of Th2-related cytokines and a compensatory decrease in the expression of native cell- and Th1-related cytokines. OBJECTIVE: To determine if there are any mutations associated with the development of atopy and asthma present in the coding exons and 5' flanking region of the IRF-1 gene. METHODS AND RESULTS: We have screened the promoter and coding regions of the IRF-1 gene in atopic asthmatics and controls by SSCP method. We found three novel nuclear variants (the -300G/T and 4396 A/G polymorphisms and the 6355G > A rare variant) in the IRF-1 gene. No variants causing amino acid alterations of IRF-1 were detected. The -300G/T polymorphism was in nearly complete linkage disequilibrium with the 4396 A/G polymorphism. An association between the 4396 A > G polymorphism and atopy/asthma was examined by transmission disequilibrium test in 81 asthmatic families. Either of 4396 A or 4396G alleles was not significantly preferentially transmitted to atopy- or asthma-affected children. CONCLUSION: The IRF-1 gene is less likely to play a substantial role in the development of atopy and asthma in the Japanese population.

Coordinated expression of Hoxb genes and signaling molecules during development of the chick respiratory tract.

To elucidate the molecular mechanism for regulating the region-specific morphogenesis of the chicken respiratory tract, we analyzed the spatiotemporal expression patterns of the Hoxb genes, Bmp-2, Bmp-4, Wnt-5a, and Wnt-11 in the developing respiratory tract. We found region-specific expression of these genes in the mesenchymal layer of the respiratory tract. Before bronchial branching proceeds, Hoxb genes show nested expression patterns around the ventral-distal tip of the lung bud. As morphogenesis proceeds, these expression domains correspond to the morphological subdivisions of the chick respiratory tract. Hoxb-5 and Hoxb-6 expression domains demarcate the trachea, bronchial tree, and air sacs. Particularly the expression domains of Hoxb-6 to -9 correspond to the morphological subdivisions of the air sacs along the proximodistal axis. Bmp-4 and Bmp-2 are expressed throughout the entire pulmonary mesenchyme and its dorsal half, respectively. Wnt-5a and Wnt-11 are expressed in the tracheal mesenchyme. Interestingly, the expression domain of Bmp-2 is complementary to the Hoxb-6 domain. The respiratory mesenchyme influences the process of epithelial branching during morphogenesis. By tissue recombination experiments, we found that the dorsal and the ventral pulmonary mesenchyme, demarcated by Hoxb-6 expression, have different inductive capacities toward the tracheal epithelium. These observations suggest the possibility that Hoxb genes are involved in the system specifying regional differences in morphogenesis and cytodifferentiation of respiratory tract. In addition, it is possible that BMPs and WNTs mediate region-specific epithelial-mesenchymal interaction in this system.