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Chronic gut inflammatory diseases are associated with disruption of intestinal epithelial barriers and impaired mucosal immunity. HIV-1 (HIV) causes depletion of mucosal CD4+ T cells early in infection and disruption of gut epithelium, resulting in chronic inflammation and immunodeficiency. Although antiretroviral therapy (ART) is effective in suppressing viral replication, it is incapable of restoring the "leaky gut," which poses an impediment for HIV cure efforts. Strategies are needed for rapid repair of the epithelium to protect intestinal microenvironments and immunity in inflamed gut. Using an in vivo nonhuman primate intestinal loop model of HIV/AIDS, we identified the pathogenic mechanism underlying sustained disruption of gut epithelium and explored rapid repair of gut epithelium at the intersection of microbial metabolism. Molecular, immunological, and metabolomic analyses revealed marked loss of peroxisomal proliferator-activated receptor-α (PPARα) signaling, predominant impairment of mitochondrial function, and epithelial disruption both in vivo and in vitro. To elucidate pathways regulating intestinal epithelial integrity, we introduced probiotic Lactobacillus plantarum into Simian immunodeficiency virus (SIV)-inflamed intestinal lumen. Rapid recovery of the epithelium occurred within 5 h of L. plantarum administration, independent of mucosal CD4+ T cell recovery, and in the absence of ART. This intestinal barrier repair was driven by L. plantarum-induced PPARα activation and restoration of mitochondrial structure and fatty acid β-oxidation. Our data highlight the critical role of PPARα at the intersection between microbial metabolism and epithelial repair in virally inflamed gut and as a potential mitochondrial target for restoring gut barriers in other infectious or gut inflammatory diseases.

Hydrophobic composites of cellulose nanofibrils (CNF) with acrylic polymers are obtained by methyl methacrylate (MMA) and butyl methacrylate (BMA) polymerization in Pickering emulsion, stabilized with cellulose nanofibrils. Successful modification of CNF surface by grafting MMA or BMA was confirmed by infrared spectroscopy, gel permeation chromatography, and scanning electron microscopy. The obtained composites were also characterized by simultaneous thermal analysis and wetting contact angle measurement. Composites based on CNF exhibit good thermal and oil sorption properties.

Orofacial clefting represents the most common craniofacial birth defect. Cleft lip with or without cleft palate (CL/P) is genetically distinct from cleft palate only (CPO). Numerous transcription factors (TFs) regulate normal development of the midface, comprising the premaxilla, maxilla and palatine bones, through control of basic cellular behaviors. Within the Pbx family of genes encoding Three Amino-acid Loop Extension (TALE) homeodomain-containing TFs, we previously established that in the mouse, Pbx1 plays a preeminent role in midfacial morphogenesis, and Pbx2 and Pbx3 execute collaborative functions in domains of coexpression. We also reported that Pbx1 loss from cephalic epithelial domains, on a Pbx2- or Pbx3-deficient background, results in CL/P via disruption of a regulatory network that controls apoptosis at the seam of frontonasal and maxillary process fusion. Conversely, Pbx1 loss in cranial neural crest cell (CNCC)-derived mesenchyme on a Pbx2-deficient background results in CPO, a phenotype not yet characterized. In this study, we provide in-depth analysis of PBX1 and PBX2 protein localization from early stages of midfacial morphogenesis throughout development of the secondary palate. We further establish CNCC-specific roles of PBX TFs and describe the developmental abnormalities resulting from their loss in the murine embryonic secondary palate. Additionally, we compare and contrast the phenotypes arising from PBX1 loss in CNCC with those caused by its loss in the epithelium and show that CNCC-specific Pbx1 deletion affects only later secondary palate morphogenesis. Moreover, CNCC mutants exhibit perturbed rostro-caudal organization and broadening of the midfacial complex. Proliferation defects are pronounced in CNCC mutants at gestational day (E)12.5, suggesting altered proliferation of mutant palatal progenitor cells, consistent with roles of PBX factors in maintaining progenitor cell state. Although the craniofacial skeletal abnormalities in CNCC mutants do not result from overt patterning defects, osteogenesis is delayed, underscoring a critical role of PBX factors in CNCC morphogenesis and differentiation. Overall, the characterization of tissue-specific Pbx loss-of-function mouse models with orofacial clefting establishes these strains as unique tools to further dissect the complexities of this congenital craniofacial malformation. This study closely links PBX TALE homeodomain proteins to the variation in maxillary shape and size that occurs in pathological settings and during evolution of midfacial morphology.

MicroRNA sequences are now publicly available. Page 6270, last paragraph in Materials and Methods, line 1: "Microarray data accession number" should read "Accession numbers." Page 6270, last paragraph in Materials and Methods, line 4: The following sentence should be added. "MicroRNA sequencing data have been deposited in the NCBI BioProject database under accession no. PRJNA429684 and in the NCBI Sequence Read Archive under accession no. SRP128960.".

Coal remains one of the most used solid fuels for heat and electricity generation but burning coal releases large amounts of CO2 into the urban atmosphere in addition to harmful substances. In order to reduce the consumption of solid fossil fuels, it is necessary to search for fuels capable of replacing coal in terms of its thermal and environmental characteristics. One of the best alternative fuels is biomass, which is considered carbon neutral, but its thermal characteristics are worse than those of solid fossil fuels. In this work, an alternative to coal was studied for the first time, which was semi-coke, obtained by gasification at a temperature of 700–900 °C, the heat of combustion of which turned out to be higher than that of biomass before thermal treatment by 75%. We also studied fuel mixtures based on the resulting semi-coke. The aim of the work is to determine the main characteristics of combustion of semi-coke obtained from coniferous wood and mixtures based on them. The method of thermogravimetric analysis in oxidising medium at a heating rate of 20 °C/min was applied for the research. According to the results of this analysis, the ignition and burnout temperatures were determined, the combustion index was determined, the duration of coke residue combustion was determined, and synergetic interactions between the mixture components influencing the combustion characteristics were established. It was found that the ignition temperature of semi-coke is more than 50% higher than that of biomass and the burnout temperature is 10% higher. Adding 50% of biomass to semi-coke increases the combustion index by more than 30% and decreases the ignition temperature and burnout temperature. The mixture components synergistically interact with each other during combustion to reduce the value of maximum mass loss rate. It was found that the atomic ratios of O/C and H/C in semi-coke are lower than in biomass before gasification. [ABSTRACT FROM AUTHOR]

This paper presents the results of analytical studies of the combustion process of semi-coke, cedar sawdust, and their mixtures using the TGA method at three different heating rates with the determination of the main characteristics of heating: the presence of synergetic interaction between the components of the mixture affecting the maximum rate of combustion and kinetic parameters. Calculations of activation energy and pre-exponential multiplier of the Arrhenius equation by the Friedman and Ozawa–Flynn–Wall priori methods for initial combustibles and their mixtures have been carried out. Semi-coke was obtained by thermal treatment of brown coal at 700–900 °C to remove volatile substances, which makes it more environmentally friendly than the original coal. Semi-coke has a higher heat of combustion than biomass, and biomass has a higher reactivity than semi-coke. The combustion process of biomass occurs in a lower temperature range, and adding biomass to semi-coke shifts the combustion process to a lower temperature range than such for biomass. Adding at least 50% of biomass to semi-coke increases the combustion index by at least 1.1 times. Regardless of the heating rate of mixtures, synergetic interaction between the mixture's components increases the maximum combustion rate of coke residue by 20%. [ABSTRACT FROM AUTHOR]

The results of experiments on high-temperature plasma confinement in a quasi-stationary fusion facility are presented. The results were obtained on the L-2M stellarator in which superposition of magnetic fields with three-dimensional spatial symmetry is created with the help of external windings. The plasma was created and heated using microwave pulses with a record specific power of 2 to 4 MW/m3. Under these conditions, spontaneous transition processes were observed in a plasma stable with respect to large-scale instabilities, leading to an abrupt increase in energy. High thermal loads on the wall of the vacuum chamber are observed in the area of the helical separatrix, which leads to an increase in the penetration of impurities into the plasma. Plasma energy and confinement time correspond to L-2M single-machine scaling at lower powers while at specific powers above 3 MW/m3, confinement time decreases due to the accumulation of impurities. The research results can be used to develop fusion energy facilities or to simulate astrophysical phenomena. [ABSTRACT FROM AUTHOR]

HIV-1 disease progression is paradoxically characterized by systemic chronic immune activation and gut mucosal immune dysfunction, which is not fully defined. Annexin A1 (ANXA1), an inflammation modulator, is a potential link between systemic inflammation and gut immune dysfunction during the simian immunodeficiency virus (SIV) infection. Gene expression of ANXA1 and cytokines were assessed in therapy-naïve rhesus macaques during early and chronic stages of SIV infection and compared with SIV-negative controls. ANXA1 expression was suppressed in the gut but systemically increased during early infection. Conversely, ANXA1 expression increased in both compartments during chronic infection. ANXA1 expression in peripheral blood was positively correlated with HLA-DR+CD4+ and CD8+ T-cell frequencies, and negatively associated with the expression of pro-inflammatory cytokines and CCR5. In contrast, the gut mucosa presented an anergic cytokine profile in relation to ANXA1 expression. In vitro stimulations with ANXA1 peptide resulted in decreased inflammatory response in PBMC but increased activation of gut lymphocytes. Our findings suggest that ANXA1 signaling is dysfunctional in SIV infection, and may contribute to chronic inflammation in periphery and with immune dysfunction in the gut mucosa. Thus, ANXA1 signaling may be a novel therapeutic target for the resolution of immune dysfunction in HIV infection.

HIV causes rapid CD4+ T cell depletion in the gut mucosa, resulting in immune deficiency and defects in the intestinal epithelial barrier. Breakdown in gut barrier integrity is linked to chronic inflammation and disease progression. However, the early effects of HIV on the gut epithelium, prior to the CD4+ T cell depletion, are not known. Further, the impact of early viral infection on mucosal responses to pathogenic and commensal microbes has not been investigated. We utilized the SIV model of AIDS to assess the earliest host-virus interactions and mechanisms of inflammation and dysfunction in the gut, prior to CD4+ T cell depletion. An intestinal loop model was used to interrogate the effects of SIV infection on gut mucosal immune sensing and response to pathogens and commensal bacteria in vivo. At 2.5 days post-SIV infection, low viral loads were detected in peripheral blood and gut mucosa without CD4+ T cell loss. However, immunohistological analysis revealed the disruption of the gut epithelium manifested by decreased expression and mislocalization of tight junction proteins. Correlating with epithelial disruption was a significant induction of IL-1β expression by Paneth cells, which were in close proximity to SIV-infected cells in the intestinal crypts. The IL-1β response preceded the induction of the antiviral interferon response. Despite the disruption of the gut epithelium, no aberrant responses to pathogenic or commensal bacteria were observed. In fact, inoculation of commensal Lactobacillus plantarum in intestinal loops led to rapid anti-inflammatory response and epithelial tight junction repair in SIV infected macaques. Thus, intestinal Paneth cells are the earliest responders to viral infection and induce gut inflammation through IL-1β signaling. Reversal of the IL-1β induced gut epithelial damage by Lactobacillus plantarum suggests synergistic host-commensal interactions during early viral infection and identify these mechanisms as potential targets for therapeutic intervention.

UnlabelledEpithelial barrier dysfunction during human immunodeficiency virus (HIV) infection has largely been attributed to the rapid and severe depletion of CD4(+) T cells in the gastrointestinal (GI) tract. Although it is known that changes in mucosal gene expression contribute to intestinal enteropathy, the role of small noncoding RNAs, specifically microRNA (miRNA), has not been investigated. Using the simian immunodeficiency virus (SIV)-infected nonhuman primate model of HIV pathogenesis, we investigated the effect of viral infection on miRNA expression in intestinal mucosa. SIV infection led to a striking decrease in the expression of mucosal miRNA compared to that in uninfected controls. This decrease coincided with an increase in 5'-3'-exoribonuclease 2 protein and alterations in DICER1 and Argonaute 2 expression. Targets of depleted miRNA belonged to molecular pathways involved in epithelial proliferation, differentiation, and immune response. Decreased expression of several miRNA involved in maintaining epithelial homeostasis in the gut was localized to the proliferative crypt region of the intestinal epithelium. Our findings suggest that SIV-induced decreased expression of miRNA involved in epithelial homeostasis, disrupted expression of miRNA biogenesis machinery, and increased expression of XRN2 are involved in the development of epithelial barrier dysfunction and gastroenteropathy.ImportanceMicroRNA (miRNA) regulate the development and function of intestinal epithelial cells, and many viruses disrupt normal host miRNA expression. In this study, we demonstrate that SIV and HIV disrupt expression of miRNA in the small intestine during infection. The depletion of several key miRNA is localized to the proliferative crypt region of the gut epithelium. These miRNA are known to control expression of genes involved in inflammation, cell death, and epithelial maturation. Our data indicate that this disruption might be caused by altered expression of miRNA biogenesis machinery during infection. These findings suggest that the disruption of miRNA in the small intestine likely plays a role in intestinal enteropathy during HIV infection.

ObjectiveThe human intestine harbors trillions of commensal microbes that live in homeostasis with the host immune system. Changes in the composition and complexity of gut microbial communities are seen in inflammatory bowel disease (IBD), indicating disruption in host-microbe interactions. Multiple factors including diet and inflammatory conditions alter the microbial complexity. The goal of this study was to develop an optimized methodology for fecal sample processing and to detect changes in the gut microbiota of patients with Crohn's disease receiving specialized diets.DesignFecal samples were obtained from patients with Crohn's disease in a pilot diet crossover trial comparing the effects of a specific carbohydrate diet (SCD) versus a low residue diet (LRD) on the composition and complexity of the gut microbiota and resolution of IBD symptoms. The gut microbiota composition was assessed using a high-density DNA microarray PhyloChip.ResultsDNA extraction from fecal samples using a column based method provided consistent results. The complexity of the gut microbiome was lower in IBD patients compared to healthy controls. An increased abundance of Bacteroides fragilis (B. fragilis) was observed in fecal samples from IBD positive patients. The temporal response of gut microbiome to the SCD resulted in an increased microbial diversity while the LRD diet was associated with reduced diversity of the microbial communities.ConclusionChanges in the composition and complexity of the gut microbiome were identified in response to specialized carbohydrate diet. The SCD was associated with restructuring of the gut microbial communities.

Abstract Background Women and men have diverse responses to many infectious diseases. These differences are amplified following menopause. However, despite extensive information regarding the effects of sex hormones on immune cells, our knowledge is limited regarding the effects of sex and gender on the function of the mucosal immune system. Sex differences also manifest in the prevalence of gut associated inflammatory and autoimmune disorders, including Crohn’s disease, ulcerative colitis and Celiac disease. It is thus hypothesized that a baseline sex-associated difference in immune activation may predispose women to inflammation-associated disease. Methods Peripheral blood samples and small intestinal biopsies were obtained from 34 healthy men and women. Immunophenotypic analysis of isolated lymphocytes was performed by flow cytometry. Oligonucleotide analysis was used to study the transcriptional profile in the gut mucosal microenvironment while real-time PCR analysis was utilized to identify differential gene expression in isolated CD4+ T cells. Transcriptional analysis was confirmed by protein expression levels for genes of interest using fluorescent immunohistochemistry. Data was analyzed using the GraphPad software package. Results Women had higher levels of immune activation and inflammation-associated gene expression in gut mucosal samples. CD4+ and CD8+ T cells had a significantly higher level of immune activation-associated phenotype in peripheral blood as well as in gut associated lymphoid tissue along with higher levels of proliferating T cells. CD4+ T cells that showed upregulation of IL1β as well as the TH17 pathway-associated genes contributed a large part of the inflammatory profile. Conclusion In this study, we demonstrated an upregulation in gene expression related to immune function in the gut microenvironment of women compared to men, in the absence of disease or pathology. Upon closer investigation, CD4+ T cell activation levels were higher in the LPLs in women than in men. Sex differences in the mucosal immune system may predispose women to inflammation-associated diseases that are exacerbated following menopause. Our study highlights the need for more detailed analysis of the effects of sex differences in immune responses at mucosal effector sites.

Chronic immune activation despite long-term therapy poses an obstacle to immune recovery in HIV infection. The role of antigen presenting cells (APCs) in chronic immune activation during HIV infection remains to be fully determined. APCs, the frontline of immune defense against pathogens, are capable of distinguishing between pathogens and non-pathogenic, commensal bacteria. We hypothesized that HIV infection induces dysfunction in APC immune recognition and response to some commensal bacteria and that this may promote chronic immune activation. Therefore we examined APC inflammatory cytokine responses to commensal lactobacilli. We found that APCs from HIV-infected patients produced an enhanced inflammatory response to Lactobacillus plantarum WCFS1 as compared to APCs from healthy, HIV-negative controls. Increased APC expression of TLR2 and CD36, signaling through p38-MAPK, and decreased expression of MAP kinase phosphatase-1 (MKP-1) in HIV infection was associated with this heightened immune response. Our findings suggest that chronic HIV infection enhances the responsiveness of APCs to commensal lactobacilli, a mechanism that may partly contribute to chronic immune activation.

BackgroundDevelopment of inflammatory bowel disease (IBD) involves the interplay of environmental and genetic factors with the host immune system. Mechanisms contributing to immune dysregulation in IBD are not fully defined. Development of novel therapeutic strategies is focused on controlling aberrant immune response in IBD. Current IBD therapy utilizes a combination of immunomodulators and biologics to suppress pro-inflammatory effectors of IBD. However, the role of immunomodulatory factors such as annexin A1 (ANXA1) is not well understood. The goal of this study was to examine the association between ANXA1 and IBD, and the effects of anti-TNF-α, Infliximab (IFX), therapy on ANXA1 expression.MethodsANXA1 and TNF-α transcript levels in PBMC were measured by RT PCR. Clinical follow up included the administration of serial ibdQs. ANXA1 expression in the gut mucosa was measured by IHC. Plasma ANXA1 levels were measured by ELISA.ResultsWe found that the reduction in ANXA1 protein levels in plasma coincided with a decrease in the ANXA1 mRNA expression in peripheral blood of IBD patients. ANXA1 expression is upregulated during IFX therapy in patients with a successful intervention but not in clinical non-responders. The IFX therapy also modified the cellular immune activation in the peripheral blood of IBD patients. Decreased expression of ANXA1 was detected in the colonic mucosa of IBD patients with incomplete resolution of inflammation during continuous therapy, which correlated with increased levels of TNF-α transcripts. Gut mucosal epithelial barrier disruption was evident by increased plasma bacterial 16S levels.ConclusionLoss of ANXA1 expression may support inflammation during IBD and can serve as a biomarker of disease progression. Changes in ANXA1 levels may be predictive of therapeutic efficacy.

BackgroundThe small intestinal epithelium mediates vital functions of nutrient absorption and host defense. The spatial organization of the epithelial cells along the crypt-villus axis segregates them into regions of specialized function. However, the differences in transcriptional programming and the molecular machinery that governs the migration, adhesion, and differentiation of intestinal epithelial cell lineages in humans remain under-explored. To increase our understanding of these mechanisms, we have evaluated gene expression patterns of ileal epithelial cells isolated by laser capture microdissection from either the villus epithelial or crypt cell regions of healthy human small intestinal mucosa. Expression profiles in villus and crypt epithelium were determined by DNA microarray, quantitative real-time PCR, and immunohistochemistry based methods. The expression levels of selected epithelial biomarkers were also compared between gastrointestinal tissues.ResultsPreviously established biomarkers as well as a novel and distinct set of genes believed to be linked to epithelial cell motility, adhesion, and differentiation were found to be enriched in each of the two corresponding cell populations (GEO accession: GSE10629). Additionally, high baseline expression levels of innate antimicrobials, alpha defensin 5 (HD5) and regenerating islet-derived 3 alpha (Reg3A), were detected exclusively within the small bowel crypt, most notably in the ileum in comparison to other sites along the gastrointestinal tract.ConclusionThe elucidation of differential gene expression patterns between crypt and villus epithelial cell lineages in human ileal tissue provides novel insights into the molecular machinery that mediates their functions and spatial organization. Moreover, our findings establish an important framework of knowledge for future investigations of human gastrointestinal diseases.

When designing settlements according to the "Green Building" principle, it is necessary to develop a heating system based on climatic conditions. For example, in areas with a sharply continental climate (cold and prolonged winters), it is sometimes necessary to use solid fuel boilers (in the absence of gas). However, to use these, it is necessary to use biomass or biomass-coal blends as fuel to increase their combustion heat. The addition of biomass waste to coal can be aimed at achieving various objectives: utilization of biomass waste; reduction of solid fossil fuel consumption; improvement of environmental performance at coal-fired boiler houses; improvement of the reactivity of coals or to improve the technical and economic performance of heat-generating plants due to the fact that biomass is a waste from various types of production, and its cost depends only on the distance of its transportation to the boiler house. In this work, combustion of various biomass wastes, including sewage sludge, was carried out on a fire bench emulating the operation of a boiler furnace. Fuel particles were ignited by convective heat transfer in a stream of hot air at a velocity of 5 m/s in the temperature range of 500–800 °C, and the experimental process was recorded on a high-speed, color video camera. The obtained values were compared with the characteristics of different coals used in thermal power generation (lignite and bituminous coal). The aim of the work is to determine the reactivity of various types of biomass, including fuel mixtures based on coal and food waste. The work presents the results of technical and elemental analysis of the researched fuels. Scanning electron microscopy was used to analyze the fuel particle surfaces for the presence of pores, cracks and channels. It was found that the lowest ignition delay is characteristic of cedar needles and hydrolyzed lignin; it is four times less than that of lignite coal and nine times less than that of bituminous coal. The addition of hydrolysis lignin to coal improves its combustion characteristics, while the addition of brewer's spent grain, on the contrary, reduces it, increasing the ignition time delay due to the high moisture content of the fuel particles. [ABSTRACT FROM AUTHOR]

The technological and technical possibility of deep processing of coal by its liquefaction using the methods of extreme mechanochemical and physical effects has been determined; recommendations have been developed for the applied use of the obtained materials in heat power engineering. The organic part of the solid mass of the prepared coal-oil suspension, which has turned into a relatively heavy organic liquid, can be used as a boiler or motor fuel, as well as a feedstock for the production of various hydrocarbon liquids. The resulting mixture of hydrocarbons can be subjected to rectification to obtain hydrocarbon fractions for the production of plastics, oil fractions and the entire spectrum of hydrocarbons for secondary use. The effective use of the above substances will make it possible to obtain not only economic, but also a significant environmental effect. The possibility of liquefying the organic mass of coal using decalin as a hydrogen donor is shown. It was found that the addition of 3% decalin improves the liquefaction process during cavitation treatment. Liquefaction of the organic mass of coal is accompanied by the splitting of the structures of macromolecules of organic substances of coal into aromatic fragments with a lower molecular weight. It should be noted that the developed technology will solve the problem of increasing the value of the final coal product, including by involving unused fine coal sludge into circulation.

The insufficient validity of the positioning of regions in different Russian investment ratings, in particular, the observed convergence of regional assessments, is due to a number of methodological problems. The purpose of the study is to develop a tool to determine the impact of various components of investment attractiveness on the growth of investment activity in the regions and to ensure a balance of interests of the actors of the investment process (regional government bodies, private investors, the population). We developed an original system of indicators for comprehensive assessment of the investment attractiveness of regions including productional, financial, socio-economic, natural, innovative, infrastructure, and personnel components and proposed the balanced assessment method. Based on the matrix of integral indicators we show significant interregional differentiation of investment attractiveness for the North-Western Federal District and determine the key factors of investment attractiveness formation for those regions, including natural resources - for 5 regions, innovations, infrastructure and personnel for 3, production-financial factors for 2, and socio – economic factors for 1 region. The developed methodology allows to justify the priority directions of increasing investment attractiveness aimed at activating investment processes in Russia’s regions.

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.ydbio.2005.08.018 Byline: Irina B. Grishina (a), Sung Yup Kim (a), Christopher Ferrara (a), Helen P. Makarenkova (b), Paul D. Walden (a) Keywords: BMP7; pSmad1; Notch1; Hes1; Prostate; Branching morphogenesis; Urogenital sinus; Epithelium; Mesenchyme Abstract: The mouse prostate gland develops by branching morphogenesis from the urogenital epithelium and mesenchyme. Androgens and developmental factors, including FGF10 and SHH, promote prostate growth (Berman, D.M., Desai, N., Wang, X., Karhadkar, S.S., Reynon, M., Abate-Shen, C., Beachy, P.A., Shen, M.M., 2004. Roles for Hedgehog signaling in androgen production and prostate ductal morphogenesis. Dev. Biol. 267, 387-398; Donjacour, A.A., Thomson, A.A., Cunha, G.R., 2003. FGF-10 plays an essential role in the growth of the fetal prostate. Dev. Biol. 261, 39-54), while BMP4 signaling from the mesenchyme has been shown to suppresses prostate branching (Lamm, M.L., Podlasek, C.A., Barnett, D.H., Lee, J., Clemens, J.Q., Hebner, C.M., Bushman, W., 2001. Mesenchymal factor bone morphogenetic protein 4 restricts ductal budding and branching morphogenesis in the developing prostate. Dev. Biol. 232, 301-314). Here, we show that Bone Morphogenetic Protein 7 (BMP7) restricts branching of the prostate epithelium. BMP7 is expressed in the periurethral urogenital mesenchyme prior to formation of the prostate buds and, subsequently, in the prostate epithelium. We show that BMP7.sup.lacZ/lacZ null prostates show a two-fold increase in prostate branching, while recombinant BMP7 inhibits prostate morphogenesis in organ culture in a concentration-dependent manner. We further explore the mechanisms by which the developmental signals may be interpreted in the urogenital epithelium to regulate branching morphogenesis. We show that Notch1 activity is associated with the formation of the prostate buds, and that Notch1 signaling is derepressed in BMP7 null urogenital epithelium. Based on our studies, we propose a model that BMP7 inhibits branching morphogenesis in the prostate and limits the number of domains with high Notch1/Hes1 activity. Author Affiliation: (a) Department of Urology, New York University School of Medicine, VAMC, 423 East 23rd Street, 18064-South, New York, NY 10010, USA (b) The Neuroscience Institute, 10640 John Jay Hopkins Drive, San Diego, CA 92121, USA Article History: Received 10 June 2004; Revised 11 August 2005; Accepted 11 August 2005