Another case for diet restriction: TAp73-expressing medulloblastomas are stunted by glutamine withdrawal.

Medulloblastomas are among the most common malignant brain cancers in the pediatric population and consist of at least four distinct subgroups with unique molecular and genetic features and clinical outcomes. In this issue of Genes & Development, Niklison-Chirou and colleagues (pp. 1738-1753) identify the p53 family member and p73 isoform TAp73 as a crucial factor causing glutamine addiction in aggressive medulloblastomas. Their findings pave the way for the use of glutamine restriction as an adjuvant treatment for TAp73-expressing medulloblastomas.

Unifying the p73 knockout phenotypes: TAp73 orchestrates multiciliogenesis.

Multiciliogenesis is essential for the function of different epithelia, and its failure results in brain defects, respiratory diseases, and infertility. In this issue of Genes & Development, Nemajerova and colleagues (pp. 1300-1312) reveal the p53 family member and p73 isoform TAp73 as a transcription factor dictating the differentiation of multiciliated cells. Their findings provide the long-awaited unifying explanation for the diverse phenotypes of the p73 knockout mice.

Effect of a Multistrain Probiotic on Leaky Gut in Patients with Diarrhea-Predominant Irritable Bowel Syndrome: A Pilot Study.

BACKGROUND: A probiotic mixture prevented epithelial barrier impairment in various experimental models. The objective was to evaluate its effects in patients suffering from IBS with diarrhea (IBS-D) with confirmed leaky gut. METHODS: IBS-D patients with increased intestinal permeability measured by radionuclide tracers were enrolled in this pilot, open-label, prospective, interventional, single-center, Phase IV study. Patients received two capsules of a multistrain probiotic a day for 30 days and were evaluated by repeated intestinal permeability tests, the Bristol Stool Scale, and patient-perceived quality of life and satisfaction. RESULTS: Of the 30 enrolled patients (mean age: 42.1 [SD: 13.1] years; female: 60%), 27 completed the study (full analysis set [FAS]), and 18 had no major protocol violation (per protocol set [PPS]). On D30, an improvement of intestinal permeability was observed in 81.5% of patients in FAS, normalization being observed in 37% of the participants (44% in PPS). The mean intestinal permeability was significantly decreased: baseline minus D30, 3.4 (95% CI: 1.7, 5.2); the IBS-QOL total score was significantly increased: D30 minus baseline, 8.0 (95% CI: 3.0, 12.9); and stool consistency was significantly improved. On D15 and D30, 96.3% of patients claimed that their IBS symptoms had been satisfactory alleviated, and a significant improvement was reported for the following VAS-IBS items: abdominal pain, diarrhea, and impact of gastrointestinal problems in daily life. Compliance and tolerance were satisfactory. CONCLUSION: The multistrain probiotic tested may reduce intestinal permeability in a considerable proportion of patients and may improve abdominal pain, stool consistency, and quality of life. These results pave the way for larger, placebo-controlled clinical studies.

Differential Response of Wheat Rhizosphere Bacterial Community to Plant Variety and Fertilization.

The taxonomic assemblage and functions of the plant bacterial community are strongly influenced by soil and host plant genotype. Crop breeding, especially after the massive use of nitrogen fertilizers which led to varieties responding better to nitrogen fertilization, has implicitly modified the ability of the plant root to recruit an effective bacterial community. Among the priorities for harnessing the plant bacterial community, plant genotype-by-microbiome interactions are stirring attention. Here, we analyzed the effect of plant variety and fertilization on the rhizosphere bacterial community. In particular, we clarified the presence in the bacterial community of a varietal effect of N and P fertilization treatment. 16S rRNA gene amplicon sequence analysis of rhizospheric soil, collected from four wheat varieties grown under four N-P fertilization regimes, and quantification of functional bacterial genes involved in the nitrogen cycle (nifH; amoA; nirK and nosZ) were performed. Results showed that variety played the most important role and that treatments did not affect either bacterial community diversity or bacterial phyla abundance. Variety-specific response of rhizosphere bacterial community was detected, both in relation to taxa (Nitrospira) and metabolic functions. In particular, the changes related to amino acid and aerobic metabolism and abundance of genes involved in the nitrogen cycle (amoA and nosZ), suggested that plant variety may lead to functional changes in the cycling of the plant-assimilable nitrogen.

The family that eats together stays together: new p53 family transcriptional targets in autophagy.

Autophagy is a biological process that is crucial to maintain cellular homeostasis and is regulated by several metabolic pathways, including the p53 tumor suppressor pathway. In this issue of Genes & Development, Kenzelmann Broz and colleagues (pp. 1016-1031) show how the p53 family as a whole, including p63 and p73, collaborate in controlling autophagy to support tumor suppression.

The p53 family reaches the final frontier: the variegated regulation of the dark matter of the genome by the p53 family in cancer.

The tumour suppressor p53 and its paralogues, p63 and p73, are essential to maintain cellular homoeostasis and the integrity of the cell's genetic material, thus meriting the title of 'guardians of the genome'. The p53 family members are transcription factors and fulfill their activities by controlling the expression of protein-coding and non-coding genes. Here, we review how the latter group transcended from the 'dark matter' of the transcriptome, providing unexpected and intriguing anti-cancer therapeutic strategies.

miR-205 Regulates Basal Cell Identity and Stem Cell Regenerative Potential During Mammary Reconstitution.

Mammary gland development is fueled by stem cell self-renewal and differentiation. External cues from the microenvironment coupled with internal cues such as post-transcriptional regulation exerted by microRNAs regulate stem cell behavior and fate. Here, we have identified a miR-205 regulatory network required for mammary gland ductal development and stem cell regeneration following transplantation into the cleared mammary fat pad. In the postnatal mammary gland, miR-205 is predominantly expressed in the basal/stem cell enriched population. Conditional deletion of miR-205 in mammary epithelial cells impairs stem cell self-renewal and mammary regenerative potential in the in vitro mammosphere formation assay and in vivo mammary reconstitution. miR-205 null transplants display significant changes in basal cells, basement membrane, and stroma. NKD1 and PTPA, which inhibit the Wnt signaling pathway, and AMOT, which causes YAP cytoplasmic retention and inactivation were identified as miR-205 downstream mediators. These studies also confirmed that miR-205 is a direct ΔNp63 target gene that is critical for the regulation of basal cell identity. Stem Cells 2018;36:1875-15.

Effects of deciduous shade trees on surface temperature and pedestrian thermal stress during summer and autumn.

In a context of urban warming, the effects of trees on outdoor thermal stress are important even during the increasingly hot autumn season. This study examines the effects of a deciduous tree species (Tilia x europaea L) on surface temperature over different ground materials and in turn on human thermal comfort, with a particular focus on tree shade variation due to leaf fall. Grass, asphalt, and gravel-covered ground surfaces, both sun-exposed and under the Tilia, were monitored in Florence, Italy, during the summer (2014) and autumn (2017) seasons. The Index of Thermal Stress (ITS) was used to gauge the micrometeorological effects of the changing tree canopy, with tree defoliation quantified by the Plant Area Index. On clear summer days, thermal discomfort was especially pronounced over exposed asphalt, and even more intense above exposed gravel due to its higher reflectivity-while shaded surfaces showed large reductions in thermal stress. Even though incoming solar radiation decreases over the course of the fall season, the direct radiation under the gradually defoliating tree canopy actually increases. Due to this diminished shading effect, the differences in surface temperature between exposed and shaded asphalt shrink dramatically from about 20 to 3 °C. However, since ambient conditions become milder as the season progresses, the Tilia demonstrated a double benefit in terms of ITS: providing thermal comfort under its full canopy at the beginning of autumn and maintaining comfort even as its canopy thins out. At the same time, tree species with earlier defoliation may be unable to replicate such benefits.

The p53 family orchestrates the regulation of metabolism: physiological regulation and implications for cancer therapy.

The p53 family of transcription factors is essential to counteract tumour formation and progression. Although previously this was exclusively associated with the ability of the p53 family to induce cell cycle arrest and apoptosis, an increasing number of reports have now indisputably demonstrated that the tumour suppressive functions of the p53 family members also rely on their ability to control and regulate cellular metabolism and maintain cellular oxidative homeostasis. Here, we review how each p53 family member, including p63 and p73, controls metabolic pathways in physiological conditions, and how these mechanisms could be exploited to provide anticancer therapeutic opportunities.

DLX5, FGF8 and the Pin1 isomerase control ΔNp63α protein stability during limb development: a regulatory loop at the basis of the SHFM and EEC congenital malformations.

Ectrodactyly, or Split-Hand/Foot Malformation (SHFM), is a congenital condition characterized by the loss of central rays of hands and feet. The p63 and the DLX5;DLX6 transcription factors, expressed in the embryonic limb buds and ectoderm, are disease genes for these conditions. Mutations of p63 also cause the ectodermal dysplasia-ectrodactyly-cleft lip/palate (EEC) syndrome, comprising SHFM. Ectrodactyly is linked to defects of the apical ectodermal ridge (AER) of the developing limb buds. FGF8 is the key signaling molecule in this process, able to direct proximo-distal growth and patterning of the skeletal primordial of the limbs. In the limb buds of both p63 and Dlx5;Dlx6 murine models of SHFM, the AER is poorly stratified and FGF8 expression is severely reduced. We show here that the FGF8 locus is a downstream target of DLX5 and that FGF8 counteracts Pin1-ΔNp63α interaction. In vivo, lack of Pin1 leads to accumulation of the p63 protein in the embryonic limbs and ectoderm. We show also that ΔNp63α protein stability is negatively regulated by the interaction with the prolyl-isomerase Pin1, via proteasome-mediated degradation; p63 mutant proteins associated with SHFM or EEC syndromes are resistant to Pin1 action. Thus, DLX5, p63, Pin1 and FGF8 participate to the same time- and location-restricted regulatory loop essential for AER stratification, hence for normal patterning and skeletal morphogenesis of the limb buds. These results shed new light on the molecular mechanisms at the basis of the SHFM and EEC limb malformations.

Urban Soil: Assessing Ground Cover Impact on Surface Temperature and Thermal Comfort.

The urban population growth, together with the contemporary deindustrialization of metropolitan areas, has resulted in a large amount of available land with new possible uses. It is well known that urban green areas provide several benefits in the surrounding environment, such as the improvement of thermal comfort conditions for the population during summer heat waves. The purpose of this study is to provide useful information on thermal regimes of urban soils to urban planners to be used during an urban transformation to mitigate surface temperatures and improve human thermal comfort. Field measurements of solar radiation, surface temperature (), air temperature (), relative humidity, and wind speed were collected on four types of urban soils and pavements in the city of Florence during summer 2014. Analysis of days under calm, clear-sky condition is reported. During daytime, sun-to-shadow differences for , apparent temperature index (ATI), and were significantly positive for all surfaces. Conversely, during nighttime, differences among all surfaces were significantly negative, whereas ATI showed significantly positive differences. Moreover, was significantly negative for grass and gravel. Relative to the shaded surfaces, was higher on white gravel and grass than gray sandstone and asphalt during nighttime, whereas gray sandstone was always the warmest surface during daytime. Conversely, no differences were found during nighttime for ATI and measured over surfaces that were exposed to sun during the day, whereas showed higher values on gravel than grass and asphalt during nighttime. An exposed surface warms less if its albedo is high, leading to a significant reduction of during daytime. These results underline the importance of considering the effects of surface characteristics on surface temperature and thermal comfort. This would be fundamental for addressing urban environment issues toward the heat island mitigation considering also the impact of urban renovation on microclimate.

Modeling Tree Shade Effect on Urban Ground Surface Temperature.

There is growing interest in the role that urban forests can play as urban microclimate modifiers. Tree shade and evapotranspiration affect energy fluxes and mitigate microclimate conditions, with beneficial effects on human health and outdoor comfort. The aim of this study was to investigate surface temperature () variability under the shade of different tree species and to test the capability in predicting of a proposed heat transfer model. Surface temperature data on asphalt and grass under different shading conditions were collected in the Cascine park, Florence, Italy, and were used to test the performance of a one-dimensional heat transfer model integrated with a routine for estimating the effect of plant canopies on surface heat transfer. Shading effects of 10 tree species commonly used in Italian urban settings were determined by considering the infrared radiation and the tree canopy leaf area index (LAI). The results indicate that, on asphalt, was negatively related to the LAI of trees ( reduction ranging from 13.8 to 22.8°C). On grass, this relationship was weaker probably because of the combined effect of shade and grass evapotranspiration on ( reduction ranged from 6.9 to 9.4°C). A sensitivity analysis confirmed that other factors linked to soil water content play an important role in reduction of grassed areas. Our findings suggest that the energy balance model can be effectively used to estimate of the urban pavement under different shading conditions and can be applied to the analysis of microclimate conditions of urban green spaces.

Transport of Glyphosate and Aminomethylphosphonic Acid under Two Soil Management Practices in an Italian Vineyard.

Worldwide, glyphosate is the most widely used herbicide in controlling the growth of annual and perennial weeds. An increasing number of studies have highlighted the environmental risk resulting from the use of this molecule in aquatic and terrestrial ecosystems. The objective of the study was to determine the transport of glyphosate and its degradation product, aminomethylphosphonic acid (AMPA), through runoff and transported sediment from a vineyard under two different soil management systems: harrowed inter-row (HR) and permanent grass covered inter-row (GR). The study was performed over a period of 4 yr. Glyphosate and AMPA concentrations were found to be higher in runoff and in transported sediment from HR compared with GR, regardless of the amount of runoff and transported sediment. The mean annual percentages of glyphosate loss, via runoff and transported sediment, were about 1.37 and 0.73% for HR and GR, respectively. Aminomethylphosphonic acid represented approximately 30.9 and 40.0% of the total glyphosate losses in GR and HR, respectively. Moreover, results suggested that rains occurring within 4 wk after treatment could cause the transport of glyphosate and AMPA in high concentrations. Soil analyses indicated that glyphosate content was below detection within 1 yr, whereas AMPA remained in the soil profiles along the vine row and in the inter-row. Results indicated that GR can reduce soil and herbicide loss by runoff in vineyard cropping system.

Leaching of Glyphosate and Aminomethylphosphonic Acid through Silty Clay Soil Columns under Outdoor Conditions.

Glyphosate [-(phosphono-methyl)-glycine] is the main herbicide used in the Chianti vineyards. Considering the pollution risk of the water table and that the vineyard tile drain may deliver this pollutant into nearby streams, the objective of the present study was to estimate the leaching losses of glyphosate under natural rainfall conditions in a silty clay soil in the Chianti area. The leaching of glyphosate and its metabolite (aminomethylphosphonic acid [AMPA]) through soils was studied in 1-m-deep soil columns under outdoor conditions over a 3-yr period. Glyphosate was detected in the leachates for up to 26 d after treatments at concentrations ranging between 0.5 and 13.5 µg L. The final peak (0.28 µg L) appeared in the leachates approximately 319 d after the first annual treatment. Aminomethylphosphonic acid first appeared (21.3 µg L) in the soil leachate 6.8 d after the first annual treatment. Aminomethylphosphonic acid detection frequency and measured concentration in the leachates were more than that observed for the glyphosate. Aminomethylphosphonic acid was detected in 20% of the soil leachates at concentrations ranging from 1 to 24.9 µg L. No extractable glyphosate was detected in the soil profile. However, the AMPA content in the lowest layer ranged from 13.4 to 21.1 mg kg, and on the surface layer, it ranged from 86.7 to 94 mg kg. Overall, these results indicate that both glyphosate and AMPA leaching through a 1-m soil column may be potential groundwater contaminants.

Genome-wide p63-Target Gene Analyses Reveal TAp63/NRF2-Dependent Oxidative Stress Responses.

The p53 family member TP63 encodes two sets of N-terminal isoforms, TAp63 and ΔNp63 isoforms. They each regulate diverse biological functions in epidermal morphogenesis and in cancer. In the skin, where their activities have been extensively characterized, TAp63 prevents premature aging by regulating the quiescence and genomic stability of stem cells required for wound healing and hair regeneration, while ΔNp63 controls maintenance and terminal differentiation of epidermal basal cells. This functional diversity is surprising given that these isoforms share a high degree of similarity, including an identical sequence for a DNA-binding domain. To understand the mechanisms of the transcriptional programs regulated by each p63 isoform and leading to diverse biological functions, we performed genome-wide analyses using p63 isoform-specific chromatin immunoprecipitation, RNA sequencing, and metabolomics of TAp63-/- and ΔNp63-/- mouse epidermal cells. Our data indicate that TAp63 and ΔNp63 physically and functionally interact with distinct transcription factors for the downstream regulation of their target genes, thus ultimately leading to the regulation of unique transcriptional programs and biological processes. Our findings unveil novel transcriptomes regulated by the p63 isoforms to control diverse biological functions, including the cooperation between TAp63 and NRF2 in the modulation of metabolic pathways and response to oxidative stress providing a mechanistic explanation for the TAp63 knock out phenotypes. SIGNIFICANCE: The p63 isoforms, TAp63 and ΔNp63, control epithelial morphogenesis and tumorigenesis through the interaction with distinct transcription factors and the subsequent regulation of unique transcriptional programs.

Evaluation of tolerability and major factors affecting the adherence to probiotic therapy in patients with irritable bowel syndrome: a prospective, observational, real-life study.

BACKGROUND: Probiotics have been evaluated in multiple clinical trials on irritable bowel syndrome (IBS). However, in real-life long-term compliance could be low. Our study is single-center, observational and prospective, aiming both to evaluate the adherence to prescription of probiotic therapy in real-life and to identify factors able to influence adherence to therapy. METHODS: Fifty patients diagnosed with IBS according to Rome IV and receiving a clinical prescription of a multistrain probiotic preparation (VSL#3® manufactured by Nutrilinea Srl and marketed in Italy by Ferring S.p.A., Milan, Italy) have been enrolled and 49 completed the follow-up. Two months after baseline a second visit was made to assess adherence and eventual reasons for discontinuation. RESULTS: Sixty percent of patients took all the prescribed probiotic therapy in real-life setting, with perceived benefits in more than 60% of cases. Among the 20 patients with reduced adherence, 5 took less than 50%, 12 took 50% and 2 took more than 50% but less than 80% of the prescribed doses. Principal reasons of not complete adherence among the 20 patients were: price of the product (8/20), mild adverse events (AEs) (6/20) and poor appreciation of flavour (3/20). CONCLUSIONS: This study suggested that the adherence to probiotic therapy is affected by different factors in patients with IBS in a real-life setting. The main reason for lack of adherence was the price of the product. Other reasons are mild AEs (mainly bloating) and low palatability.

Effect of Fertilization Regime of Common Wheat (Triticum aestivum) on Flour Quality and Shelf-Life of PDO Tuscan Bread.

The shelf-life of bread is influenced by flour components, such as starch, composed of amylose and amylopectin. The aim was to test the effect of different balances of N (45, 90, 135 kg/ha) and P (48, 96 kg/ha) fertilizers on the flour characteristics and consequently the shelf-life of PDO Tuscan bread, stored in different modified atmosphere packaging (Ar, N2, Air). The amylose and phytochemical compounds were increased by N and decreased by the addition of P, but excessive doses of N (135 kg/ha) had a negative effect on flour quality. In the bread, the study highlighted the tendency of N2 and Ar, as storage filler gases, to reduce water loss, slow down the staling process, and prolong shelf-life. However, the most significant influence on shelf-life was related to the different fertilizations of wheat. In fact, when N was present in equal dose to P (90/96 or 45/48 kg/ha) or slightly higher (90/48 kg/ha), the bread tended to last longer over time. Instead, when these ratios were unbalanced in favor of N (135/48 or 135/96 kg/ha) and in favor of P (45/96 kg/ha), the shelf-life decreased considerably.

The rebel angel: mutant p53 as the driving oncogene in breast cancer.

Breast cancer is the most frequent invasive tumor diagnosed in women, causing over 400 000 deaths yearly worldwide. Like other tumors, it is a disease with a complex, heterogeneous genetic and biochemical background. No single genomic or metabolic condition can be regarded as decisive for its formation and progression. However, a few key players can be pointed out and among them is the TP53 tumor suppressor gene, commonly mutated in breast cancer. In particular, TP53 mutations are exceptionally frequent and apparently among the key driving factors in triple negative breast cancer -the most aggressive breast cancer subgroup-whose management still represents a clinical challenge. The majority of TP53 mutations result in the substitution of single aminoacids in the central region of the p53 protein, generating a spectrum of variants ('mutant p53s', for short). These mutants lose the normal p53 oncosuppressive functions to various extents but can also acquire oncogenic properties by gain-of-function mechanisms. This review discusses the molecular processes translating gene mutations to the pathologic consequences of mutant p53 tumorigenic activity, reconciling cell and animal models with clinical outcomes in breast cancer. Existing and speculative therapeutic methods targeting mutant p53 are also discussed, taking into account the overlap of mutant and wild-type p53 regulatory mechanisms and the crosstalk between mutant p53 and other oncogenic pathways in breast cancer. The studies described here concern breast cancer models and patients-unless it is indicated otherwise and justified by the importance of data obtained in other models.