Ocean biogeochemistry exhibits contrasting responses to a large scale reduction in dust deposition

Dust deposition of iron is thought to be an important control on ocean biogeochemistry and air-sea CO<sub>2</sub> exchange. In this study, we examine the impact of a large scale, yet climatically realistic, reduction in the aeolian Fe input during a 240 year transient simulation. In contrast to previous studies, we find that the ocean biogeochemical cycles of carbon and nitrogen are relatively insensitive (globally) to a 60% reduction in Fe input from dust. Net primary productivity (NPP) is reduced in the Fe limited regions, but the excess macronutrients that result are able to fuel additional NPP elsewhere. Overall, NPP and air-sea CO<sub>2</sub> exchange are only reduced by around 3% between 1860 and 2100. While the nitrogen cycle is perturbed more significantly (by ~15%), reduced N<sub>2</sub> fixation is balanced by a concomitant decline in denitrification. Feedbacks between N<sub>2</sub> fixation and denitrification are controlled by variability in surface utilization of inorganic nitrogen and subsurface oxygen consumption, as well as the direct influence of Fe on N<sub>2</sub> fixation. Overall, there is relatively little impact of reduced aeolian Fe input (<4%) on cumulative CO<sub>2</sub> fluxes over 240 years. The lower sensitivity of our model to changes in dust input is primarily due to the more detailed representation of the continental shelf Fe, which was absent in previous models

Neoadjuvant therapy for breast cancer

Objective: To evaluate the frequency of neoadjuvant therapy (NT) in women with stage I–III breast cancer in Italy and whether it is influenced by biological characteristics, screening history, and geographic area. Methods: Data from the High Resolution Study conducted in 7 Italian cancer registries were used; they are a representative sample of incident cancers in the study period (2009–2013). Included were 3546 women aged <85 years (groups <50, 50–69, 70–64, and 75+) with stage I–III breast cancer at diagnosis who underwent surgery. Women were classified as receiving NT if they received chemotherapy, target therapy, and/or hormone therapy before the first surgical treatment. Logistic models were built to test the association with biological and contextual variables. Results: Only 8.2% of women (290 cases) underwent NT; the treatment decreases with increasing age (14.5% in age <50 and 2.2% in age 75+), is more frequent in women with negative receptors (14.8%), HER2-positive (15.7%), and triple-negative (15.6%). The multivariable analysis showed the probability of receiving NT is higher in stage III (odds ratio [OR] 3.83; 95% confidence interval [CI] 2.83–5.18), luminal B (OR 1.87; 95% CI 1.27–2.76), triple-negatives (OR 1.88; 95% CI 1.15–3.08), and in symptomatic cancers (OR 1.98; 95% CI 1.13–3.48). Use of NT varied among geographic areas: Reggio Emilia had the highest rates (OR 2.29; 95% CI 1.37–3.82) while Palermo had the lowest (OR 0.41; 95% CI 0.24–0.68). Conclusions: The use of NT in Italy is limited and variable. There are no signs of greater use in hospitals with more advanced care

The CFT dual of AdS gravity with torsion

We consider the Mielke-Baekler model of three-dimensional AdS gravity with torsion, which has gravitational and translational Chern-Simons terms in addition to the usual Einstein-Hilbert action with cosmological constant. It is shown that the topological nature of the model leads to a finite Fefferman-Graham expansion. We derive the holographic stress tensor and the associated Ward identities and show that, due to the asymmetry of the left- and right-moving central charges, a Lorentz anomaly appears in the dual conformal field theory. Both the consistent and the covariant Weyl and Lorentz anomaly are determined, and the Wess-Zumino consistency conditions for the former are verified. Moreover we consider the most general solution with flat boundary geometry, which describes left-and right-moving gravitational waves on AdS_3 with torsion, and shew that in this case the holographic energy-momentum tensor is given by the wave profiles. The anomalous transformation laws of the wave profiles under diffeomorphisms preserving the asymptotic form of the bulk solution yield the central charges of the dual CFT and confirm the results that appeared earlier on in the literature. We finally comment on some points concerning the microstate counting for the Riemann-Cartan black hole.Comment: 17 pages, uses JHEP3.cls. References added, minor errors correcte

Thermal and Economic Efficiency of Progressive Retrofit Strategies for School Buildings by a Statistical Analysis based Tool

Design alternatives in air conditioned buildings may be easily compared just by summing the hourly consumption of primary energy, while quantitative approachs for bioclimatic design strategies are difficult to be assessed and compared. A actively heated and passively cooled school building is considered as an application field of a novel methodology to promote an informed choice about the retrofit strategies to be adopted for buildings, defined as the Gained Comfort Cost (GCC). A functional and significant unit (i.e. a classroom), is used to test different energy retrofit solutions and their performances were compared with a baseline, in terms of the capacity to reduce the indoor air temperature variation. The novel methodology is a visual tool allowing to understand the “distance” of indoor conditions from comfort; the retrofit strategies are promoted to reduce this distance considering however the associated costs (LCC) to deal with actual feasibility

Poly(I:C) and CpG-ODN combined aerosolization to treat lung metastases and counter the immunosuppressive microenvironment

The immunostimulatory ability of synthetic oligonucleotides containing CpG motifs (CpG-ODN), agonists of Toll-like receptor 9 (TLR9), can be harnessed to promote antitumor immunity by their application at the tumor site to stimulate local activation of innate immunity; however, particularly in the lung, tumor-associated immunosuppression can subvert such antitumor innate immune responses. To locally maintain continuous activation of innate subpopulations while inhibiting immunosuppressive cells, we evaluated aerosol delivery CpG-ODN combined with Poly(I:C), a TLR3 agonist able to convert tumor-supporting macrophages to tumoricidal effectors, in the treatment of B16 melanoma lung metastases in C57BL/6 mice. Aerosolization of CpG-ODN with Poly(I:C) into the bronchoalveolar space reduced the presence of M2-associated arginase- and IL-10-secreting macrophages in tumor-bearing lungs and increased the antitumor activity of aerosolized CpG-ODN alone against B16 lung metastases without apparent signs of toxicity or injury of the bronchial-bronchiolar structures and alveolar walls. Moreover, CpG-ODN/Poly(I:C) aerosol combined with dacarbazine, a therapeutic agent used in patients with inoperable metastatic melanoma able to exert immunostimulatory effects, led to a significant increase in antitumor activity as compared to treatments with aerosolized CpG-ODN/Poly(I:C) or dacarbazine alone. This effect was related to an enhanced recruitment and cytotoxic activity of tumor-infiltrating NK cells in the lung. Our results point to aerosol delivery as a convenient approach for repeated applications of immunostimulants in patients with lung metastases to maintain a continuous local activation of innate immune cells while suppressing polarization of tumor-infiltrating macrophages to an M2 phenotype

THE SUBTLE BIOFILM REGULATION IN ESCHERICHIA COLI: CSGD AND THE YDDV-DOS OPERON

In this PhD thesis work I investigated the expression modulation of the major adhesion factors in Escherichia coli; in particular I focused on the role of GGDEF and EAL proteins, on their modulation in E. coli biofilm formation in response to environmental signals and on regulation of curli fibers, cellulose and poly-N-acetylglucosamine (PNAG), the most important biofilm determinants in E. coli. E. coli is an Enterobacterium, normally living inside the mammalian gut, at temperature of 37\ub0 C and in relatively nutrient-rich environment. Once outside the host, bacteria usually face much lower temperatures (< 30\ub0C) and a nutrient-limiting environment. The biofilm determinants studied in this thesis are all expressed in response to environmental conditions such as low temperature, low osmolarity and starvation, suggesting that E. coli bacteria switch to a biofilm mode of growth as part of their adaptation to the natural environment. In response to reduction in growth rates, E. coli seems to canalize its energy consumption into production of extracellular features such as curli or exopolysaccharides. Biofilms can be thus considered as a \u201cresistance form\u201d of growth able to withstand stress conditions more efficiently than cells living in a planktonic mode of growth. The CsgD protein is the master regulator of E. coli biofilm formation. It is a transcriptional factor necessary for curli genes transcription and, through the AdrA protein, for cellulose biosynthesis. Gene regulation by CsgD is tightly connected to production and sensing of cyclic di-GMP, a bacterial second messenger involved in various cellular processes, including biosynthesis of extracellular polysaccharides (Simm et al., 2004), biofilm formation (Hickman et al., 2005), and virulence (Pratt et al., 2007; Tischler and Camilli, 2005), as well as morphological and physiological differentiation (Paul et al., 2004). The CsgD-dependent adrA gene, involved in cellulose biosynthesis (Zogaj et al., 2001), encodes a cyclic di-GMP synthase (Simm et al., 2004). CsgD can also activate yoaD, whose gene product is a cyclic di-GMP phosphodiesterase, suggesting that CsgD is directly involved in feedback regulation of cyclic di-GMP intracellular levels and of cellulose biosynthesis (Brombacher et al., 2006). CsgD is also able to activate the iraP gene: IraP acts as a stabilization factor for the \u3c3s protein, an alternative sigma factor of RNA polymerase which directs transcription of genes involved in adaptation to slow growth and to cellular stresses. Here I showed that CsgD transcription activation of the iraP gene does result in a significant increase of \u3c3s intracellular concentration by positively affecting \u3c3s protein stability, thus leading to altered expression of \u3c3s-dependent genes. CsgD-mediated increase of \u3c3s cellular concentrations via the iraP gene would trigger an autoactivation loop leading to an increased production of CsgD-dependent adhesion determinants such as curli fibers and cellulose. This autoregulatory circuitry might be further fueled by \u3c3s-dependent induction of genes encoding di-guanylate cyclases, i.e., proteins able to synthesize the second messenger di-cyclic- GMP, which, in turn, can positively affect csg gene expression (Kader et al., 2006; Weber et al., 2002). The yddV-dos operon is the most expressed among c-di-GMP-related genes showing dependence on \u3c3s (Weber et al., 2006; Sommerfeldt et al., 2009). It encodes, respectively, a protein with DGC activity and a PDE that can degrade c-di- GMP to pGpG. Both Dos and YddV are heme-binding oxygen sensors, and interact to form a stable protein complex (Tuckerman et al., 2009). Although it has been reported that YddV overexpression can stimulate biofilm formation (Mendez-Ortiz et al., 2006), the targets of yddV-dependent biofilm induction had not yet been identified. Here I showed that YddV acts modulating curli and PNAG expression. Control of curli production by yddV-dos takes place at the level of transcription regulation of the csgBAC operon, encoding curli structural subunits, and is mediated by the DGC and PDE activities of YddV and Dos. In contrast, the YddV\u2013Dos protein complex does not strongly influence csgDEFG expression, nor does it affect the expression of the CsgD-dependent adrA gene, encoding a positive effector for cellulose biosynthesis. Regarding PNAG production, we showed that YddV is able to prevent degradation of pgaABCD transcript in the MG1655csrA background, thus suggesting that a DGC might regulate gene expression by affecting mRNA stability in E. coli. YddV regulation of pgaABCD operon in a wild type contest is still controversial: pgaABCD genes are expressed at low levels in MG1655 (the standard laboratory strain of E. coli) and their mRNA half-life is lower than two minutes regardless of the growth conditions tested; thus, possible effects of yddV inactivation on destabilization of the pga transcript are not easy to evaluate in the wt contest. In the last part of my thesis I tried to characterize a biofilm-forming mutant of E. coli, able to express pgaABCD genes at high levels. Even if initial data suggested that a mutation in the csrA gene could be responsible for pga mRNA stabilization in this mutant, actual the mutation leading to the adhesive phenotype and to PNAG production is outside the csrA gene and is still unknown. Moreover my data suggest a connection between pga expression and iron regulation in E. coli strains: it is conceivable that pgaABCD expression and consequent biofilm formation and the adherent phenotype depends on concerted production of different determinants, whose expression is also affected by iron concentration. Thus, my research highlighted that biofilm production is the result of coordinated expression of different adhesion determinants, whose regulation is complex and not fully understood. In particular, the precise extent and the molecular mechanism of c-di-GMP adhesion factors regulation remains to be largely identified and represents an exciting challenge for future research in the biofilm field

Clostridium difficile infection in children: epidemiology and risk of recurrence in a low-prevalence country

Clostridium difficile infection (CDI) is increasingly found in children worldwide, but limited data are available from children living in southern Europe. A 6-year retrospective study was performed to investigate the epidemiology, clinical features, treatment, and risk of recurrence in Italy. Data of children with community- and hospital-acquired CDI (CA-CDI and HA-CDI, respectively) seen at seven pediatric referral centers in Italy were recorded retrospectively. Annual infection rates/10,000 hospital admissions were calculated. Logistic regression was used to investigate risk factors for recurrence. A total of 177 CDI episodes was reported in 148 children (83 males, median age 55.3 months), with a cumulative infection rate of 2.25/10,000 admissions, with no significant variability over time. The majority of children (60.8 %) had CA-CDI. Children with HA-CDI (39.2 %) had a longer duration of symptoms and hospitalization (p = 0.003) and a more common previous use of antibiotics (p = 0.0001). Metronidazole was used in 70.7 % of cases (87/123) and vancomycin in 29.3 % (36/123), with similar success rates. Recurrence occurred in 16 children (10.8 %), and 3 (2 %) of them presented a further treatment failure. The use of metronidazole was associated with a 5-fold increase in the risk of recurrence [odds ratio (OR) 5.18, 95 % confidence interval (CI) 1.1-23.8, p = 0.03]. Short bowel syndrome was the only underlying condition associated with treatment failure (OR 5.29, 95 % CI 1.17-23.8, p = 0.03). The incidence of pediatric CDI in Italy is low and substantially stable. In this setting, there is a limited risk of recurrence, which mainly concerns children treated with oral metronidazole and those with short bowel syndrome

Anti-tumor activity of CpG-ODN aerosol in mouse lung metastases

Studies in preclinical models have demonstrated the superior anti-tumor effect of CpG oligodeoxynucleotides (CpG-ODN) when administered at the tumor site rather than systemically. We evaluated the effect of aerosolized CpG-ODN on lung metastases in mice injected with immunogenic N202.1A mammary carcinoma cells or weakly immunogenic B16 melanoma cells. Upon reaching the bronchoalveolar space, aerosolized CpG-ODN activated a local immune response, as indicated by production of IL-12p40, IFN-γ and IL-1β and by recruitment and maturation of DC cells in bronchoalveolar lavage fluid of mice. Treatment with aerosolized CpG-ODN induced an expansion of CD4+ cells in lung and was more efficacious than systemic i.p. administration against experimental lung metastases of immunogenic N202.1A mammary carcinoma cells, whereas only i.p. delivery of CpG-ODN provided anti-tumor activity, which correlated with NK cell expansion in the lung, against lung metastases of the poorly immunogenic B16 melanoma. The inefficacy of aerosol therapy to induce NK expansion was related to the presence of immunosuppressive macrophages in B16 tumor-bearing lungs, as mice depleted of these cells by clodronate treatment responded to aerosol CpG-ODN through expansion of the NK cell population and significantly reduced numbers of lung metastases. Our results indicate that tumor immunogenicity and the tumor-induced immunosuppressive environment are critical factors to the success of CpG therapy in the lung, and point to the value of routine sampling of the lung immune environment in defining an optimal immunotherapeutic strategy

Gravity in the 3+1-Split Formalism II: Self-Duality and the Emergence of the Gravitational Chern-Simons in the Boundary

We study self-duality in the context of the 3+1-split formalism of gravity with non-zero cosmological constant. Lorentzian self-dual configurations are conformally flat spacetimes and have boundary data determined by classical solutions of the three-dimensional gravitational Chern-Simons. For Euclidean self-dual configurations, the relationship between their boundary initial positions and initial velocity is also determined by the three-dimensional gravitational Chern-Simons. Our results imply that bulk self-dual configurations are holographically described by the gravitational Chern-Simons theory which can either viewed as a boundary generating functional or as a boundary effective action.Comment: 25 pages; v2: minor improvements, references adde