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In recent years, anti-complement drugs and neonatal fc receptor (FcRn) inhibitors have shown promising results in the treatment of generalized MG (gMG), especially in patients refractory to standard immunotherapies. However, a small part of these patients, could be unresponsive also to new targeted molecular therapies. We conducted a retrospective case series analysis involving gMG patients referred to our neuromuscular centre treated with anti-complement drugs (Eculizumab, Ravulizumab and Zilucoplan) and FcRn inhibitors (Efgartigimod, Rozanolixizumab), who showed unsatisfactory response or had to stop treatments because of adverse events. Data concerning demographic and clinical characteristics, clinical scales, adverse events, were collected. Of 23 gMG patients treated with new targeted drugs, 7 (30%) (3 males, 4 females, mean age 59.1, range 31-79) discontinued the treatment. Three patients had MGFA class IIIA while 4 patients IIIB. All patients underwent both treatments. 6/7 patient showed no clinical response with anti-complement treatment. One patient, despite MG symptoms improvement, started to complain of progressive somnolence and ideomotor slowing one month after anti-complement therapy start, that lead to withdrawal. FcRn inhibitors were discontinued in 5/7 patients for unsatisfactory clinical response. The other 2 patients discontinued because of adverse events: one patient developed endocarditis, while another patient had continuous diarrhea. Despite the safety and efficacy of new available drugs for gMG, a small percentage of patients are still unresponsive or show drug-related adverse effects. Further studies on larger samples are warranted, aimed to detect biomarkers of disease activity and predictors of treatment responsiveness. [ABSTRACT FROM AUTHOR]

Watchkeeping schedules are essential for maintaining submarine operations, but come with human risk factors including, disrupted sleep, circadian misalignment, and cognitive deficits. There is now an emerging literature examining the strengths and weaknesses of submarine watchkeeping schedules trialled in the field and under simulated laboratory conditions. The aim of this scoping review was to summarise this literature. A systematic search of peer-reviewed journal articles and industry reports listed in MEDLINE, PsychINFO, PubMed, Scopus, Embase and Google Scholar undertaken in May 2023 returned 7298 papers. Following screening procedures, 13 studies were identified for inclusion. The findings revealed that sleep was sufficiently preserved regardless of watchkeeping schedule (total sleep time = 5.46–7.89 h), circadian misalignment was greater for non-24 h schedules, and longer off-watch periods were associated with better cognitive performance. Taken together, when comparing between watchkeeping schedules, the present findings suggest that the 4 h-on/8 h-off and 8 h-on/16 h-off schedules may be a good compromise when balancing human risk factors and operational demands. However, submarines are complex and challenging environments to study and there is a need to expand the literature. More research comparing watchkeeping schedules is needed. Future studies should focus on cognitive performance measures, such as problem-solving, prioritisation and executive decision-making to address present shortcomings, and an examination of sleep and circadian countermeasures to assist with adaptation either initiated pre-deployment or by modifying the submarine environment itself should be considered. [ABSTRACT FROM AUTHOR]

As evidence grows supporting certain mechanisms of change in psychological treatments and we improve statistical approaches to measuring them, it is important that we also explore how mechanisms and processes are related to each other, and how they together affect treatment outcomes. To answer these questions about interrelating processes and mechanisms, we need to take advantage of frequent assessment and modeling techniques that allow for an examination of the influence of one mechanism on another over time. Within cognitive behavioral therapy, studies have shown support for both decentering, the ability to observe thoughts and feelings as objective events in the mind, and anticipatory processing, the repetitive thinking about upcoming social situations, as potentially related mechanisms of change. Therefore, the current study examined weekly ratings of decentering and a single-item anticipatory processing question to examine the interrelation among these change mechanisms in 59 individuals who received a 12-weeks of Cognitive Behavioral Group Therapy for social anxiety disorder. Overall, these results found that both anticipatory processing and decentering changed over the course therapy for clients. Change in both anticipatory processing and decentering was related to outcome. The bivariate latent difference score analysis showed that anticipatory processing was a leading indicator of change in decentering, but not the reverse, indicating that change in anticipatory processing is leading to change in decentering. It may be that with the focus on cognitive reappraisal in this treatment, that reducing anticipatory processing is freeing up the cognitive resources for decentering to occur. [ABSTRACT FROM AUTHOR]

Highlights • The ES of climate regulation provided by GI has been analyzed in Rome, Italy. • A UHI phenomenon is evident in Rome during the hot Mediterranean summer conditions. • Cooling capacity differs between peri-urban forest, urban forest and street trees. • NDVI and the surface covered by trees are the main indicators of this ES. • Specific GI management policies are required in Mediterranean cities. Abstract The Urban Heat Island (UHI) effect is one of the main environmental impacts of urbanization, affecting directly human health and well-being of the city dwellers, and also contributing to worsen environmental quality. As a key strategy to address sustainable urban development, the EU has advocated the development of Nature-Based solutions, such as the implementation of Green Infrastructure (GI), which can deliver a wide range of Regulating Ecosystem Services (ES). In this article, the ES of climate regulation provided by GI has been analyzed in the Municipality of Rome, Italy, characterized by a complex territory and by a Mediterranean climate. The methodological approach allowed to characterize the UHI and to analyze its features in a spatially explicit way and on a seasonal basis, through the Land Surface Temperature (LST) derived from Landsat-8 data. The cooling capacity of different GI elements (peri-urban forest, urban forest, street trees), as well as the effect of vegetation cover and tree diversity on the provision of this regulating ES were assessed. The results show that GI significantly mitigates the hot urban climate during summer, with an effect that is dependent on the GI element and the environmental constrains to which it is exposed. NDVI and tree cover resulted the main indicators of the provision of the ES of climate regulation, highlighting that GI elements such as urban and peri-urban forests have the highest potential to provide this ES in a Mediterranean city. In the context of the Mapping and Assessment of Ecosystems and their Services (MAES) process, our results lend support to claims that GI is important for an ecosystem-based climate adaptation strategy in urban environments, contributing to the definition of knowledge based criteria and indicators, relevant for decision-making in Mediterranean cities. [ABSTRACT FROM AUTHOR]

Highlights • ESBL-PE sepsis was predicted by admission at ICU and ESBL-PE colonization. • Neonates infected with ESBL-PE had significantly high mortality. • ESBL-producing Klebsiella pneumoniae (ST45) carrying bla CTX-M-15 were predominant. • Whole genome SNP analysis revealed clonal origin in 50% of ESBL-PE paired cases with similar sequence type. Abstract The study was conducted to establish predictors of extended-spectrum beta-lactamase-producing Enterobacteriaceae (ESBL-PE) neonatal sepsis and mortality in a tertiary hospital, Tanzania. Between July and December 2016, blood culture was performed in neonates with clinical features of sepsis and neonates/mothers/guardians were screened for ESBL colonization. Selected isolates underwent whole genome sequencing to investigate relatedness. Logistic regression analysis was performed to determine predictors for ESBL-PE associated neonatal sepsis and mortality. Neonatal ESBL-PE sepsis was detected in 32(10.5%) of the 304 neonates investigated. Neonatal ESBL-PE sepsis was independently predicted by admission at the Intensive care Unit and positive mother and neonate ESBL-PE colonization. Deaths occurred in 55(18.1%) of neonates. Neonates infected with ESBL-PE, admitted at ICU, increased age and those transferred from other centres had significantly high mortality rates. Gram-negative bacteria formed the majority (76%) of the isolates, of which 77% were ESBL-PE. Virulent Klebsiella pneumoniae ST45 carrying bla CTX-M-15 were commonly isolated from neonates. Klebsiella pneumoniae (ST45) were the predominant cause of ESBL-PE neonatal sepsis and mortality. Improved infection control and antibiotic stewardship are crucial in controlling the spread of resistant strains. Rapid diagnostic tests to detect ESBL-PE in low-income countries are needed to guide treatment and reduce ESBL-PE-associated mortality. [ABSTRACT FROM AUTHOR]

Only two trials have compared acceptance and commitment therapy (ACT) and traditional cognitive behavior therapy (tCBT) in the treatment of social anxiety disorder (SAD), with both finding no significant differences. These trials did not examine effects on observer-rated behavioral outcomes and did not explicitly quantify the dose of exposure therapy within each treatment. In a replication trial, one hundred and two individuals with SAD (per DSM-IV criteria) were randomized to 12 sessions of ACT ( n  = 49) or tCBT ( n  = 53) controlling for exposure dose and assessing behavioral outcomes. Assessments were completed at pre- and post-treatment using clinician-rated and self-report measures of social anxiety, quality of life, and overall functioning. Observer-rated behavioral measures of social performance were completed for a subsample of participants. Results indicated that participants across conditions received equivalent doses of exposure. Those who received tCBT evidenced greater improvements in self-reported social anxiety symptoms and overall functioning, which contrasts with prior studies finding no differences between tCBT and ACT in the treatment of social anxiety. Medium effect sizes, while not statistically significant, indicate that ACT participants may have had greater improvements in observer-rated social behavior than tCBT participants. The discrepancy between these symptom and behavioral outcomes, building upon prior literature, calls for more research to assess the differences between tCBT and ACT treatments in behavioral domains. [ABSTRACT FROM AUTHOR]

Several international initiatives, including the European Biodiversity Strategy to 2020, promote the identification and mapping of ecosystems as basic tools for the conservation of biodiversity and related services. On coarse scales, the spatial representation of ecosystems is usually based on broad land cover categories that largely overlook important ecological and biogeographic features of the biotic communities they are meant to exemplify. This paper presents a nationwide ecosystem mapping approach that promotes a degree of thematic detail, which is more suited than that found in the continental maps to meeting biodiversity conservation targets in Italy. The approach is based on the rationale that current and potential vegetation cover are valuable proxies for outlining ecosystems. The resulting Ecosystem Map of Italy includes 43 types of forest ecosystems instead of the 5 woodland, forest and other wooded land types recognized at the European level. We outline the expected advantages of this enhanced thematic detail for a number of conservation purposes and highlight how the resulting maps may help to meet biodiversity conservation targets at the national level. In particular, we refer to the assessment of conservation status, the definition of restoration priorities, the planning of green infrastructure and the identification of collapse risks for the ecosystems identified. Comprehensively, the definition, characterization and assessment of ecosystem types represent the carrying structure of the recently launched national system of natural capital accounting. [ABSTRACT FROM AUTHOR]

Neuroendocrine neoplasms represent a heterogeneous group of rare tumors, more frequently arising from gastroenteropancreatic tract and lungs. At the time of diagnosis, 20% of cases are metastatic, and 10% of cases are considered as cancer of unknown primary origin. Several immunohistochemical markers are routinely used to confirm the neuroendocrine differentiation, first among all Synaptophysin and Chromogranin-A; on the other hand, different immunohistochemical markers are used to establish primary anatomical site, as TTF1, CDX2, Islet-1 and Calcitonin, but no marker is available in order to distinguish among different sites of the digestive tract. DOG1 (discovered on GIST-1) is a gene normally expressed in interstitial cells of Cajal and, in routine practice, DOG1 immunostaining is used in diagnosis of GIST (gastrointestinal stromal tumor). DOG1 expression has been described in several neoplasms other than GIST, both in mesenchymal and epithelial neoplasms. In the present study, DOG1 immunostaining has been performed in a large cohort of neuroendocrine neoplasms, including neuroendocrine tumors and neuroendocrine carcinomas, in order to evaluate frequency, intensity and pattern of expression in different anatomical site and in different tumor grade. DOG1 expression was detected in a large percentage of neuroendocrine tumors, with statistically significant association between DOG1 expression and gastrointestinal tract neuroendocrine tumors. As a consequence, DOG1 could be included in marker panel for the identification of primary site in neuroendocrine metastases of unknown primary origin; moreover, these results recommend careful evaluation of DOG1 expression in gastrointestinal neoplasms, in particular in differential diagnosis between epithelioid GIST and neuroendocrine tumors. [ABSTRACT FROM AUTHOR]

The study of soil quality requires the establishment of quality standards. To this end, several authors have highlighted the need to create databases of quality indicators, such as biochemical properties, for different types of undisturbed soils under various climates and to establish standardised methodologies for their development. In Spain, studies of the quality of native soils were initiated > 15 years ago by several groups of authors from differing locations, but little is known regarding the biochemical characteristics of native soils in Catalonia (NE Spain). This study examines representative, minimally disturbed soils from Catalonia with a wide range of organic carbon contents. We examined the total and extractable organic carbon contents, total and extractable carbohydrates contents, enzyme activities (β-glucosidase, β-galactosidase, BAA-protease and urease), microbial biomass carbon and basal respiration of ten selected soils. Statistical analyses were applied to absolute values (i.e., per g of soil) and relative values (i.e., per g of soil organic carbon). The aim of this work was to determine the dependence of these properties on the organic matter content and the suitability of the relative values as soil quality indicators. The biochemical and microbiological parameter values of the native Catalan soils showed unusually wide ranges, although all of the values were similar to those already published for native soils in other Mediterranean climate areas. Overall, the sampled soils could be distinguished by their contents of organic carbon and total and extractable carbohydrates, rather than by their enzyme activities or microbiological variables; nevertheless, when the relative values were considered, the soils could be distinguished by their specific enzyme activities, particularly that of β-glucosidase, and by the labile proportion of organic matter. With the exception of the total carbohydrates/C ratio, the biochemical and microbiological parameters, expressed as functions of soil organic carbon content, were useful in distinguishing groups of native soils according to field observations and soil physicochemical properties. [ABSTRACT FROM AUTHOR]

Objective Mindfulness-informed cognitive behavioral interventions for obesity are promising. However, results on the efficacy of such treatments are inconsistent which in part may be due to their substantially different methods of practice. This study is the first direct comparison of two theoretically distinct mindfulness-based weight loss approaches: increasing awareness of homeostatic/innate physiological cues versus hedonic/externally-driven cues for eating. Methods Overweight adults were randomized to one of three group-based workshops: Mindful Eating (ME; n = 21), Mindful Decision-Making (MD; n = 17), or active standard behavioral control (SC; n = 19). Outcome measures included percent weight change and reduction in caloric intake from baseline to 6 weeks. Results Differences in weight loss and calorie reduction did not differ significantly among groups. However, the difference in weight loss between the MD and ME groups trended towards significance, with medium-large effect sizes. Conclusions Results provide modest preliminary evidence for the utility of mindful decision-making strategies over mindful eating for short-term weight loss and calorie reduction. [ABSTRACT FROM AUTHOR]

Urban and periurban forests, which are integrated within the concept of Green Infrastructure, provide important Ecosystem Services, including air purification. In this study, we quantified the Ecosystem Service of particulate matter (PM 10 ) and Ozone (O 3 ) removal from urban and periurban forests in ten metropolitan cities in Italy, and its total monetary value. In order to gain a better understanding of how Ecosystem Services can be regulated on a wider scale, the vegetation ecosystem types were grouped into Physiognomic-Structural Categories of Vegetation according to morphofunctional criteria. The pollution removal was mapped using a remote sensing and GIS approach, by applying a deposition model and a stomatal flux model. We estimated, for the ten metropolitan cities, an overall pollution abatement of 7150 Mg of PM 10 and 30,014 Mg of O 3 in the year 2003, which was an extremely hot year. Our findings indicate that structural characteristics (i.e. Leaf Area Index) and functional diversity, linked to stomatal conductance, exert a marked influence on the provision of the regulating Ecosystem Services, whose total monetary value was estimated to be equal to 47 and 297 million USD for PM 10 and O 3 removal, respectively. This study represent the first national-scale assessment of the Ecosystem Services of air pollution removal in Europe, thus providing information that may be useful to stakeholders to manage Green Infrastructure more efficiently. [ABSTRACT FROM AUTHOR]

Green infrastructures (GI), such as urban forests, deliver ecosystem services (ESs) and benefits. Among ESs the amelioration of urban air quality through the removal of air pollutants deserves large attention owing to the positive impact on human well-being. Experimental data, as detailed descriptions of functional parameters, are needed for reliable quantification of ESs. The present study was carried out in the metropolitan area of Rome, considering an urban and a periurban forest. Both forests are dominated by Quercus ilex L., which has been chosen as target species for its wide natural distribution in the Mediterranean Basin, as well as for its widespread use in urban contexts. The two studied sites were characterized by different environmental stressor and forest management practices, resulting in different trends of leaf gas exchanges, photosystems functionality and plant water status. During spring, gas exchanges were lower in the urban than in the periurban forest, due to higher air temperature and vapor pressure deficit in the latter site. During summer, instead, in the periurban area the functionality of Q. ilex was affected by drought, which did not occur in the urban forest due to higher summer rainfalls as well as periodic irrigations. The water use efficiency was basically lower in the urban park, as well as the photosystems functionality. Differences in the intensity of the main phenological phases were also highlighted. Our results point out that the two GIs fulfill a complementary role in the ESs provision in the metropolitan area of Rome, in relation to the ozone removal and the resulting air quality improvement and climate regulation. [ABSTRACT FROM AUTHOR]

Neuroendocrine carcinomas show overlapping morphological and immunohistochemical features independently of their site of origin, which makes identification of the primary location problematic when they are diagnosed as metastases of unknown origin. Neuroendocrine carcinomas are easily morphologically differentiated from neuroendocrine tumors in surgical material, although this distinction can be difficult when using small biopsy specimens. The diagnostic usefulness of different transcription factors as site-specific markers or as discriminating markers between neuroendocrine carcinomas and neuroendocrine tumors has been previously studied with sometimes contradictory results. In this respect, the role of achaete-scute homolog 1 has been poorly investigated, although some recent findings demonstrate its expression in neuroendocrine carcinomas. Using immunohistochemistry and quantitative real-time polymerase chain reaction, we investigated the expression of achaete-scute homolog 1 in 335 neuroendocrine neoplasms (194 neuroendocrine carcinomas and 141 neuroendocrine tumors) of different sites, to check its possible utility as diagnostic marker. High concordance between immunohistochemical and molecular findings was found. Achaete-scute homolog 1 expression was identified in 82% of lung neuroendocrine carcinomas and 70% of extrapulmonary neuroendocrine carcinomas. Achaete-scute homolog 1 was not detected in any gastroenteropancreatic neuroendocrine tumor and was found in only a minority of lung carcinoids. The diagnostic sensitivity and specificity of achaete-scute homolog 1 expression were 82.4% and 89.7% in distinguishing neuroendocrine carcinomas from neuroendocrine tumors of the lung, 40.6% and 100% to differentiate extrapulmonary neuroendocrine carcinomas from neuroendocrine tumors, and 82.4% and 59.4% in distinguishing lung from extrapulmonary neuroendocrine carcinomas. Our data suggest that achaete-scute homolog 1 is not a site-specific marker. However, achaete-scute homolog 1 may be proposed as a diagnostic marker of poor differentiation and may help to differentiate neuroendocrine carcinomas from neuroendocrine tumors in difficult cases. [ABSTRACT FROM AUTHOR]

Abstract: Limestone quarrying reduces the land''s capacity to support a complete functional ecosystem. Adding sewage sludge to mining residues facilitates the establishment of a vegetation cover and can stimulate C and N cycling. We aimed to evaluate the effects of three composted and three thermally dried sewage sludges, on some biological properties of two types of debris (extraction soil and trituration soil) from a limestone quarry. Lysimeters filled with debris-sludge mixtures and control soils were sampled immediately after preparation and after being left in the open for 13 months. Total carbohydrates (TCH), 0.5M K2SO4 extractable (ECH) carbohydrates, 0.5M K2SO4 extractable organic C (EOC), microbial biomass carbon (MBC), microbial respiration (MR), β-glucosidase activity and β-galactosidase activity were determined immediately after sampling. The treated soils were also analyzed for their more general physicochemical characteristics. Adding sewage sludge clearly improved the physicochemical and biological properties of the residual soil and the effect of the type of sludge was greater than that of the type of soil. The sludge effect was generally more durable over the trituration soil. The sludge effect decreased the most in MR and EOC followed by MBC and ECH. Total carbohydrates showed the least enhancement but the sludge effect on this endpoint had the smaller decrease with time. Root exudates and plant debris contributed to β-glucosidase and β-galactosidase activities in the treated soils. Activities present in mixtures partly corresponded to enzymes free in the soil aqueous face. β-Glucosidase was also partly associated with humified organic matter. Thirteen months after sludge addition a fraction of the organic matter present in soils was still moderately labile. Results observed in BMC and MR suggests the sludge did not cause major toxic effects on residual soils. The sludge effect differed with the pre and post treatments of the sludges; thermal drying made the sludge organic matter more easily decomposable. [Copyright &y& Elsevier]

• The ecosystem service of microclimate regulation of green areas in 601 european cities has been assessed. • The model simulates the temperature difference between a baseline and a no-vegetation scenario. • The indicator estimates the amount of vegetation needed to cool urban temperature by a certain degree. • Green areas cool european cities by 1.07 °C on average, and up to 2.9 °C. • In order to achieve a 1 °C drop in urban temperatures, a tree cover of at least 16% is required. The Urban Heat Island (UHI) effect is one of the most harmful environmental hazards for urban dwellers. Climate change is expected to increase the intensity of the UHI effect. In this context, the implementation of Urban Green Infrastructure (UGI) can partially reduce UHI intensity, promoting a resilient urban environment and contributing to climate change adaptation and mitigation. In order to achieve this result, there is a need to systematically integrate UGI into urban planning and legislation, but this process is subject to the availability of widely applicable, easily accessible and quantitative evidence. To offer a big picture of urban heat intensity and opportunities to mitigate high temperatures, we developed a model that reports the Ecosystem Service (ES) of microclimate regulation of UGI in 601 European cities. The model simulates the temperature difference between a baseline and a no-vegetation scenario, extrapolating the role of UGI in mitigating UHI in different urban contexts. Finally, a practical, quantitative indicator that can be applied by policymakers and city administrations has been elaborated, allowing to estimate the amount of urban vegetation that is needed to cool summer temperatures by a certain degree. UGI is found to cool European cities by 1.07 °C on average, and up to 2.9 °C, but in order to achieve a 1 °C drop in urban temperatures, a tree cover of at least 16% is required. The microclimate regulation ES is mostly dependent on the amount of vegetation inside a city and by transpiration and canopy evaporation. Furthermore, in almost 40% of the countries, more than half of the residing population does not benefit from the microclimate regulation service provided by urban vegetation. Widespread implementation of UGI, in particular in arid regions and cities with insufficient tree cover, is key to ensure healthy urban living conditions for citizens. [ABSTRACT FROM AUTHOR]

The investigation of the interactions between cells and active materials is pivotal in the emerging 3D printing-biomaterial application fields. Here, lipidomics has been used to explore the early impact of alginate (ALG) hydrogel architecture (2D films or 3D printed scaffolds) and the type of gelling agent (CaCl 2 or FeCl 3) on the lipid profile of human fibroblasts. 2D and 3D ALG scaffolds were prepared and characterized in terms of water content, swelling, mechanical resistance and morphology before human fibroblast seeding (8 days). Using a liquid chromatography-triple quadrupole-tandem mass spectrometry approach, selected ceramides (CER), lysophosphatidylcholines (LPC), lysophosphatidic acids (LPA) and free fatty acids (FFA) were analyzed. The results showed a clear alteration in the CER expression profile depending of both the geometry and the gelling agent used to prepare the hydrogels. As for LPCs, the main parameter affecting their distribution is the scaffold architecture with a significant decrease in the relative expression levels of the species with higher chain length (C20 to C22) for 3D scaffolds compared to 2D films. In the case of FFAs and LPAs only slight differences were observed as a function of scaffold geometry or gelling agent. Variations in the cell membrane lipid profile were observed for 3D cell cultures compared to 2D and these data are consistent with activation processes occurring through the mutual interactions between fibroblasts and ALG support. These unknown physiologically relevant changes add insights into the discussion about the relationship between biomaterial and the variations of cell biological functions. • 2D films and 3D printed scaffolds from alginate. • LC-MS/MS lipid investigation on ALG action mechanism on fibroblasts. • Ceramides modulation after cell-biomaterial interactions. [ABSTRACT FROM AUTHOR]

• Mismatch of Regulating Ecosystem Services varies considerably in the city structure. • Urban planning strategies generally do not consider the Ecosystem Services mismatch. • Mapping priority areas helps to exploit the multifunctionality of Ecosystem Services. • Green Infrastructure also provides important economic benefits to the society. • Targeted urban planning improves human health and well-being. Balancing the ecosystem service (ES) mismatch should be a goal of sustainable urban planning. However, (i) many urban areas lack an assessment of this mismatch and (ii) scientific findings are not easily translatable into good practices. In this study, we assessed the mismatch for two regulating ESs—regulation of air quality (intended as PM 10 removal by vegetation) and urban temperature regulation—in the Municipality of Rome (Italy). The spatial distribution of the ES mismatch was then used to identify priority intervention areas (PIAs), namely those that would benefit the most from targeted urban planning. To do so, we computed composite indicators of supply and demand for each ES, adopting a process-based approach. Additionally, a monetary valuation of the related benefits associated with urban green infrastructure is provided. Our findings suggest that regulation of air quality falls short in highly urbanized areas, whereas a mismatch in urban temperature regulation is observed in both highly urbanized areas and some agricultural lands. The majority of the PIAs fall in the eastern and southern sectors of the Municipality of Rome. Our findings also indicate that urban planning should consider urban regeneration practices and reforestation of existing green areas within the PIAs. Sustainable urban planning can produce remarkable environmental benefits, as estimated, for the Municipality of Rome, up to several hundred million euros per year, depending on the methodology used for the monetary valuation. [ABSTRACT FROM AUTHOR]

Like normal hematopoietic stem cells, leukemic stem cells depend on their bone marrow (BM) microenvironment for survival, but the underlying mechanisms remain largely unknown. We have studied the contribution of nestin+ BM mesenchymal stem cells (BMSCs) to MLL-AF9-driven acute myeloid leukemia (AML) development and chemoresistance in vivo. Unlike bulk stroma, nestin+ BMSC numbers are not reduced in AML, but their function changes to support AML cells, at the expense of non-mutated hematopoietic stem cells (HSCs). Nestin+ cell depletion delays leukemogenesis in primary AML mice and selectively decreases AML, but not normal, cells in chimeric mice. Nestin+ BMSCs support survival and chemotherapy relapse of AML through increased oxidative phosphorylation, tricarboxylic acid (TCA) cycle activity, and glutathione (GSH)-mediated antioxidant defense. Therefore, AML cells co-opt energy sources and antioxidant defense mechanisms from BMSCs to survive chemotherapy. • Nestin+ BMSCs support leukemogenesis and chemoresistance • BMSCs support metabolic requirements of LSCs • BMSCs provide LSCs with essential antioxidant defense from chemotherapy • GSH and GSH peroxidases underlie BMSC-derived antioxidant AML protection Forte et al. reveal that nestin+ bone marrow stromal cells directly contribute to leukemogenesis and chemotherapy resistance in an in vivo model of acute myeloid leukemia. Nestin+ BMSCs support leukemic stem cells through a dual mechanism of increased bioenergetic capacity through OXPHOS and TCA and glutathione-dependent antioxidant defense. [ABSTRACT FROM AUTHOR]

The lacZ reversion assay in Escherichia coli measures point mutations that occur by specific base substitutions and frameshift mutations. The tester strains cannot use lactose as a carbon source (Lac − ), and revertants are easily detected by growth on lactose medium (Lac + ). Six strains identify the six possible base substitutions, and five strains measure +G, −G, −CG, +A and −A frameshifts. Strong mutagens give dose-dependent increases in numbers of revertants per plate and revertant frequencies. Testing compounds that are arguably nonmutagens or weakly mutagenic, we often noted statistically significant dose-dependent increases in revertant frequency that were not accompanied by an absolute increase in numbers of revertants. The increase in frequency was wholly ascribable to a declining number of viable cells owing to toxicity. Analysis of the conditions revealed that the frequency of spontaneous revertants is higher when there are fewer viable cells per plate. The phenomenon resembles “adaptive” or “stress” mutagenesis, whereby lactose revertants accumulate in Lac − bacteria under starvation conditions in the absence of catabolite repression. Adaptive mutation is observed after long incubation and might be expected to be irrelevant in a standard assay using 48-h incubation. However, we found that elevated revertant frequencies occur under typical assay conditions when the bacterial lawn is thin, and this can cause increases in revertant frequency that mimic chemical mutagenesis when treatments are toxic but not mutagenic. Responses that resemble chemical mutagenesis were observed in the absence of mutagenic treatment in strains that revert by different frameshift mutations. The magnitude of the artifact is affected by cell density, dilution, culture age, incubation time, catabolite repression and the age and composition of media. Although the specific reversion assay is effective for quickly distinguishing classes of mutations induced by potent mutagens, its utility for discerning effects of weak mutagens may be compromised by the artifact. [ABSTRACT FROM AUTHOR]

[Display omitted] 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) has been identified as the primary enzyme responsible for the activation of hepatic cortisone to cortisol in specific peripheral tissues resulting in the concomitant antagonism of insulin action within these tissues. Dysregulation of 11β-HSD1, particularly in adipose tissues, has been associated with metabolic syndrome and type 2 diabetes mellitus. Therefore, inhibition of 11β-HSD1 with a small nonsteroidal molecule is therapeutically desirable. Implementation of a scaffold-hopping approach revealed a three-point pharmacophore for 11β-HSD1 that was utilized to design a steroid mimetic scaffold. Reiterative optimization provided valuable insight into the bioactive conformation of our novel scaffold and led to the discovery of INCB13739. Clinical evaluation of INCB13739 confirmed for the first time that tissue-specific inhibition of 11β-HSD1 in patients with type 2 diabetes mellitus was efficacious in controlling glucose levels and reducing cardiovascular risk factors. [ABSTRACT FROM AUTHOR]

Sodium 4-phenylbutyrate (4PBA) corrects trafficking of ΔF508-CFTR in Cystic Fibrosis (CF) epithelia, which is hypothesized to, at least in part, result from increased expression of Hsp70 (stress-induced 70 kDa heat shock protein). To identify other 4PBA-regulated proteins that may promote correction of ΔF508 trafficking, we performed differential display RT-PCR on mRNA from IB3-1 CF bronchiolar epithelial cells treated for 0-24 h with 1 mm 4PBA. In this screen, a STAT-3 (signal transducer and activator of transcription-3)-interacting protein, StIP-1 that regulates STAT-3 activation had transiently increased expression. StIP-1 is identical to Elongator protein 2 (Elp2), a component of the Elongator complex that regulates RNA polymerase II. Previous studies have suggested that Elongator regulates Hsp70 mRNA transcription, and that the Hsp70 promoter contains functional STAT-3-binding sites. We therefore tested the hypothesis that 4PBA increases Hsp70 expression by an Elongator- and STAT-3-dependent mechanism. 4PBA treatment of IB3-1 CF bronchiolar epithelial cells caused transiently increased expression of Hsp70 protein, as well as Elp2 protein and mRNA. Elp2 depletion by transfection of small interfering RNAs, reduced both Elp2 and Hsp70 protein expression. 4PBA also caused transient activation of STAT-3, and increased abundance of nuclear proteins that bind to the STAT-3-responsive element of the Hsp70 promoter. Luciferase reporter assays demonstrated that both Elp2 overexpression and 4PBA increase Hsp70 promoter activity, while Elp2 depletion blocked the ability of 4PBA to stimulate Hsp70 promoter activity. Together, these data suggest that Elp2 and STAT-3 mediate, at least in part, the stimulation of Hsp70 expression by 4PBA. [ABSTRACT FROM AUTHOR]

Abstract: A serendipitous discovery that the metalloprotease binding profile of a novel class of 2-carboxamide-3-hydroxamic acid piperidines could be significantly attenuated by the modification of the unexplored P1 substituent enabled the design and synthesis of a novel 2-carboxamide-1-hydroxamic acid cyclohexyl scaffold core that exhibited excellent HER-2 potency and unprecedented MMP-selectivity that we believe would not have been possible via conventional P1′ perturbations. [Copyright &y& Elsevier]

Abstract: A series of β-sulfonamide piperidine hydroxamates were prepared and shown to be potent inhibitors of the human epidermal growth factor receptor-2 (HER-2) sheddase with excellent selectivity against MMP-1, −2, −3, and −9. This was achieved by exploiting subtle differences within the otherwise highly conserved binding pocket of the active sites within the metalloprotease family. In addition, it was discovered that the introduction of polarity to the P1 and groups reduced the projected human clearance. [Copyright &y& Elsevier]

Abstract: In an effort to obtain a MMP selective and potent inhibitor of HER-2 sheddase (ADAM-10), the P1′ group of a novel class of (6S,7S)-7-[(hydroxyamino)carbonyl]-6-carboxamide-5-azaspiro[2.5]octane-5-carboxylates was attenuated and the structure–activity relationships (SAR) will be discussed. In addition, it was discovered that unconventional perturbation of the P2′ moiety could confer MMP selectivity, which was hypothesized to be a manifestation of the P2′ group effecting global conformational changes. [Copyright &y& Elsevier]