Damage assessment in single-nave churches and analysis of the most recurring mechanisms after the 2016–2017 central Italy earthquakes

Assessment of churches based on empirical data at a territorial scale is a suitable tool to have an overview of the seismic behaviour of this peculiar structural typology and to evaluate their current state of vulnerability. Fragility and vulnerability curves are also aimed to perform the analysis of different seismic scenarios. The paper presents a detailed typological analysis of 633 single-nave churches, as a selected subset of the database previously examined by the authors, with the aim of evaluating more in detail the influence of some parameters, such as masonry typology, church dimensions and presence of the bell tower, on the vulnerability of the overall church. Then, specific analyses are carried out to assess the influence played by single mechanisms on the definition of the overall damage index, with the focus of providing qualitative evaluations and explicit vulnerability and fragility curves related to the most recurring and significant collapse mechanisms. This is an original contribution of the paper in the field of the vulnerability assessment of churches, since nowadays little information is available in the literature about the damage levels related to specific mechanisms, while most attention is still focused on global damage

Shake table tests for the seismic fragility evaluation of hospital rooms

© 2014 John Wiley & Sons, Ltd. Health care facilities may undergo severe and widespread damage that impairs the functionality of the system when it is stricken by an earthquake. Such detrimental response is emphasized either for the hospital buildings designed primarily for gravity loads or without employing base isolation/supplemental damping systems. Moreover, these buildings need to warrant operability especially in the aftermath of moderate-to-severe earthquake ground motions. The provisions implemented in the new seismic codes allow obtaining adequate seismic performance for the hospital structural components; nevertheless, they do not provide definite yet reliable rules to design and protect the building contents. To date, very few experimental tests have been carried out on hospital buildings equipped with nonstructural components as well as building contents. The present paper is aimed at establishing the limit states for a typical health care room and deriving empirical fragility curves by considering a systemic approach. Toward this aim, a full scale three-dimensional model of an examination (out patients consultation) room is constructed and tested dynamically by using the shaking table facility of the University of Naples, Italy. The sample room contains a number of typical medical components, which are either directly connected to the panel boards of the perimeter walls or behave as simple freestanding elements. The outcomes of the comprehensive shaking table tests carried out on the examination room have been utilized to derive fragility curves based on a systemic approach

Reduction in regulatory T cells in preterm newborns is associated with necrotizing enterocolitis

BackgroundDespite multifactorial pathogenesis, dysregulation of inflammatory immune response may play a crucial role in necrotizing enterocolitis (NEC). Regulatory T cells (Tregs) are involved in immune tolerance early in life. We aimed to investigate the predicting role of Tregs in developing NEC in neonates at high risk.MethodsWe studied six newborns with a diagnosis of NEC (cases) in comparison with 52 controls (without NEC). We further classified controls as neonates with feeding intolerance (FI) and neonates without it (FeedTol). The rate of female and male neonates (sex defined as a biological attribute) was similar. We analyzed the blood frequency of Tregs (not overall numbers) at three time points: 0-3 (T0), 7-10 (T1), and 27-30 (T2) days after birth by flow cytometry. Neonates' sex was defined based on the inspection of external genitalia at birth.ResultsWe observed, at T0, a significantly lower frequency of Tregs in NEC cases (p < 0.001) compared with both FI (p < 0.01) and FeedTol controls (p < 0.01). Multivariate analysis reported that the occurrence of NEC was independently influenced by Treg frequency at birth (ss 2.98; p = 0.039).ConclusionTregs frequency and features in the peripheral blood of preterm neonates, early in life, may contribute to identifying neonates at high risk of developing NEC.ImpactRegulatory T cells may play a pivotal role in regulating the immune response in early life. Reduction of Tregs in early life could predispose preterm newborns to necrotizing enterocolitis.Early markers of necrotizing enterocolitis are still lacking. We demonstrated a predicting role of assessment of regulatory T cells in the diagnosis of this gastrointestinal emergency.Early identification of newborns at high risk of necrotizing enterocolitis through measurement of regulatory T cells may guide clinicians in the management of preterm newborns in order to reduce the development of this severe condition

Structural Determinants of the Dictyostatin Chemotype for Tubulin Binding Affinity and Antitumor Activity Against Taxane- and Epothilone-Resistant Cancer Cells

A combined biochemical, structural, and cell biology characterization of dictyostatin is described, which enables an improved understanding of the structural determinants responsible for the high-affinity binding of this anticancer agent to the taxane site in microtubules (MTs). The study reveals that this macrolide is highly optimized for MT binding and that only a few of the structural modifications featured in a library of synthetic analogues resulted in small gains in binding affinity. The high efficiency of the dictyostatin chemotype in overcoming various kinds of clinically relevant resistance mechanisms highlights its potential for therapeutic development for the treatment of drug-resistant tumors. A structural explanation is advanced to account for the synergy observed between dictyostatin and taxanes on the basis of their differential effects on the MT lattice. The X-ray crystal structure of a tubulin−dictyostatin complex and additional molecular modeling have allowed the rationalization of the structure−activity relationships for a set of synthetic dictyostatin analogues, including the highly active hybrid 12 with discodermolide. Altogether, the work reported here is anticipated to facilitate the improved design and synthesis of more efficacious dictyostatin analogues and hybrids with other MT-stabilizing agents.We thank Peter T. Northcote for peloruside A, W.-S. Fang for Flutax-2, K. H. Altmann for epothilone D, Dr. Paraskevi Giannakakou (Weill Cornell Medical Center, New York) for the 1A9, PTX10, PTX22, and A8 cell lines, and Prof. Richard Ludueñ a (University of Texas) for the HeLa βIII-transfected cells. We thank Matadero INCOVA (Segovia) for the calf brains for tubulin purification. This work was supported in part by grants BIO2013-42984-R (J.F.D.) and SAF2012-39760-C02-02 (F.G.) from Ministerio de Economia y Competitividad, grant S2010/ ́ BMD-2457 BIPEDD2 from Comunidad Autonoma de Madrid ́ (F.G. and J.F.D.), and the Swiss National Science Foundation grants 310030B_138659 and 31003A_166608 (M.O.S.). The authors acknowledge networking contribution by the COST Action CM1407 “Challenging organic syntheses inspired by naturefrom natural products chemistry to drug discovery” and the COST action CM1470. I.P. thanks the EPSRC and AstraZeneca for funding, Dr. John Leonard (AstraZeneca) for useful discussions, Dr. Stuart Mickel (Novartis) for the provision of chemicals, and the EPSRC UK National Mass Spectrometry Facility at Swansea University for mass spectra

Silica encapsulation of ZnO nanoparticles reduces their toxicity for cumulus cell-oocyte-complex expansion

Background Metal oxide nanoparticles (NPs) are increasingly used in many industrial and biomedical applications, hence their impact on occupational and public health has become a concern. In recent years, interest on the effect that exposure to NPs may exert on human reproduction has grown, however data are still scant. In the present work, we investigated whether different metal oxide NPs interfere with mouse cumulus cell-oocyte complex (COC) expansion. Methods Mouse COCs from pre-ovulatory follicles were cultured in vitro in the presence of various concentrations of two types of TiO2 NPs (JRC NM-103 and NM-104) and four types of ZnO NPs (JRC NM-110, NM-111, and in-house prepared uncoated and SiO2-coated NPs) and the organization of a muco-elastic extracellular matrix by cumulus cells during the process named cumulus expansion was investigated. Results We show that COC expansion was not affected by the presence of both types of TiO2 NPs at all tested doses, while ZnO NM-110 and NM-111 induced strong toxicity and inhibited COCs expansion at relatively low concentration. Medium conditioned by these NPs showed lower toxicity, suggesting that, beside ion release, inhibition of COC expansion also depends on NPs per se. To further elucidate this, we compared COC expansion in the presence of uncoated or SiO2-coated NPs. Differently from the uncoated NPs, SiO2-coated NPs underwent slower dissolution, were not internalized by the cells, and showed an overall lower toxicity. Gene expression analysis demonstrated that ZnO NPs, but not SiO2-coated ZnO NPs, affected the expression of genes fundamental for COC expansion. Dosimetry analysis revealed that the delivered-to-cell mass fractions for both NPs was very low. Conclusions Altogether, these results suggest that chemical composition, dissolution, and cell internalization are all responsible for the adverse effects of the tested NPs and support the importance of a tailored, safer-by-design production of NPs to reduce toxicity

Structural Determinants of the Dictyostatin Chemotype for Tubulin Binding Affinity and Antitumor Activity Against Taxane- and Epothilone-Resistant Cancer Cells

A combined biochemical, structural, and cell biology characterization of dictyostatin is described, which enables an improved understanding of the structural determinants responsible for the high-affinity binding of this anticancer agent to the taxane site in microtubules (MTs). The study reveals that this macrolide is highly optimized for MT binding and that only a few of the structural modifications featured in a library of synthetic analogues resulted in small gains in binding affinity. The high efficiency of the dictyostatin chemotype in overcoming various kinds of clinically relevant resistance mechanisms highlights its potential for therapeutic development for the treatment of drug-resistant tumors. A structural explanation is advanced to account for the synergy observed between dictyostatin and taxanes on the basis of their differential effects on the MT lattice. The X-ray crystal structure of a tubulin−dictyostatin complex and additional molecular modeling have allowed the rationalization of the structure−activity relationships for a set of synthetic dictyostatin analogues, including the highly active hybrid 12 with discodermolide. Altogether, the work reported here is anticipated to facilitate the improved design and synthesis of more efficacious dictyostatin analogues and hybrids with other MT-stabilizing agents.We thank Peter T. Northcote for peloruside A, W.-S. Fang for Flutax-2, K. H. Altmann for epothilone D, Dr. Paraskevi Giannakakou (Weill Cornell Medical Center, New York) for the 1A9, PTX10, PTX22, and A8 cell lines, and Prof. Richard Ludueñ a (University of Texas) for the HeLa βIII-transfected cells. We thank Matadero INCOVA (Segovia) for the calf brains for tubulin purification. This work was supported in part by grants BIO2013-42984-R (J.F.D.) and SAF2012-39760-C02-02 (F.G.) from Ministerio de Economia y Competitividad, grant S2010/ ́ BMD-2457 BIPEDD2 from Comunidad Autonoma de Madrid ́ (F.G. and J.F.D.), and the Swiss National Science Foundation grants 310030B_138659 and 31003A_166608 (M.O.S.). The authors acknowledge networking contribution by the COST Action CM1407 “Challenging organic syntheses inspired by naturefrom natural products chemistry to drug discovery” and the COST action CM1470. I.P. thanks the EPSRC and AstraZeneca for funding, Dr. John Leonard (AstraZeneca) for useful discussions, Dr. Stuart Mickel (Novartis) for the provision of chemicals, and the EPSRC UK National Mass Spectrometry Facility at Swansea University for mass spectra

Salicylaldoximes and anthranylaldoximes as alternatives to phenol-based estrogen receptor ligands

Estrogens play a crucial role in the development and function of female reproductive tissues. They have positive effects on the maintenance of bone mineral density, on the liver, and on the cardiovascular and central nervous systems. Selective Estrogen Receptor Modulators (SERMs) are particularly attractive as therapeutic agents because they are able to block estrogen action at those sites where stimulation would be undesirable, such as the breast and uterus, but at the same time stimulate estrogen actions in other tissues where they are desired, such as the bone and liver. Most synthetic estrogen receptor ligands possess a phenolic ring, mimicking the phenolic "Aring" of the natural ligand estradiol. In an attempt to increase the structural diversity of estrogen receptor (ER) ligands, we designed and synthesized molecules containing unprecedented replacements of the prototypical phenolic "A-ring" of estrogens with an oxime and a hydroxy- (salicylaldoximes) or aminomoieties (anthranylaldoximes), forming intramolecularly H-bonded pseudocycles. These new classes of compounds showed interesting ER binding properties on both receptor subtypes (ERα and ERβ). These results proved that the six-membered ring formed by an intramolecular hydrogen bond, and containing an exocyclic oxime OH, is an effective stereoelectronic replacement of the phenolic ring of typical ER ligands

The pigmented life of a redhead.

As a redhead I have had a personal interest in red hair, freckles and sunburns since childhood. An observation of a formaldehyde-induced fluorescence in human epidermal melanocytes initiated my scientific interest in these cells. Prota and Nicolaus demonstrated that oxidation products of cysteinyldopas are the main components of pheomelanin. Our identification of 5-S-cysteinyldopa as the source of formaldehyde-induced fluorescence of normal and pathological melanocytes started a series of investigations into this amino acid, enzymatic and non-enzymatic oxidation of catecholic compounds and the metabolism of thiols. All melanocytes with functioning tyrosinase produce cysteinyldopas and the levels of 5-S-cysteinyldopa in serum and urine are related to the size and pigment forming activity of the melanocyte population. The determination of 5-S-cysteinyldopa in serum or urine is a sensitive diagnostic method in the detection of melanoma metastasis. Some non-specific formation of cysteinyldopa is present in the body, as demonstrated by 5-S-cysteinyldopa in individuals with tyrosinase-negative albinism

Structural Determinants of the Dictyostatin Chemotype for Tubulin Binding Affinity and Antitumor Activity Against Taxane- and Epothilone-Resistant Cancer Cells

13 p.-5 fig.-2 tab.-1 graph.abst.A combined biochemical, structural, and cell biology characterization of dictyostatin is described, which enables an improved understanding of the structural determinants responsible for the high-affinity binding of this anticancer agent to the taxane site in microtubules (MTs). The study reveals that this macrolide is highly optimized for MT binding and that only a few of the structural modifications featured in a library of synthetic analogues resulted in small gains in binding affinity. The high efficiency of the dictyostatin chemotype in overcoming various kinds of clinically relevant resistance mechanisms highlights its potential for therapeutic development for the treatment of drug-resistant tumors. A structural explanation is advanced to account for the synergy observed between dictyostatin and taxanes on the basis of their differential effects on the MT lattice. The X-ray crystal structure of a tubulin–dictyostatin complex and additional molecular modeling have allowed the rationalization of the structure–activity relationships for a set of synthetic dictyostatin analogues, including the highly active hybrid 12 with discodermolide. Altogether, the work reported here is anticipated to facilitate the improved design and synthesis of more efficacious dictyostatin analogues and hybrids with other MT-stabilizing agents.This work was supported in part by grants BIO2013-42984-R (J.F.D.) and SAF2012-39760-C02-02 (F.G.) from Ministerio de Economía y Competitividad, grant S2010/BMD-2457 BIPEDD2 from Comunidad Autónoma de Madrid (F.G. and J.F.D.), and the Swiss National Science Foundation grants 310030B_138659 and 31003A_166608 (M.O.S.). The authors acknowledge networking contribution by the COST Action CM1407 “Challenging organic syntheses inspired by nature—from natural products chemistry to drug discovery” and the COST action CM1470. I.P. thanks the EPSRC and AstraZeneca for funding, Dr. John Leonard (AstraZeneca) for useful discussions, Dr. Stuart Mickel (Novartis) for the provision of chemicals, and the EPSRC UK National Mass Spectrometry Facility at Swansea University for mass spectra