Understanding the determinants of stability and folding of small globular proteins from their energetics

The results of minimal model calculations suggest that the stability and the kinetic accessibility of the native state of small globular proteins are controlled by few "hot" sites. By mean of molecular dynamics simulations around the native conformation, which simulate the protein and the surrounding solvent at full--atom level, we generate an energetic map of the equilibrium state of the protein and simplify it with an Eigenvalue decomposition. The components of the Eigenvector associated with the lowest Eigenvalue indicate which are the "hot" sites responsible for the stability and for the fast folding of the protein. Comparison of these predictions with the results of mutatgenesis experiments, performed for five small proteins, provide an excellent agreement

Role of defects in the electronic properties of amorphous/crystalline Si interface

The mechanism determining the band alignment of the amorphous/crystalline Si heterostructures is addressed with direct atomistic simulations of the interface performed using a hierarchical combination of various computational schemes ranging from classical model-potential molecular dynamics to ab-initio methods. We found that in coordination defect-free samples the band alignment is almost vanishing and independent on interface details. In defect-rich samples, instead, the band alignment is sizeably different with respect to the defect-free case, but, remarkably, almost independent on the concentration of defects. We rationalize these findings within the theory of semiconductor interfaces.Comment: 4 pages in two-column format, 2 postscript figures include

Neoadjuvant eribulin mesylate following anthracycline and taxane in triple negative breast cancer: Results from the HOPE study

Background Eribulin mesylate (E) is indicated for metastatic breast cancer patients previously treated with anthracycline and taxane. We argued that E could also benefit patients eligible for neoadjuvant chemotherapy. Methods Patients with primary triple negative breast cancer 2 cm received doxorubicin 60 mg/m2 and paclitaxel 200 mg/m2 x 4 cycles (AT) followed by E 1.4 mg/m2 x 4 cycles. Primary endpoint was pathological complete response (pCR) rate; secondary and explorative endpoints included clinical/metabolic response rates and safety, and biomarker analysis, respectively. Using a two-stage Simon design, 43 patients were to be included provided that 4 of 13 patients had achieved pCR in the first stage of the study. Results In stage I of the study 13 women were enrolled, median age 43 years, tumor size 2–5 cm in 9/13 (69%), positive nodal status in 8/13 (61%). Main grade 3 adverse event was neutropenia (related to AT and E in 4 and 2 cases, respectively). AT followed by E induced clinical complete + partial responses in 11/13 patients (85%), pCR in 3/13 (23%). Median measurements of maximum standardized uptake value (SUVmax) resulted 13, 3, and 1.9 at baseline, after AT and E, respectively. Complete metabolic response (CMR) occurred after AT and after E in 2 and 3 cases, respectively. Notably, 2 of the 5 (40%) patients with CMR achieved pCR at surgery. Immunostaining of paired pre-/post-treatment tumor specimens showed a reduction of β-catenin, CyclinD1, Zeb-1, and c-myc expression, in the absence of N-cadherin modulation. The study was interrupted at stage I due to the lack of the required patients with pCR. Conclusions Despite the early study closure, preoperative E following AT showed clinical and biological activity in triple negative breast cancer patients. Furthermore, the modulation of β-catenin pathway core proteins, supposedly outside the domain of epithelial–mesenchymal transition, claims for further investigation. Trial registration EU Clinical Trial Register, EudraCT number 2012-004956-12

Variation of the chemical and biological properties of a Technosol during seven years after a single application of compost

Technosols are composed of natural soils mixed with artificial materials and can be an inhospitable environment for the soil microbial community. The main goal of the current research was to evaluate temporal variations of Technosol quality through an integrated approach, considering all of the evaluated chemical, physical and biological characteristics for a period of seven years after a single application of compost. The soil samples were evaluated using the following parameters: pH; water content; water holding capacity; bulk density; porosity; organic matter and N contents; C/N ratio; fungal biomass; microbial biomass; respiration; metabolic quotient (qCO 2 ); and endogenous mineralisation coefficient (CEM). The overall evaluation showed that a single application of compost improved the soil quality in the short term. A decrease in Technosol quality over the long term appears to be due to deterioration of the physical and chemical properties, rather than a change in biological properties

Women working in Refrigeration, Air-Conditioning and Heat Pumps: a Worldwide Survey

The International Institute of Refrigeration (IIR) and the United Nations Environment Programme (UNEP) OzonAction undertook a worldwide survey on women in cooling. The aim was to better understand the background, motivation, challenges, and opportunities faced by women working in the in Refrigeration, Air-Conditioning and Heat Pumps (RACHP) sector. In total 810 women replied to the survey. The results indicated a high industry retention rate, with 47% of the women working in the RACHP sector for more than 10 years. The three main challenges identified were: difficulties in managing a healthy work-life balance, lack of career advancement opportunities and stereotypes or prejudice about women from clients or customers. Conversely, the most proud career achievements were earning the respect and confidence of colleagues, developing a new product/service and training/teaching people. The survey identified the challenges and opportunities faced by women working in the RACHP sector providing valuable insight to the development of new policies and initiatives to support women

Sublingual grass allergen tablet immunotherapy provides sustained clinical benefit with progressive immunologic changes over 2 years

Background: This is an interim analysis of a randomized, double-blind, placebo-controlled phase III trial with 3 years of daily treatment with grass tablet immunotherapy (GRAZAX; ALK-Abello A/S, Horsholm, Denmark) or placebo, followed by 2 years of follow-up to assess the persistent efficacy. Objective: We sought to evaluate the efficacy and safety of specific immunotherapy with grass allergen tablets compared with placebo after treatment covering 2 consecutive grass pollen seasons. Methods: The interim analyses included 351 adult participants with moderate-to-severe allergic rhinoconjunctivitis caused by grass pollen. Participants were treated with active (n = 189) or placebo (n = 162) tablets for an average of 22 months. All participants were allowed to use symptomatic rescue medication. Results: The primary efficacy analysis showed highly significant mean reductions of 36% in rhinoconjunctivitis symptom score (P Conclusion: Grass allergen tablet immunotherapy showed progressive immunologic changes and highly significant efficacy over 2 years of continued treatment

Neutralization of extracellular NAMPT (nicotinamide phosphoribosyltransferase) ameliorates experimental murine colitis

Extracellular nicotinamide phosphoribosyltransferase (eNAMPT) is increased in inflammatory bowel disease (IBD) patients, and its serum levels correlate with a worse prognosis. In the present manuscript, we show that eNAMPT serum levels are increased in IBD patients that fail to respond to anti-TNF\u3b1 therapy (infliximab or adalimumab) and that its levels drop in patients that are responsive to these therapies, with values comparable with healthy subjects. Furthermore, eNAMPT administration in dinitrobenzene sulfonic acid (DNBS)-treated mice exacerbates the symptoms of colitis, suggesting a causative role of this protein in IBD. To determine the druggability of this cytokine, we developed a novel monoclonal antibody (C269) that neutralizes in vitro the cytokine-like action of eNAMPT and that reduces its serum levels in rodents. Of note, this newly generated antibody is able to significantly reduce acute and chronic colitis in both DNBS- and dextran sulfate sodium (DSS)-induced colitis. Importantly, C269 ameliorates the symptoms by reducing pro-inflammatory cytokines. Specifically, in the lamina propria, a reduced number of inflammatory monocytes, neutrophils, Th1, and cytotoxic T lymphocytes are found upon C269 treatment. Our data demonstrate that eNAMPT participates in IBD and, more importantly, that eNAMPT-neutralizing antibodies are endowed with a therapeutic potential in IBD. Key messages: What are the new findings?Higher serum eNAMPT levels in IBD patients might decrease response to anti-TNF therapy.The cytokine-like activity of eNAMPT may be neutralized with a monoclonal antibody.Neutralization of eNAMPT ameliorates acute and chronic experimental colitis.Neutralization of eNAMPT limits the expression of IBD inflammatory signature.Neutralization of eNAMPT impairs immune cell infiltration in lamina propria

Evaluation of coffee reference genes for relative expression studies by quantitative real-time RT-PCR.

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Aggiornamenti e novità sulle conoscenze di Pancratium maritimum (Amaryllidaceae)

Pancratium maritimum L., bulbosa perenne degli ambienti dunali costieri, è un taxon relativamente recente se comparato con le specie del genere a gravitazione mediterranea. Gli studi noti su questa specie hanno analizzato vari aspetti della biologia (riproduttivi, biochimici, filogenetici, genetici, ecc.). Tuttavia, esistono ancora lacune scientifiche, tra cui l’assenza di studi su ampio areale di genetica di conservazione e sugli adattamenti eco-morfofisiologici alle condizioni di stress. Per ampliare le conoscenze su P. maritimum, la Fondazione Nando Peretti nel novembre 2012 ha finanziato un progetto triennale sulla conoscenza e la salvaguardia di questa specie (Progetto 2012-83). In questo contributo si presentano i risultati ottenuti per le diverse linee di ricerca finora affrontate, che vanno dalle analisi ad ampio areale dei popolamenti, usando un approccio sia genetico che GIS, alla caratterizzazione morfologica e eco-fisiologica di varie popolazioni

Optimal low-thrust trajectories to asteroids through an algorithm based on differential dynamic programming

In this paper an optimisation algorithm based on Differential Dynamic Programming is applied to the design of rendezvous and fly-by trajectories to near Earth objects. Differential dynamic programming is a successive approximation technique that computes a feedback control law in correspondence of a fixed number of decision times. In this way the high dimensional problem characteristic of low-thrust optimisation is reduced into a series of small dimensional problems. The proposed method exploits the stage-wise approach to incorporate an adaptive refinement of the discretisation mesh within the optimisation process. A particular interpolation technique was used to preserve the feedback nature of the control law, thus improving robustness against some approximation errors introduced during the adaptation process. The algorithm implements global variations of the control law, which ensure a further increase in robustness. The results presented show how the proposed approach is capable of fully exploiting the multi-body dynamics of the problem; in fact, in one of the study cases, a fly-by of the Earth is scheduled, which was not included in the first guess solution