Greedy kernel methods for accelerating implicit integrators for parametric ODEs

We present a novel acceleration method for the solution of parametric ODEs by single-step implicit solvers by means of greedy kernel-based surrogate models. In an offline phase, a set of trajectories is precomputed with a high-accuracy ODE solver for a selected set of parameter samples, and used to train a kernel model which predicts the next point in the trajectory as a function of the last one. This model is cheap to evaluate, and it is used in an online phase for new parameter samples to provide a good initialization point for the nonlinear solver of the implicit integrator. The accuracy of the surrogate reflects into a reduction of the number of iterations until convergence of the solver, thus providing an overall speedup of the full simulation. Interestingly, in addition to providing an acceleration, the accuracy of the solution is maintained, since the ODE solver is still used to guarantee the required precision. Although the method can be applied to a large variety of solvers and different ODEs, we will present in details its use with the Implicit Euler method for the solution of the Burgers equation, which results to be a meaningful test case to demonstrate the method's features

Gadolinium tagged osteoprotegerin-mimicking peptide: a novel magnetic resonance imaging biospecific contrast agent for the inhibition of osteoclastogenesis and osteoclast activity

The control of osteoblast/osteoclast cross-talk is crucial in the bone remodelling process and provides a target mechanism in the development of drugs for bone metabolic diseases. Osteoprotegerin is a key molecule in this biosignalling pathway as it inhibits osteoclastogenesis and osteoclast activation to prevent run-away bone resorption. This work reports the synthesis of a known osteoprotegerin peptide analogue, YCEIEFCYLIR (OP3-4), and its tagging with a gadolinium chelate, a standard contrast agent for magnetic resonance imaging. The resulting contrast agent allows the simultaneous imaging and treatment of metabolic bone diseases. The gadolinium-tagged peptide was successfully synthesised, showing unaltered magnetic resonance imaging contrast agent properties, a lack of cytotoxicity, and dose-dependent inhibition of osteoclastogenesis in vitro. These findings pave the way toward the development of biospecific and bioactive contrast agents for the early diagnosis, treatment, and follow up of metabolic bone diseases such as osteoporosis and osteosarcoma

In vitro activity of pertuzumab in combination with trastuzumab in uterine serous papillary adenocarcinoma

BACKGROUND: Uterine serous papillary adenocarcinoma (USPC) is a rare but highly aggressive variant of endometrial cancer. Pertuzumab is a new humanised monoclonal antibody (mAb) targeting the epidermal growth factor type II receptor (HER2/neu). We evaluated pertuzumab activity separately or in combination with trastuzumab against primary USPC cell lines expressing different levels of HER2/neu. METHODS: Six USPC cell lines were assessed by immunohistochemistry (IHC), flow cytometry, and real-time PCR for HER2/neu expression. c-erbB2 gene amplification was evaluated using fluorescent in situ hybridisation (FISH). Sensitivity to pertuzumab and trastuzumab-induced antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) was evaluated in 5 h chromium release assays. Pertuzumab cytostatic activity was evaluated using proliferation-based assays. RESULTS: Three USPC cell lines stained heavily for HER2/neu by IHC and showed amplification of the c-erbB2 gene by FISH. The remaining FISH-negative USPCs expressed HER2/neu at 0/1\ufe levels. In cytotoxicity experiments against USPC with a high HER2/neu expression, pertuzumab and trastuzumab were similarly effective in inducing strong ADCC. The addition of complementcontaining plasma and interleukin-2 increased the cytotoxic effect induced by both mAbs. In low HER2/neu USPC expressors, trastuzumab was more potent than pertuzumab in inducing ADCC. Importantly, in this setting, the combination of pertuzumab with trastuzumab significantly increased the ADCC effect induced by trastuzumab alone (P\ubc0.02). Finally, pertuzumab induced a significant inhibition in the proliferation of all USPC cell lines tested, regardless of their HER-2/neu expression. CONCLUSION: Pertuzumab and trastuzumab induce equally strong ADCC and CDC in FISH-positive USPC cell lines. Pertuzumab significantly increases tratuzumab-induced ADCC against USPC with a low HER2/neu expression and may represent a new therapeutic agent in patients harbouring advanced/recurrent and/or refractory USPC

Anti-angiogenic potential of VEGF blocker dendron-laden gellan gum hydrogels for tissue engineering applications

Damage of non-vascularised tissues such as cartilage and cornea can result in healing processes accompanied by a non-physiological angiogenesis. Peptidic aptamers have recently been reported to block the vascular endothelial growth factor (VEGF). However, the therapeutic applications of these aptamers is limited due to their short half-life in vivo. In this work, an enhanced stability and bioavailability of a known VEGF blocker aptamer sequence (WHLPFKC) was pursued through its tethering of molecular scaffolds based on hyperbranched peptides, the poly(É -lysine) dendrons, bearing three branching generations. The proposed design allowed simultaneous and orderly-spaced exposure of sixteen aptamers per dendrimer to the surrounding biological microenvironent, as well as a relatively hydrophobic core based on di-phenylalanine aiming to promote an hydrophobic interaction with the hydrophobic moieties of ionically-crosslinked metacrylated gellan gum (iGG-MA) hydrogels. The VEGF blocker dendrons were entrapped in iGG-MA hydrogels and their capacity to prevent endothelial cell sprouting was assessed qualitatively and quantitatively using 3D in vitro models and the in vivo chick chorioallantoic membrane (CAM) assay. The data demonstrate that at nanoscale concentrations, the dendronised structures were able to enhance control of the biological actvity of WHLPFKC at the material/tissue interface and hence the anti-angiogenic capacity of iGG-MA hydrogels not only preventing blood vessel invasion, but also inducing their regression at the tissue/iGG-MA interface. The in ovo study confirmed that iGG-MA functionalised with the dendron VEGF blockers do inhibit angiogenesis by controlling both size and ramifications of blood vessels in proximity of the implanted gel surface.This work was mainly supported by the EC FP7 project Disc Regeneration (Contract No NMP3-LA-2008-213904). This study was also funded by the EC FP7 Programme contract agreement no REGPOT-CT2012-316331-POLARIS

Functionalisation of methacrylated gellan gum hydrogels by anti-angiogenic dendrons

The regeneration of cartilage in the intervertebral disc nucleus pulposus and joints is impaired by the formation of fibrocartilage that is caused by the invasion of the tissue by blood vessels. Peptides have been identified by phage display technique which are able to bind VEGF thus inhibiting angiogenesis. The present works focusses on the synthesis of poly(epsilon-lysine) dendrons of three branching generations in which the molecular root of the dendron bears a di-phenylalanine sequence to promote hydrophobic interactions with material surfaces and the uppermost molecular branches are functionalised with the amino acid sequenceWHLPFKC that is known to block VEGF. These biofunctionalised dendrons were entrapped in methacrylated Gellan Gum (GG-MA) hydrogels and tested for their ability to inhibit endothelial cell sprouting by both a 3D in vitro cell models and an in ovo model. The results show that when GG-MA is functionalised with the dendronised VEGF blockers, a regression of angiogenesis takes place around the hydrogel boundary. The in ovo study supports these findings as the GG-MA functionalised with the dendronised VEGF blockers did not elicit any acute inflammatory response, and decrease the number of converging macroscopic blood vessels as compared to positive controls. Moreover, the hydrogels prevented the infiltration of blood vessels, after 4 days of implantation.Fundação para a Ciência e TecnologiaEU 7th Framework ProgrammeMICINNJunta de Castilla y LeónCIBER-BBNFundo Social EuropeuPrograma Operacional Potencial Human

Reuso de efluentes nos estoques de carbono e nitrogênio no solo e na produtividade da cana sem despalha a fogo.

A cana-de-açúcar é uma cultura que se destaca para o reuso agrícola de efluentes, devido às grandes extensões de área cultivada e ao potencial de resposta ao cultivo irrigado em áreas sujeitas a deficiência hídrica. Com o objetivo de avaliar os efeitos da irrigação da cana-de-açúcar com esgoto tratado, sobre os estoques de carbono e nitrogênio do solo e na produtividade da segunda soca da cultura, foi conduzido um experimento com lâminas crescentes de irrigação em comparação com cana não irrigada, em área adjacente à uma estação de tratamento de esgoto (lagoas de estabilização) em Piracicaba, SP. A irrigação da cultura de cana-de-açúcar com esgoto tratado contribuiu para o estoque de carbono e nitrogênio no solo, com aumento de 38% (18,0 Mg C ha-1) e 28% (1,3 Mg N ha-1) na camada de 10-20 cm da lâmina de 100% da evapotranspiração da cultura (ETc), respectivamente. A irrigação com efluente mostrou-se uma prática viável para a cultura da cana-de-açúcar, possibilitando incremento significativo de produtividade (58%), sendo a lâmina de 100% da ETc é recomendada, com 130 Mg ha-1

The Relevance of Pyrogenic Carbon for Carbon Budgets From Fires: Insights From the FIREX Experiment

Vegetation fires play an important role in global and regional carbon cycles. Due to climate warming and land use shifts, fire patterns are changing and fire impacts increasing in many of the world's regions. Reducing uncertainties in carbon budgeting calculations from fires is therefore fundamental to advance our current understanding and forecasting capabilities. Here we study 20 chamber burns from the FIREX FireLab experiment, which burnt a representative set of North American wildland fuels, to assess the following: (i) differences in carbon emission estimations between the commonly used “consumed biomass” approach and the “burnt carbon” approach; (ii) pyrogenic carbon (PyC) production rates; and (iii) thermal and chemical recalcitrance of the PyC produced, as proxies of its biogeochemical stability. We find that the “consumed biomass” approach leads to overestimation of carbon emissions by 2–27% (most values between 2% and 10%). This accounting error arises largely from not considering PyC production and, even if relatively small, can therefore have important implications for medium‐ and long‐term carbon budgeting. A large fraction (34–100%) of this PyC was contained in the charred fine residue, a postfire material frequently overlooked in fire carbon research. However, the most recalcitrant PyC was in the form of woody charcoal, with estimated half‐lives for most samples exceeding 1,000 years. Combustion efficiency was relatively high in these laboratory burns compared to actual wildland fire conditions, likely leading to lower PyC production rates. We therefore argue that the PyC production values obtained here, and associated overestimation of carbon emissions, should be taken as low‐end estimates for wildland fire conditions

Measuring close proximity interactions in summer camps during the COVID-19 pandemic

Policy makers have implemented multiple non-pharmaceutical strategies to mitigate the COVID-19 worldwide crisis. Interventions had the aim of reducing close proximity interactions, which drive the spread of the disease. A deeper knowledge of human physical interactions has revealed necessary, especially in all settings involving children, whose education and gathering activities should be preserved. Despite their relevance, almost no data are available on close proximity contacts among children in schools or other educational settings during the pandemic. Contact data are usually gathered via Bluetooth, which nonetheless offers a low temporal and spatial resolution. Recently, ultra-wideband (UWB) radios emerged as a more accurate alternative that nonetheless exhibits a significantly higher energy consumption, limiting in-field studies. In this paper, we leverage a novel approach, embodied by the Janus system that combines these radios by exploiting their complementary benefits. The very accurate proximity data gathered in-field by Janus, once augmented with several metadata, unlocks unprecedented levels of information, enabling the development of novel multi-level risk analyses. By means of this technology, we have collected real contact data of children and educators in three summer camps during summer 2020 in the province of Trento, Italy. The wide variety of performed daily activities induced multiple individual behaviors, allowing a rich investigation of social environments from the contagion risk perspective. We consider risk based on duration and proximity of contacts and classify interactions according to different risk levels. We can then evaluate the summer camps’ organization, observe the effect of partition in small groups, or social bubbles, and identify the organized activities that mitigate the riskier behaviors. Overall, we offer an insight into the educator-child and child-child social interactions during the pandemic, thus providing a valuable tool for schools, summer camps, and policy makers to (re)structure educational activities safely

Serum amyloid A (SAA): a novel biomarker for uterine serous papillary cancer

BACKGROUND: Uterine serous papillary carcinoma (USPC) is a biologically aggressive variant of endometrial cancer. We investigated the expression of Serum Amyloid A (SAA) and evaluated its potential as a serum biomarker in USPC patients. METHODS: SAA gene and protein expression levels were evaluated in USPC and normal endometrial tissues (NEC) by real-time PCR, immunohistochemistry (IHC), flow cytometry and by a sensitive bead-based immunoassay. SAA concentration in 123 serum samples from 51 healthy women, 42 women with benign diseases, and 30 USPC patients were also studied. RESULTS: SAA gene expression levels were significantly higher in USPC when compared with NEC (mean copy number by RT\u2013PCR\ubc162 vs 2.21; P\ubc0.0002). IHC revealed diffuse cytoplasmic SAA protein staining in USPC tissues. High intracellular levels of SAA were identified in primary USPC cell lines evaluated by flow cytometry and SAA was found to be actively secreted in vitro. SAA concentrations (mgml 1) had a median (95% CIs) of 6.0 (4.0\u20138.9) in normal healthy females and 6.0 (4.2\u20138.1) in patients with benign disease (P\ubc0.92). In contrast, SAA values in the serum of USPC patients had a median (95% CI) of 15.6 (9.2\u201356.2), significantly higher than those in the healthy group (P\ubc0.0005) and benign group (P\ubc0.0006). Receiver operating characteristics (ROC) analysis of serum SAA to classify advanced- and early-stage USPC yielded an area under the ROC curve of 0.837 (P\ubc0.0024). CONCLUSION: SAA is not only a liver-secreted protein but is also a USPC cell product. SAA may represent a novel biomarker for USPC to assist in staging patients preoperatively, and to monitor early-disease recurrence and response to therapy

hI-con1, a factor VII-IgGFc chimeric protein targeting tissue factor for immunotherapy of uterine serous papillary carcinoma

BACKGROUND: Uterine serous papillary adenocarcinoma (USPC) is a highly aggressive variant of endometrial cancer. Human immunoconjugate molecule (hI-con1) is an antibody-like molecule targeted against tissue factor (TF), composed of two human Factor VII (fVII) as the targeting domain, fused to human immunoglobulin (Ig) G1 Fc as an effector domain. We evaluated hI-con1 potential activity against primary chemotherapy-resistant USPC cell lines expressing different levels of TF. METHODS: A total of 16 formalin-fixed, paraffin-embedded USPC samples were evaluated by immunohistochemistry (IHC) for TF expression. Six primary USPC cell lines, half of which overexpress the epidermal growth factor type II (HER2/neu) receptor at 3\ufe levels, were assessed by flow cytometry and real-time PCR for TF expression. Sensitivity to hI-con1-dependent cell-mediated cytotoxicity (IDCC) was evaluated in 5-hour-chromium release assays. Finally, to investigate the effect of interleukin-2 (IL-2) on IDCC, 5-h 51Cr assays were also conducted in the presence of low doses of IL-2 (i.e., 50\u2013100 IU ml 1). RESULTS: Cytoplasmic and/or membrane TF expression was observed in all 16 (100%) USPC samples tested by IHC, but not in normal endometrium. High expression of TF was found in 50% (three out of six) of the USPC cell lines tested by real-time PCR and flow cytometry when compared with normal endometrial cells (NECs; Po0.001). Uterine serous papillary adenocarcinoma cell lines overexpressing TF, regardless of their high or low HER2/neu expression, were highly sensitive to IDCC (mean killing\ub1s.d., 65.6\ub13.7%, range 57.5\u201377.0%, Po0.001), although negligible cytotoxicity against USPC was seen in the absence of hI-con1 or in the presence of Rituximab control antibody. The addition of low doses of IL-2 further increased the cytotoxic effect induced by hI-con1 against chemotherapy-resistant USPC. CONCLUSION: hI-con1 induces strong cytotoxicity against primary chemotherapy-resistant USPC cell lines overexpressing TF. The hI-con1 may represent a novel therapeutic agent for the treatment of patients harbouring advanced, recurrent and/or metastatic USPC refractory to standard treatment modalities