On multi-degree splines

Multi-degree splines are piecewise polynomial functions having sections of different degrees. For these splines, we discuss the construction of a B-spline basis by means of integral recurrence relations, extending the class of multi-degree splines that can be derived by existing approaches. We then propose a new alternative method for constructing and evaluating the B-spline basis, based on the use of so-called transition functions. Using the transition functions we develop general algorithms for knot-insertion, degree elevation and conversion to B\'ezier form, essential tools for applications in geometric modeling. We present numerical examples and briefly discuss how the same idea can be used in order to construct geometrically continuous multi-degree splines

Dietary supplements for Lipedema

Lipedema is a chronic disease that mostly manifests in females as the abnormal distribution of subcutaneous adipose connective tissue, usually coupled with bruising, pain, and edema. Lipedema molecular pathophysiology is currently not clear, but several studies suggest that genetics and hormonal imbalance participate in lipedema pathogenesis. Women with lipedema present in some cases with elevated body mass index, and the appearance of obesity in addition to lipedema, where the obesity can cause serious health issues as in lipedema-free individuals with obesity, such as diabetes and cardiovascular disorders.  Unlike obesity, lipedema tissue does not respond well to diet or physical exercise alone. Therefore, in this review we discuss the effect of various dietary supplements that, along with diet and physical exercise, cause fat burning and weight loss, and which could potentially be important in the treatment of lipedema. Indeed, an effective fat burner should convert stored fats into energy, mobilize and break down triglycerides in adipocytes, boost metabolism and inhibit lipogenesis. Common ingredients of fat burning supplements are green tea, caffeine, chromium, carnitine, and conjugated linoleic acid. The use of fat burners could act synergistically with a healthy diet and physical exercise for decreasing adipose tissue deposition in patients with lipedema and resolve related health issues. The effects of fat burners in human studies are sometimes contradictory, and further studies should test their effectiveness in treating lipedema

A fast interactive reverse-engineering system

A new method of reverse engineering for fast, simple and interactive acquisition and reconstruction of a virtual three-dimensional (3D) model is presented. We propose an active stereo acquisition system, whichmakes use of two infrared cameras and awireless active-pen device, supported by a reconstruction method based on subdivision surfaces. In the 3D interactive hand sketching process the user draws and refines the 3D style-curves, which characterize the shape to be constructed, by simply dragging the active-pen device; then the systemautomatically produces a low-resolutionmesh that is naturally refined through subdivision surfaces. Several examples demonstrate the ability of the proposed advanced design methodology to produce complex 3D geometric models by the interactive and iterative process that provides the user with a real-time visual feedback on the ongoing work

Feed frequency in a Sequencing Batch Reactor strongly affects the production of polyhydroxyalkanoates (PHAs) from volatile fatty acids

The production of polyhydroxyalkanoates (PHAs) by activated sludge selected in a sequencing batch reactor (SBR) has been investigated. Several SBR runs were performed at the same applied organic load rate (OLR), hydraulic retention time (HRT) and feed concentration (8.5gCODL-1 of volatile fatty acids, VFAs) under aerobic conditions. The effect of the feeding time was only evaluated with a cycle length of 8h; for this particular cycle length, an increase in the storage response was observed by increasing the rate at which the substrate was fed into the reactor (at a fixed feeding frequency). Furthermore, a significantly stronger effect was observed by decreasing the cycle length from 8h to 6h and then to 2h, changing the feed frequency or changing the organic load given per cycle (all of the other conditions remained the same): the length of the feast phase decreased from 26 to 20.0 and then to 19.7% of the overall cycle length, respectively, due to an increase in the substrate removal rate. This removal rate was high and similar for the runs with cycle lengths of 2h and 6h in the SBR. This result was due to an increase in the selective pressure and the specific storage properties of the selected biomass. The highest polymer productivity after long-term accumulation batch tests was 1.7gPHAL-1d-1, with PHA content in the biomass of approximately 50% on a COD basis under nitrogen limitation. The DGGE profiles showed that the good storage performance correlated to the development of Lampropedia hyalina, which was only observed in the SBR runs characterized by a shorter cycle length. © 2013 Elsevier B.V

Comparison of structure and ligand-based classification models for hERG liability profiling

The human ether-à-go-go-related potassium channel (hERG) is a voltage-gated potassium channel involved in the repolarization of the cardiac action potential. The off-target inhibition of hERG is the most frequent cause of drug-induced cardiotoxicity. Therefore, assessing hERG related cardiotoxicity in the early phase of the drug discovery process is crucial to avoid undesired cardiotoxic effects. For this purpose, we developed several machine learning classification models for hERG liability profiling basing on Random Forest algorithm by means of Weka software. The models were trained on a dataset of molecules collected from the public repository ChEMBL (https://www.ebi.ac.uk/chembl/) and the commercial GOSTAR database (https://www.gostardb.com/). The training molecules were encoded by both ligand- and structure-based attributes. The former consist of a set of physicochemical descriptors and fingerprints computed by RDKit node available in KNIME, while the latter comprise different scores obtained by docking and rescoring calculations performed by LiGen and Rescore+ tools, respectively. The following models are made available: hERG_LB, trained on ligand-based descriptors hERG_LiGen_AV, trained on a set of scores computed on the docking poses yielded by LiGen, considering for each score the mean value over all the computed poses. hERG_LiGen_AV-LB, trained on the combination of the descriptors used to build hERG_LB and hERG_LiGen_AV-LB models. The input datasets used for the models training and evaluation are made available too

Designer peptide antagonist of the leptin receptor with peripheral antineoplastic activity.

The obesity hormone leptin has been implicated in the development and progression of different cancer types, and preclinical studies suggest that targeting leptin signaling could be a new therapeutic option for the treatment of cancer, especially in obese patients. To inhibit pro-neoplastic leptin activity, we developed leptin receptor (ObR) peptide antagonists capable of blocking leptin effects in vitro and in vivo. Our lead compound (Allo-aca), however, crosses the blood-brain-barrier (BBB), inducing undesirable orexigenic effects and consequent weight gain. Thus, redesigning Allo-aca to uncouple its central and peripheral activities should produce a superior compound for cancer treatment. The aim of this study was to generate novel Allo-aca analogs and test their biodistribution in vivo and anti-neoplastic activity in vitro in breast and colorectal cancer cells. Examination of several Allo-aca analogs resulted in the identification of the peptidomimetic, d-Ser, that distributed only in the periphery of experimental animals. d-Ser inhibited leptin-dependent-proliferation of ObR-positive breast and colorectal cancer cells in vitro at 1nM concentration without exhibiting any partial agonistic activity. d-Ser efficacy was demonstrated in monolayer and three-dimensional cultures, and its antiproliferative action was associated with the inhibition of several leptin-induced pathways, including JAK/STAT3, MAPK/ERK1/2 and PI3K/AKT, cyclin D1, and E-cadherin. In conclusion, d-Ser is the first leptin-based peptidomimetic featuring peripheral ObR antagonistic activity. The novel peptide may serve as a prototype to develop new therapeutics, particularly for the management of obesity-related cancers

Computational Insights into the Sequence-Activity Relationships of the NGF(1–14) Peptide by Molecular Dynamics Simulations

The Nerve Growth Factor (NGF) belongs to the neurothrophins protein family involved in the survival of neurons in the nervous system. The interaction of NGF with its high-affinity receptor TrkA mediates different cellular pathways related to Alzheimer’s disease, pain, ocular dysfunction, and cancer. Therefore, targeting NGF-TrkA interaction represents a valuable strategy for the development of new therapeutic agents. In recent years, experimental studies have revealed that peptides belonging to the N-terminal domain of NGF are able to partly mimic the biological activity of the whole protein paving the way towards the development of small peptides that can selectively target specific signaling pathways. Hence, understanding the molecular basis of the interaction between the N-terminal segment of NGF and TrkA is fundamental for the rational design of new peptides mimicking the NGF N-terminal domain. In this study, molecular dynamics simulation, binding free energy calculations and per-residue energy decomposition analysis were combined in order to explore the molecular recognition pattern between the experimentally active NGF(1–14) peptide and TrkA. The results highlighted the importance of His4, Arg9 and Glu11 as crucial residues for the stabilization of NGF(1–14)-TrkA interaction, thus suggesting useful insights for the structure-based design of new therapeutic peptides able to modulate NGF-TrkA interaction

From fine-needle aspiration cytology to fluorescent in-situ hybridization in an unusual case of pharyngeal synovial sarcoma

Synovial sarcoma arising in the pharynx is a rare entity, with very few cases described in literature, mainly as surgical-oriented case reports. We report the case of a healthy 20-year old man who presented with a painless right neck mass, clinically suspicious for a thyroid nodule. Ultrasound scan and fine-needle aspiration cytology failed to provide a definitive result, although suggesting a mesenchymal proliferation, in accordance with magnetic resonance imaging findings. Therefore, the lesion was removed with a minimally invasive surgical intervention. Definitive histologic and immunohistochemical examination of the surgical specimen revealed a biphasic synovial sarcoma, further validated by the detection of SS18 gene rearrangement on fluorescent in-situ hybridization examination. Although rarely, synovial sarcoma may arise in the pharynx. Radiological, cytological, histological and molecular findings are needed along each step of the diagnostic process

The identification of a small but significant subset of patients still targetable with anti-HER2 inhibitors when affected by triple negative breast carcinoma

Purpose: Triple (ER-, PR-, HER2-) negative breast carcinoma lack targeted therapies, making this group of tumors difficult to treat. By definition, the lack of HER2 expression means a case scoring 0 or 1+ after immunophenotypical analysis and makes the patients avoiding therapeutical chances with anti-HER2 inhibitors. We sought to recruit from a group of triple negative breast carcinoma, patients eligible for effective personalized targeted therapy with anti-HER therapies on the basis of their HER2 gene status. Methods: 135 patients diagnosed with IHC triple negative breast carcinoma were studied. Whole tissue sections were used for in situ hybridization analysis. Results: 8/100 (8 %) of ductal-type triple negative breast carcinoma presented Her-2/neu gene amplification versus 2/35 (5.7 %) non-ductal triple negative breast carcinoma. Three cases showed a ratio 2.5. One case showed Her-2/neu heterogeneous gene amplification, ratio 2.3. The other six showed from 7 to 8 absolute Her-2/neu gene copy number. Two cases staged pT1c, and eight cases staged pT2. Eight cases graded G3 and two cases G2. Conclusion: (1) Eight percentage of ductal and 5.7 % non-ductal-type triple negative breast carcinoma present Her-2/neu gene amplification, (2) the standard diagnostic flowchart “do not FISH in 0–1+ (HER2-) breast carcinoma” should be replaced by “do FISH in triple (ER-, PR-, HER2-) negative breast carcinoma,” to avoid loss of therapeutical chances in a cohort of such a patients, (3) we demonstrated the identification of a small but significant subset of patients targetable with anti-HER2 inhibitors, giving patients affected by (ex)triple negative breast carcinoma new personalized therapeutical chances