Using Old Schröder-Reuleaux Models in Modern Kinematics Lectures

The paper deals with the use for educational purposes of kinematic models of the Schroder/Reuleax collection preserved at the Department of Mechanical and Aerospace Engineering of Politecnico di Torino. The article first traces a brief history of the models, which were acquired at the end of the 19th C. by the Regio Museo Industriale of Turin. Four straight-line mechanisms of the collection, employed in modern kinematics lectures, are presented in detail. The didactic method adopted starts from the analysis of the models of the collection and leads the students to develop schemes and software models, in a process of transition from real to virtual. The simulation results are then interpreted and correlated with the functioning of the real model

Stair-climbing wheelchair.q05: from the concept to the prototype

In this paper, an electric stair-climbing wheelchair, named wheelchair.q05, able to move on flat ground and to climb stairs, is presented. The proposed solution has been developed through a series of studies and designs, all based on a smart hybrid triple leg-wheel locomotion unit. The stability of the device is guaranteed by a rear support of a pair of pivoting wheels during motion on flat ground, and by the support of an idle track, when climbing on or going down stairs. By means of mechanisms and actuators, it is possible to change the configuration of the wheelchair, from the flat ground motion to the stair climbing configuration

Float-Ram: A Sustainable Machine for Buildings Made by Compressed Earth Blocks

This article describes a sequence of research, design, prototyping and utilization of a new manually operated press, which has the purpose of facilitating a construction technology that uses compressed earth blocks, CEB. Buildings and houses made of CEB have better quality than traditional in poor region. They are also economical, robust, aesthetically pleasing, and sustainable from an environmental point of view. The research is addressed to some targets of the SDG 11, Sustainable Cities and Communities: (i) “ensure access for all to adequate, safe and affordable housing and basic services and upgrade slums”; (ii) “support least developed countries, including through financial and technical assistance, in building sustainable and resilient buildings utilizing local materials”. The paper presents the project path, the results and finally the impact in a specific context, the rural areas in Tanzania

Programmability and Performance of Parallel ECS-based Simulation of Multi-Agent Exploration Models

While the traditional objective of parallel/distributed simulation techniques has been mainly in improving performance and making very large models tractable, more recent research trends targeted complementary aspects, such as the “ease of programming”. Along this line, a recent proposal called Event and Cross State (ECS) synchronization, stands as a solution allowing to break the traditional programming rules proper of Parallel Discrete Event Simulation (PDES) systems, where the application code processing a specific event is only allowed to access the state (namely the memory image) of the target simulation object. In fact with ECS, the programmer is allowed to write ANSI-C event-handlers capable of accessing (in either read or write mode) the state of whichever simulation object included in the simulation model. Correct concurrent execution of events, e.g., on top of multi-core machines, is guaranteed by ECS with no intervention by the programmer, who is in practice exposed to a sequential-style programming model where events are processed one at a time, and have the ability to access the current memory image of the whole simulation model, namely the collection of the states of any involved object. This can strongly simplify the development of specific models, e.g., by avoiding the need for passing state information across concurrent objects in the form of events. In this article we investigate on both programmability and performance aspects related to developing/supporting a multi-agent exploration model on top of the ROOT-Sim PDES platform, which supports ECS

On the analytic solution of the pairing problem: one pair in many levels

We search for approximate, but analytic solutions of the pairing problem for one pair of nucleons in many levels of a potential well. For the collective energy a general formula, independent of the details of the single particle spectrum, is given in both the strong and weak coupling regimes. Next the displacements of the solutions trapped in between the single particle levels with respect to the unperturbed energies are explored: their dependence upon a suitably defined quantum number is found to undergo a transition between two different regimes.Comment: 30 pages, AMS Latex, 8 figures. Submitted to Phys. Rev.

Inhibition of mapk signalling promotes cell cycle arrest and sensitises intrahepatic cholangiocarcinoma cells to chemotherapy

Introduction: Intrahepatic cholangiocarcinoma (ICC) is the second most common primary hepatic malignancy, accounting for approximately 15% of cases of primary liver cancer. Although new treatments have increased survival for many other cancers, including the more common primary hepatocellular carcinoma, treatment strategies and survival for patients with ICC have seen little improvement. Our previous studies suggest that the mitogen-activated protein kinase (MAPK) signalling plays a central role in the regulation of cell proliferation in human ICC. However the molecular mechanisms are poorly understood. In this study, we aim to explore whether inhibition of the MAPK pathway and its downstream effectors enhances the sensitisation of ICC cells to the chemotherapeutic agent cisplatinum. Method: We used a combinatorial approach of immunohistochemical and gene expression analyses to investigate the expression of MAPK-related genes in ICC tumours. Furthermore, by using in-vitroand in-vivoanalyses we have characterised the function of a novel MAPK downstream effector in ICC cells. Results: The expression of MAPK signalling was determined by immunohistochemical staining in tumour samples from a cohort of 14 ICC patients. High expression of phospho-activated MAPK was observed in 71.4% (10/14) of ICC cases as compared with surrounding nontumour tissue. Likewise, expression of JDP, a downstream effector of the MAPK signalling, was scored as high intensity in 64.3% (9/14). Strikingly, elevated expression of JDP transcripts was also observed in two independent cohorts of human ICC (n = 149 and n = 109 per group, respectively) compared to surrounding normal liver tissue. Consistent with the in-vivo analyses of human samples, immunoblotting analyses showed constitutive activation of MAPK and expression of JDP in ICC-derived cells (i.e. SG231, CCLP-1 and HuCCT1). Using loss-of-function analyses, we demonstrates that knockdown of JDP in ICC-derived cells resulted in cell cycle arrest and reduced expression of cell cycle regulators (i.e. cyclins), and had minimal effect on apoptosis. Chemical inhibition of JDP significantly sensitises ICC-derived cells to cisplatinum (P < 0.001). Conclusion: These results demonstrate that enhanced activation of MAPK signalling is important for ICC cell proliferation and suggest that targeting its downstream effectors is a potential therapeutic strategy for ICC

Are GPs under-investigating older patients presenting with symptoms of ovarian cancer? Observational study using General Practice Research Database

Background: Recent studies suggest that older patients in the United Kingdom are not benefiting as much from improvements in cancer treatments as their younger counterparts. We investigate whether this might be partly due to differential referral rates using ovarian cancer as an example. Methods: From the General Practice Research Database (GPRD), we identified all women aged 40–80 years on 1 June 2002 with a Read code for ovarian cancer between 1 June 2002 and 31 May 2007. Using these records, we compared the GPRD incidence of ovarian cancer with rates compiled from the UK cancer registries and investigated the relationship between age and coded investigations for suspected ovarian cancer. Results: The GPRD rates peaked earlier, at 70–74, and were lower than registry rates for nearly all ages particularly for patients over 59. The proportion investigated or referred by the GP decreased significantly with age and delays between first coded symptom and investigation showed a U-shaped distribution by age. Conclusions: GPs appear to be less likely to recognise and to refer patients presenting with ovarian cancer as they get older. If our findings extend to other cancers, lack of or delays in referral to secondary care may partly explain poor UK cancer mortality rates of older people

Synergic stimulation of serotonin 5-HT1A receptor and &#945;2-adrenoceptors for neuropathic pain relief: Preclinical effects of 2-substituted imidazoline derivatives

Neuropathic pain affects millions of people causing disability and impairing quality of life. Commonly used analgesics are generally characterized by limited therapeutic outcomes. The serotonin 5-HT1A receptor and the α2 adrenergic receptors are involved in central nociceptive mechanisms with a pivotal role in the inhibitory descending pain pathway. Since their stimulation may modulate the nervous signaling altered by neuropathies, the purpose of the present research is the study of the combined activation of 5-HT1A and α2 receptors by rationally designed imidazoline ligands ((S)-(-)-1 and 2-5) in a rat model of neuropathic pain (chronic constriction injury - CCI). On day 14 after nerve damage, the acute administration per os (p.o.) of low doses of (S)-(-)-1 (0.1-1mg/kg) was able to significantly increase the pain threshold to mechanical noxious stimuli for more than 1h. (S)-(-)-1 efficacy was confirmed by the decrease of spontaneous pain evaluated as hind limb weight bearing alterations. The clinically-used compound gabapentin (100mg/kg p.o.) induced a pain relieving effect similar to (S)-(-)-1 administered at 100 fold lower dose. In the same model, the selected analogues, compounds 2-5 (1mg/kg p.o.) were effective 30min after administration. In particular, 5 fully reverted the CCI-induced hypersensitivity. The pain relieving activity of 5 was significantly prevented by the selective 5-HT1A receptor antagonist WAY 100635 (1mg/kg intraperitoneally, i.p.) and, at a lesser extent, by the α2 antagonist yohimbine (3mg/kg i.p.). A novel pharmacodynamic approach to the treatment of neuropathic pain is presented

Impact of donation mode on the proportion and function of T lymphocytes in the liver

Background Liver T-cells respond to the inflammatory insult generated during organ procurement and contribute to the injury following reperfusion. The mode of liver donation alters various metabolic and inflammatory pathways but the way it affects intrahepatic T-cells is still unclear. Methods We investigated the modifications occurring in the proportion and function of T-cells during liver procurement for transplantation. We isolated hepatic mononuclear cells (HMC) from liver perfusate of living donors (LD) and donors after brain death (DBD) or cardiac death (DCD) and assessed the frequency of T-cell subsets, their cytokine secretion profile and CD8 T-cell cytotoxicity function, responsiveness to a danger associated molecular pattern (High Mobility Group Box1, HMGB1) and association with donor and recipient clinical parameters and immediate graft outcome. Results We found that T-cells in healthy human livers were enriched in memory CD8 T-cells exhibiting a phenotype of non-circulating tissue-associated lymphocytes, functionally dominated by more cytotoxicity and IFN-γ-production in DBD donors, including upon activation by HMGB1 and correlating with peak of post-transplant AST. This liver-specific pattern of CD8 T-cell was prominent in DBD livers compared to DCD and LD livers suggesting that it was influenced by events surrounding brain death, prior to retrieval. Conclusion Mode of liver donation can affect liver T-cells with increased liver damage in DBD donors. These findings may be relevant in designing therapeutic strategies aimed at organ optimization prior to transplantation

Novel Potent Muscarinic Receptor Antagonists: Investigation on the Nature of Lipophilic Substituents in the 5- and/or 6-Positions of the 1,4-Dioxane Nucleus

A series of novel 1,4-dioxane analogues of the muscarinic acetylcholine receptor (mAChR) antagonist 2 was synthesized and studied for their affinity at M1-M5 mAChRs. The 6-cyclohexyl-6-phenyl derivative 3b, with a cis configuration between the CH2N+(CH3)3 chain in the 2-position and the cyclohexyl moiety in the 6-position, showed pKi values for mAChRs higher than those of 2 and a selectivity profile analogous to that of the clinically approved drug oxybutynin. The study of the enantiomers of 3b and the corresponding tertiary amine 33b revealed that the eutomers are (2S,6S)-(-)-3b and (2S,6S)-(-)-33b, respectively. Docking simulations on the M3 mAChR-resolved structure rationalized the experimental observations. The quaternary ammonium function, which should prevent the crossing of the blood-brain barrier, and the high M3/M2 selectivity, which might limit cardiovascular side effects, make 3b a valuable starting point for the design of novel antagonists potentially useful in peripheral diseases in which M3 receptors are involved