Order review and release in make-to-order flow shops:analysis and design of new methods

Increased customization has strengthened the importance of make-to-order companies. The advent of lean management and the introduction of smart and flexible technologies has enabled many of these companies to create flow shop routings. Order review and release (ORR) research, which originally focused on job shops, has started paying attention to flow shops. However, the results have not provided clarity on the best ORR method for flow shops. This study aims at developing such a method by applying a modular design approach. It identifies the relevant elements of ORR methods for flow shops, combines them into new methods and evaluates them in a simulation study. The simulation results demonstrate that performance in pure flow shops can be strongly improved by applying the right combination of workload measures, load balancing, and order dispatching. Specifically, the results show that (1) classical workload measures are still as effective as novel measures that have been suggested for flow shops, (2) balancing workloads explicitly through optimization at the order release stage strongly improves performance, and (3) shortest processing time dispatching is highly effective in flow shops as it avoids starvation of stations. In-depth analyses have been executed to unravel the reasons of performance improvements. As such, the article provides clarity on the improvement potential that is available for ORR in flow shops, while the new modular methods provide a first step in exploiting this potential

Cultural Heritage Exposed to Natural Hazards: the Case Study of the Convent of San Domenico in Maiori

Nowadays it is widely recognized that structural interventions on cultural heritage buildings shall comply with the minimum intervention principle. The main goal is to enhance the structural capacity respecting, at the same time, the authenticity of the monument. As such, the correct interpretation of the current damage is a first fundamental step in the design of an efficient structural intervention. Within this framework, the paper presents the results of an in depth investigation carried out to assess the structural capacity of a complex monument affected by several deficiencies. The case study is the convent of Saint Domenico, a seventeenth century’s masonry structure, belonging to the traditional architectural typology of the court building. The building is located in Maiori, a small town in the Amalfi Coast (Italy), included in the UNESCO World Heritage List since 1997 for its great cultural and naturalistic interest. The structure was abandoned during the 80s, and currently presents an extensive and diffuse crack pattern that is the consequence of several causes such as: the natural aging of material, the lack of maintenance, the modifications occurred during the centuries, the seismic events occurred in the past and the poor quality of the foundation soil. In this paper, starting from the knowledge acquisition path of the whole Convent, a special focus on the structural behavior of the East wing is provided. A numerical model of a cross section of the wing has been developed and analyzed considering the effects of lateral loads and settlements. The numerical analyses are carried out using LiaBlock_3D, an in-house software tool for the limit equilibrium analysis of rigid block assemblages. Results of the analyses are discussed in details and a comparison with the actual crack pattern of the structure is provided as well

Cultural Heritage Exposed to Natural Hazards: the Case Study of the Convent of San Domenico in Maiori

n/

In vitro and in vivo evaluation of a single chain antibody fragment generated in planta with potent rabies neutralisation activity.

Rabies causes more than 60,000 human deaths annually in areas where the virus is endemic. Importantly, rabies is one of the few pathogens for which there is no treatment following the onset of clinical disease with the outcome of infection being death in almost 100% of cases. Whilst vaccination, and the combination of vaccine and rabies immunoglobulin treatment for post-exposure administration are available, no tools have been identified that can reduce or prevent rabies virus replication once clinical disease has initiated. The search for effective antiviral molecules to treat those that have already developed clinical disease associated with rabies virus infection is considered one of the most important goals in rabies research. The current study assesses a single chain antibody molecule (ScFv) based on a monoclonal antibody that potently neutralises rabies in vitro as a potential therapeutic candidate. The recombinant ScFv was generated in Nicotiana benthamiana by transient expression, and was chemically conjugated (ScFv/RVG) to a 29 amino acid peptide, specific for nicotinic acetylcholine receptor (nAchR) binding in the CNS. This conjugated molecule was able to bind nAchR in vitro and enter neuronal cells more efficiently than ScFv. The ability of the ScFv/RVG to neutralise virus in vivo was assessed using a staggered administration where the molecule was inoculated either four hours before, two days after or four days after infection. The ScFv/RVG conjugate was evaluated in direct comparison with HRIG and a potential antiviral molecule, Favipiravir (also known as T-705) to indicate whether there was greater bioavailability of the ScFv in the brains of treated mice. The study indicated that the approach taken with the ScFv/RVG conjugate may have utility in the design and implementation of novel tools targetting rabies virus infection in the brain

Shake-table testing of a stone masonry building aggregate: overview of blind prediction study

City centres of Europe are often composed of unreinforced masonry structural aggregates, whose seismic response is challenging to predict. To advance the state of the art on the seismic response of these aggregates, the Adjacent Interacting Masonry Structures (AIMS) subproject from Horizon 2020 project Seismology and Earthquake Engineering Research Infrastructure Alliance for Europe (SERA) provides shake-table test data of a two-unit, double-leaf stone masonry aggregate subjected to two horizontal components of dynamic excitation. A blind prediction was organized with participants from academia and industry to test modelling approaches and assumptions and to learn about the extent of uncertainty in modelling for such masonry aggregates. The participants were provided with the full set of material and geometrical data, construction details and original seismic input and asked to predict prior to the test the expected seismic response in terms of damage mechanisms, base-shear forces, and roof displacements. The modelling approaches used differ significantly in the level of detail and the modelling assumptions. This paper provides an overview of the adopted modelling approaches and their subsequent predictions. It further discusses the range of assumptions made when modelling masonry walls, floors and connections, and aims at discovering how the common solutions regarding modelling masonry in general, and masonry aggregates in particular, affect the results. The results are evaluated both in terms of damage mechanisms, base shear forces, displacements and interface openings in both directions, and then compared with the experimental results. The modelling approaches featuring Discrete Element Method (DEM) led to the best predictions in terms of displacements, while a submission using rigid block limit analysis led to the best prediction in terms of damage mechanisms. Large coefficients of variation of predicted displacements and general underestimation of displacements in comparison with experimental results, except for DEM models, highlight the need for further consensus building on suitable modelling assumptions for such masonry aggregates

Testing nanoparticles for intracerebral drug delivery.

As it is well known, the blood-brain barrier (BBB) plays a protective role, limiting the access of molecules and cells into the brain. In recent years different types of nanoparticles (NPs) have been investigated for the delivery of drugs to a specific target site, also to treat brain pathological conditions. Suramin, a polysulfonate naphthylurea, is a drug used for the early-stage therapy of human African trypanosomiasis (HAT), a neglected disease also known as sleeping sickness. HAT is a severe central nervous system infection caused by the extracellular parasite Trypanosoma brucei (Tb, transmitted by tsetse flies as vectors). Suramin does not cross the BBB and is therefore ineffective once the parasites have invaded the brain. Only highly toxic arsenical compounds are currently available to cure second stage HAT, which is fatal if left untreated. The aim of this study is the delivery of suramin across the BBB using NPs as carriers, to find alternative therapeutic approaches that are urgently needed in the treatment of HAT. To reach this goal, different types of nanocarriers have been tested in vitro and in vivo. Cell viability test with CaF2 and SrF2 NPs, conjugated with lanthanide dopant ions, pointed out a toxicity of these NPs in a stabilized cell line of pure motor neurons (NSC-34) available in our laboratory. In vivo trials (in C57/BL mice) were conducted with different NPs, investigating their biodistribution with confocal microscopy. In the case of Cerium oxide NPs, the densest accumulation was found in liver and spleen after 24 h, with little or no penetration in the brain in the initial in house preparation of these NPs, which showed considerable aggregation. PolyD,L-Lactide-co-Glycolide Acid (PLGA) NPs conjugated with Prostaglandin D synthetase were found, 24 h after iv injection, in the brain of Tb brucei-infected mice (model of HAT infection). Testing other types of nanocarriers, such as carbon- nanotubes and PLGA NPs functionalized with peptide derived from ApoE, are currently ongoing. In parallel, the central effects of suramin, delivered via intracerebroventricular injection, have been investigated as a basis for the delivery of this drug with nanosystems. No tissue damage or glial cell activation was observed in the brain after histochemical and immunohistochemical analyses, encouraging efforts for a targeted delivery of this drug across the blood-brain barrier

Testing nanoparticles for intracerebral drug delivery

The (BBB) controls the passage of molecules and cells into the brain. This is crucial for the delivery of drugs in the treatment of central nervous system (CNS) diseases. Nanotechnologies, applied to the drug delivery, offer many advantages over conventional therapeutic methods. The drug suramin, used in the treatment of the peripheral infection during human African trypanosomiasis (HAT), does not cross the BBB and cannot be used to cure the encephalitic stage disease. To achieve the transport of suramin into the brain, using NPs as carriers, and to test in animal model whether this approach could cure HAT CNS infection, is the aim of the present study. The capability to cross the BBB of metal-based NPs and polymer-based NPs, was preliminary carried out. After 24h from iv injection in mice, CaF2 and SrF2 NPs, were observed mostly in liver and spleen, but also in brain parenchyma. Cerium oxide (CeO2) NPs are of special interest since they can exert neuroprotective effects. Their short-term biodistribution was investigated with different techniques, suggesting the largest accumulation in liver and spleen, even if in the brain NP-like elements were observed, exhibiting neuronal morphology. Polymeric PLGA NPs conjugated with a peptide derived from Apolypoprotein E and Prostaglandin-D-synthase, were documented to enter into the brain parenchyma, 2h after the peripheral administration, despite their relative high dimension due to polymeric structure. The present data indicate that metal-based NPs penetration into the brain should also be taken, probably due to their small dimension (~10nm), despite their accumulation in peripheral organs. Possible surface modifications are currently under discussion to overcome macrophage recognition and to improve the blood circulation time. PLGA NPs also reach the CNS, albeit in limited amount; targeting with a peptide seems to improve the BBB crossing for potential brain drug delivery. In parallel, the investigation of CeO2 NPs and PLGA NPs effect on the brain cells was initiated. Glia phenotyping was pursued to reveal astrocytes, using glial fibrillary acidic protein (GFAP) as marker, and antibodies against CD11b, to detect the resident microglia. Both cell types react to the penetration of the tested NPs into the brain, but it remains to be investigated whether this can represent a detrimental or a beneficial response. Direct delivery of suramin into the brain does not cause overt cell damage or inflammatory response in the brain, both in na\uefve mice and in Tb brucei-infected mice