Biomaterials for ocular reconstruction

Synthetic materials have played a significant role in ophthalmic applications to improve vision for many years. This has been in four main areas in ophthalmology: ocular surface reconstruction, lens replacement, vitreous replacement and structural support and cell transplantation in the retina. Corneal replacement therapies have been developed using both synthetic acrylic-based materials and more recently naturally derived materials such as amniotic membrane. Intraocular lenses as a replacement for the natural lens post cataract surgery has been used for many years. Newer developments include the opportunity to use gels so that the lenses can accommodate but these need improving in terms of the cross-linking chemistry. Silicone oils have been used as long-term tamponade agents as vitreous replacements but recent developments in their properties has enhanced the clinical outcomes and further research into their use as drug delivery vehicles will be a major advancement. Regenerative medicine therapies to repopulate the retina to repair and replace specific cell layers require the optimisation of synthetic scaffolds and this is a major area for development. Recent developments in biomaterials have emphasised the importance of the physical, chemical and mechanical properties specific to a particular ophthalmic application. Materials science has a critical role in developing strategies to overcome vision loss.     

Cumulative Sum Control Charts for Monitoring Weibull‐distributed Time Between Events

The Weibull distribution can be used to effectively model many different failure mechanisms due to its inherent flexibility through the appropriate selection of a shape and a scale parameter. In this paper, we evaluate and compare the performance of three cumulative sum (CUSUM) control charts to monitor Weibull‐distributed time‐between‐event observations. The first two methods are the Weibull CUSUM chart and the exponential CUSUM (ECUSUM) chart. The latter is considered in literature to be robust to the assumption of the exponential distribution when observations have a Weibull distribution. For the third CUSUM chart included in this study, an adjustment in the design of the ECUSUM chart is used to account for the true underlying time‐between‐event distribution. This adjustment allows for the adjusted ECUSUM chart to be directly comparable to the Weibull CUSUM chart. By comparing the zero‐state average run length and average time to signal performance of the three charts, the ECUSUM chart is shown to be much less robust to departures from the exponential distribution than was previously claimed in the literature. We demonstrate the advantages of using one of the other two charts, which show surprisingly similar performance. Copyright © 2014 John Wiley & Sons, Ltd.     

The relationship between integrated design and construction and safety on construction projects

The occurrence of accidents and injuries continues to be a major problem in construction worldwide. Even though accident statistics have been improving in most markets there are significant areas requiring further attention. The extent of integrated working between designers and constructors may be an instrumental factor. A comparison is undertaken of the accident performance of 55 large construction projects in the UK, with varying levels of design/construction integration as represented by procurement path. Although a statistical relationship between high levels of integration and low levels of accidents was weak, a follow‐up interview study provided strong support, suggesting that a lack of significance was related to the unreliability of the statistics available. The interview study also indicated reasons for this link. A key element in improved safety was seen to be better communications and a more positive relationship between designers and constructors. Further research into designing for safety for all procurement paths is recommended.     

“They have good intentions”. Young People's Experiences of Living in Melbourne's Peri-Urban Areas

While contemporary urban theories suggest that individuals have transcended their geographical community, evidence suggests that urban residents still feel ‘attached’ to place. In the literature, several socio-demographic characteristics are associated with place attachment. Scholars suggest physical features, such as community ‘greenspace’, may also influence place attachment. Yet research does not consider the relationship between one's objective proximity to greenspace or the objective availability of community greenspace on residents' place attachment. This study employs multi-level models and draws on police incident data, census data, two spatial data sets and survey data from over 4000 residents living across 148 state suburbs in Australia to assess the relationship between greenspace proximity and greenspace availability on place attachment. Our findings indicate that greater proportions and more accessible greenspace may not improve residents' attachment to their local community.     

Maternal Fructose Intake Causes Developmental Reprogramming of Hepatic Mitochondrial Catalytic Activity and Lipid Metabolism in Weanling and Young Adult Offspring

Excess dietary fructose is a major public health concern, yet little is known about its influence on offspring development and later-life disease when consumed in excess during pregnancy. To determine whether increased maternal fructose intake could have long-term consequences on offspring health, we investigated the effects of 10% w/v fructose water intake during preconception and pregnancy in guinea pigs. Female Dunkin Hartley guinea pigs were fed a control diet (CD) or fructose diet (FD; providing 16% of total daily caloric intake) ad libitum 60 days prior to mating and throughout gestation. Dietary interventions ceased at day of delivery. Offspring were culled at day 21 (D21) (weaning) and at 4 months (4 M) (young adult). Fetal exposure to excess maternal fructose intake significantly increased male and female triglycerides at D21 and 4 M and circulating palmitoleic acid and total omega-7 through day 0 (D0) to 4 M. Proteomic and functional analysis of significantly differentially expressed proteins revealed that FD offspring (D21 and 4 M) had significantly increased mitochondrial metabolic activities of β-oxidation, electron transport chain (ETC) and oxidative phosphorylation and reactive oxygen species production compared to the CD offspring. Western blotting analysis of both FD offspring validated the increased protein abundances of mitochondrial ETC complex II and IV, SREBP-1c and FAS, whereas VDAC1 expression was higher at D21 but lower at 4 M. We provide evidence demonstrating offspring programmed hepatic mitochondrial metabolism and de novo lipogenesis following excess maternal fructose exposure. These underlying asymptomatic programmed pathways may lead to a predisposition to metabolic dysfunction later in life.     

Teriflunomide Preserves Neuronal Activity and Protects Mitochondria in Brain Slices Exposed to Oxidative Stress

Teriflunomide (TFN) limits relapses in relapsing–remitting multiple sclerosis (RRMS) by reducing lymphocytic proliferation through the inhibition of the mitochondrial enzyme dihydroorotate dehydrogenase (DHODH) and the subsequent modulation of de novo pyrimidine synthesis. Alterations of mitochondrial function as a consequence of oxidative stress have been reported during neuroinflammation. Previously, we showed that TFN prevents alterations of mitochondrial motility caused by oxidative stress in peripheral axons. Here, we aimed to validate TFN effects on mitochondria and neuronal activity in hippocampal brain slices, in which cellular distribution and synaptic circuits are largely preserved. TFN effects on metabolism and neuronal activity were investigated by assessing oxygen partial pressure and local field potential in acute slices. Additionally, we imaged mitochondria in brain slices from the transgenic Thy1-CFP/COX8A)S2Lich/J (mitoCFP) mice using two-photon microscopy. Although TFN could not prevent oxidative stress-related depletion of ATP, it preserved oxygen consumption and neuronal activity in CNS tissue during oxidative stress. Furthermore, TFN prevented mitochondrial shortening and fragmentation of puncta-shaped and network mitochondria during oxidative stress. Regarding motility, TFN accentuated the decrease in mitochondrial displacement and increase in speed observed during oxidative stress. Importantly, these effects were not associated with neuronal viability and did not lead to axonal damage. In conclusion, during conditions of oxidative stress, TFN preserves the functionality of neurons and prevents morphological and motility alterations of mitochondria.     

COVID-19 and Lung Mast Cells: The Kallikrein–Kinin Activation Pathway

Mast cells (MCs) have relevant participation in inflammatory and vascular hyperpermeability events, responsible for the action of the kallikrein–kinin system (KKS), that affect patients inflicted by the severe form of COVID-19. Given a higher number of activated MCs present in COVID-19 patients and their association with vascular hyperpermeability events, we investigated the factors that lead to the activation and degranulation of these cells and their harmful effects on the alveolar septum environment provided by the action of its mediators. Therefore, the pyroptotic processes throughout caspase-1 (CASP-1) and alarmin interleukin-33 (IL-33) secretion were investigated, along with the immunoexpression of angiotensin-converting enzyme 2 (ACE2), bradykinin receptor B1 (B1R) and bradykinin receptor B2 (B2R) on post-mortem lung samples from 24 patients affected by COVID-19. The results were compared to 10 patients affected by H1N1pdm09 and 11 control patients. As a result of the inflammatory processes induced by SARS-CoV-2, the activation by immunoglobulin E (IgE) and degranulation of tryptase, as well as Toluidine Blue metachromatic (TB)-stained MCs of the interstitial and perivascular regions of the same groups were also counted. An increased immunoexpression of the tissue biomarkers CASP-1, IL-33, ACE2, B1R and B2R was observed in the alveolar septum of the COVID-19 patients, associated with a higher density of IgE⁺ MCs, tryptase⁺ MCs and TB-stained MCs, in addition to the presence of intra-alveolar edema. These findings suggest the direct correlation of MCs with vascular hyperpermeability, edema and diffuse alveolar damage (DAD) events that affect patients with a severe form of this disease. The role of KKS activation in events involving the exacerbated increase in vascular permeability and its direct link with the conditions that precede intra-alveolar edema, and the consequent DAD, is evidenced. Therapy with drugs that inhibit the activation/degranulation of MCs can prevent the worsening of the prognosis and provide a better outcome for the patient.     

Size-Dependent Cellular Uptake of RGD Peptides

Monomeric RGD peptides show unspecific fluid-phase uptake in cells, whereas multimeric RGD peptides are thought to be internalized by integrin-mediated endocytosis. However, a potential correlation between uptake mechanism and molecular mass has been neglected so far. A dual derivatization of peptide c(RGDw(7Br)K) was performed to investigate this. A fluorescent probe was installed by chemoselective Suzuki–Miyaura cross-coupling of the 7-bromotryptophan and a poly(ethylene glycol) (PEG) linker was attached to the lysine residue. Flow cytometry and live cell imaging confirmed unspecific uptake of the small, non-PEGylated peptide, whereas the PEG₅₀₀₀ peptide conjugate unveiled a selective internalization by M21 cells overexpressing α_vβ₃ and no uptake in α_v-deficient M21L cells.