Tenascin-C fragments are endogenous inducers of cartilage matrix degradation

Cartilage destruction is a hallmark of osteoarthritis (OA) and is characterized by increased protease activity resulting in the degradation of critical extracellular matrix (ECM) proteins essential for maintaining cartilage integrity. Tenascin-C (TN-C) is an ECM glycoprotein, and its expression is upregulated in OA cartilage. We aimed to investigate the presence of TN-C fragments in arthritic cartilage and establish whether they promote cartilage degradation. Expression of TN-C and its fragments was evaluated in cartilage from subjects undergoing joint replacement surgery for OA and RA compared with normal subjects by western blotting. The localization of TN-C in arthritic cartilage was also established by immunohistochemistry. Recombinant TN-C fragments were then tested to evaluate which regions of TN-C are responsible for cartilage-degrading activity in an ex vivo cartilage explant assay measuring glycosaminoglycan (GAG) release, aggrecanase and matrix metalloproteinase (MMP) activity. We found that specific TN-C fragments are highly upregulated in arthritic cartilage. Recombinant TN-C fragments containing the same regions as those identified from OA cartilage mediate cartilage degradation by the induction of aggrecanase activity. TN-C fragments mapping to the EGF-L and FN type III domains 3-8 of TN-C had the highest levels of aggrecan-degrading ability that was not observed either with full-length TN-C or with other domains of TN-C. TN-C fragments represent a novel mechanism for cartilage degradation in arthritis and may present new therapeutic targets for the inhibition of cartilage degradation

Imbibition dynamics of nano-particulate ink-jet drops on micro-porous media

Ink-jet printing of nano-metallic colloidal fluids on to porous media such as coated papers has become a viable method to produce conductive tracks for low-cost, disposable printed electronic devices. However, the formation of well-defined and functional tracks on an absorbing surface is controlled by the drop imbibition dynamics in addition to the well-studied post-impact drop spreading behavior. This study represents the first investigation of the realtime imbibition of ink-jet deposited nano-Cu colloid drops on to coated paper substrates. In addition, the same ink was deposited on to a non-porous polymer surface as a control substrate. By using high-speed video imaging to capture the deposition of ink-jet drops, the time-scales of drop spreading and imbibition were quantified and compared with model predictions. The influences of the coating pore size on the bulk absorption rate and nano-Cu particle distribution have also been studied

Delayed reception of live blowfly (Calliphora vicina and Chrysomya rufifacies) larval samples: implications for minimum postmortem interval estimates.

Forensic entomology evidence collected by police and mortuary staff may be delayed in getting to the entomologist. Live samples may continue developing and alter minimum postmortem interval (PMImin) estimates. This study investigated development of simulated evidential samples of Calliphora vicina Robineau-Desvoidy and Chrysomya rufifacies (Macquart) (Diptera: Calliphoridae) maggots. Maggots of each species were studied in three developmental classes: "small" (late second/early third instar), "mid" (mid third instar) and "large" (late third instar). Seven replicates of 11 maggots in each class were assigned without food to four treatments: (1) 24 h at 20 °C; (2) 24 h at 4 °C; (3) 48 h at 20 °C and (4) 48 h at 4 °C. There was a significant difference in absolute length change across treatments, reflecting size for C. vicina, and interaction between size, time and temperature for Ch. rufifacies. Calliphora vicina maggots showed minimal mortality, and most second instar larvae moulted by the experiment's end. Chrysomya rufifacies showed heavy mortality and minimal moulting from the second to third instar. Only "large" Ch. rufifacies maggots kept at room temperature for 48 h pupariated. Since these results confirm that development can continue in live unfed maggot samples after their collection, it is not advisable to delay their preservation

Does the NIS implementation strategy effectively address cyber security risks in the UK?

This research explored how cyber security risks are managed across UK Critical National Infrastructure (CNI) sectors following implementation of the 2018 Networks and Information Security (NIS) legislation. Being in its infancy, there has been limited study into the effectiveness of this national framework for cyber risk management. The analysis of data gathered through interviews with key stakeholders against the NIS objectives indicated a collaborative implementation approach to improve cyber-risk management capabilities in CNI sectors. However, more work is required to bridge the gaps in the NIS framework to ensure holistic security across cyber spaces as well as non-cyber elements: cyber-physical security, cross-sector CNI service security measures, outcome-based regulatory assessments and risks due to connected smart technology implementations alongside legacy systems. This paper proposes ten key recommendations to counter the danger of not meeting the NIS key strategic objectives. In particular, it recommends that the approach to NIS implementation needs further alignment with its objectives, such as bringing a step-change in the cyber-security risk management capabilities of the CNI sectors

Ecological IVIS design : using EID to develop a novel in-vehicle information system

New in-vehicle information systems (IVIS) are emerging which purport to encourage more environment friendly or ‘green’ driving. Meanwhile, wider concerns about road safety and in-car distractions remain. The ‘Foot-LITE’ project is an effort to balance these issues, aimed at achieving safer and greener driving through real-time driving information, presented via an in-vehicle interface which facilitates the desired behaviours while avoiding negative consequences. One way of achieving this is to use ecological interface design (EID) techniques. This article presents part of the formative human-centred design process for developing the in-car display through a series of rapid prototyping studies comparing EID against conventional interface design principles. We focus primarily on the visual display, although some development of an ecological auditory display is also presented. The results of feedback from potential users as well as subject matter experts are discussed with respect to implications for future interface design in this field

Shooting the messenger: a systematic review investigating extracellular vesicle isolation and characterisation methods and their influence on understanding extracellular vesicles-radiotherapy interactions in glioblastoma

BACKGROUND: Extracellular vesicles (EVs) hold promise for improving our understanding of radiotherapy response in glioblastoma due to their role in intercellular communication within the tumour microenvironment (TME). However, methodologies to study EVs are evolving with significant variation within the EV research community. METHODS: We conducted a systematic review to critically appraise EV isolation and characterisation methodologies and how this influences our understanding of the findings from studies investigating radiotherapy and EV interactions in glioblastoma. 246 articles published up to 24/07/2023 from PubMed and Web of Science were identified using search parameters related to radiotherapy, EVs, and glioblastoma. Two reviewers evaluated study eligibility and abstracted data. RESULTS: In 26 articles eligible for inclusion (16 investigating the effects of radiotherapy on EVs, five investigating the effect of EVs on radiation response, and five clinical studies), significant heterogeneity and frequent omission of key characterisation steps was identified, reducing confidence that the results are related to EVs and their cargo as opposed to co-isolated bioactive molecules. However, the results are able to clearly identify interactions between EVs and radiotherapy bi-directionally within different cell types within the glioblastoma TME. These interactions facilitate transferable radioresistance and oncogenic signalling, highlighting that EVs are an important component in the variability of glioblastoma radiotherapy response. CONCLUSIONS: Future multi-directional investigations interrogating the whole TME are required to improve subsequent clinical translation, and all studies should incorporate up to date controls and reporting requirements to increase the validity of their findings. This would be facilitated by increased collaboration between less experienced and more experienced EV research groups

The impact of experimental impact pile driving on oxygen uptake in black seabream and plaice

This is the final version of the article. Available from Acoustical Society of America via the DOI in this record.Fourth International Conference on the Effects of Noise on Aquatic Life, Dublin, Ireland, 10-16 July 2016Anthropogenic noise is a recognized global pollutant that could potentially impact many organisms, including fishes. One of the acoustic sources producing high impulsive noise and vibration is pile driving. However, the potential impacts of real pile driving on fish species has received little attention, mainly due to the logistical challenges involved. Here, we investigated the impact of pile driving on the oxygen uptake (a secondary stress response) of black seabream Spondyliosoma cantharus and European plaice Pleuronectes platessa using an experimental pile driver setup in a flooded ship-building dock. Each individual fish was tested in ambient and pile driving conditions using a counterbalanced paired design to control for potential order effects. During pile driving, black seabream increased oxygen uptake compared to the ambient control condition suggesting higher stress levels. Plaice did not show differences in oxygen consumption between the pile driving and ambient treatment. These results show the impact of pile driving on secondary stress responses in fish, highlight species-specific differences concerning acoustical impacts, and showcase the possibility of carrying out large-scale semi-field acoustic experiments.Thanks also to E.ON, NERC MREKE and Marine Scotland for financial support

Cortical oscillatory dynamics and benzodiazepine-site modulation of tonic inhibition in fast spiking interneurons.

Tonic conductance mediated by extrasynaptic GABAA receptors has been implicated in the modulation of network oscillatory activity. Using an in vitro brain slice to produce oscillatory activity and a kinetic model of GABAA receptor dynamics, we show that changes in tonic inhibitory input to fast spiking interneurons underlie benzodiazepine-site mediated modulation of neuronal network synchrony in rat primary motor cortex. We found that low concentrations (10 nM) of the benzodiazepine site agonist, zolpidem, reduced the power of pharmacologically-induced beta-frequency (15-30 Hz) oscillatory activity. By contrast, higher doses augmented beta power. Application of the antagonist, flumazenil, also increased beta power suggesting endogenous modulation of the benzodiazepine binding site. Voltage-clamp experiments revealed that pharmacologically-induced rhythmic inhibitory postsynaptic currents were reduced by 10 nM zolpidem, suggesting an action on inhibitory interneurons. Further voltage-clamp studies of fast spiking cells showed that 10 nM zolpidem augmented a tonic inhibitory GABAA receptor mediated current in fast spiking cells whilst higher concentrations of zolpidem reduced the tonic current. A kinetic model of zolpidem-sensitive GABAA receptors suggested that incubation with 10 nM zolpidem resulted in a high proportion of GABAA receptors locked in a kinetically slow desensitized state whilst 30 nM zolpidem favoured rapid transition into and out of desensitized states. This was confirmed experimentally using a challenge with saturating concentrations of GABA. Selective modulation of an interneuron-specific tonic current may underlie the reversal of cognitive and motor deficits afforded by low-dose zolpidem in neuropathological states

Regulation of immune responses in primary biliary cholangitis: a transcriptomic analysis of peripheral immune cells

BACKGROUND AIMS: In patients with primary biliary cholangitis (PBC), the serum liver biochemistry measured during treatment with ursodeoxycholic acid-the UDCA response-accurately predicts long-term outcome. Molecular characterization of patients stratified by UDCA response can improve biological understanding of the high-risk disease, thereby helping to identify alternative approaches to disease-modifying therapy. In this study, we sought to characterize the immunobiology of the UDCA response using transcriptional profiling of peripheral blood mononuclear cell subsets. METHODS: We performed bulk RNA-sequencing of monocytes and TH1, TH17, TREG, and B cells isolated from the peripheral blood of 15 PBC patients with adequate UDCA response ("responders"), 16 PBC patients with inadequate UDCA response ("nonresponders"), and 15 matched controls. We used the Weighted Gene Co-expression Network Analysis to identify networks of co-expressed genes ("modules") associated with response status and the most highly connected genes ("hub genes") within them. Finally, we performed a Multi-Omics Factor Analysis of the Weighted Gene Co-expression Network Analysis modules to identify the principal axes of biological variation ("latent factors") across all peripheral blood mononuclear cell subsets. RESULTS: Using the Weighted Gene Co-expression Network Analysis, we identified modules associated with response and/or disease status (q<0.05) in each peripheral blood mononuclear cell subset. Hub genes and functional annotations suggested that monocytes are proinflammatory in nonresponders, but antiinflammatory in responders; TH1 and TH17 cells are activated in all PBC cases but better regulated in responders; and TREG cells are activated-but also kept in check-in responders. Using the Multi-Omics Factor Analysis, we found that antiinflammatory activity in monocytes, regulation of TH1 cells, and activation of TREG cells are interrelated and more prominent in responders. CONCLUSIONS: We provide evidence that adaptive immune responses are better regulated in patients with PBC with adequate UDCA response

Bacterial and metabolic phenotypes associated with inadequate response to ursodeoxycholic acid treatment in primary biliary cholangitis

Primary biliary cholangitis (PBC) is a chronic cholestatic liver disease with ursodeoxycholic acid (UDCA) as first-line treatment. Poor response to UDCA is associated with a higher risk of progressing to cirrhosis, but the underlying mechanisms are unclear. UDCA modulates the composition of primary and bacterial-derived bile acids (BAs). We characterized the phenotypic response to UDCA based on BA and bacterial profiles of PBC patients treated with UDCA. Patients from the UK-PBC cohort (n = 419) treated with UDCA for a minimum of 12-months were assessed using the Barcelona dynamic response criteria. BAs from serum, urine, and feces were analyzed using Ultra-High-Performance Liquid Chromatography-Mass Spectrometry and fecal bacterial composition measured using 16S rRNA gene sequencing. We identified 191 non-responders, 212 responders, and a subgroup of responders with persistently elevated liver biomarkers (n = 16). Responders had higher fecal secondary and tertiary BAs than non-responders and lower urinary bile acid abundances, with the exception of 12-dehydrocholic acid, which was higher in responders. The sub-group of responders with poor liver function showed lower alpha-diversity evenness, lower abundance of fecal secondary and tertiary BAs than the other groups and lower levels of phyla with BA-deconjugation capacity (Actinobacteriota/Actinomycetota, Desulfobacterota, Verrucomicrobiota) compared to responders. UDCA dynamic response was associated with an increased capacity to generate oxo-/epimerized secondary BAs. 12-dehydrocholic acid is a potential biomarker of treatment response. Lower alpha-diversity and lower abundance of bacteria with BA deconjugation capacity might be associated with an incomplete response to treatment in some patients