The regulation of matrix metalloproteinases and their inhibitors

The matrix metalloproteinases (MMP) are a family of 23 enzymes in man. These enzymes were originally described as cleaving extracellular matrix (ECM) substrates with a predominant role in ECM homeostasis, but it is now clear that they have much wider functionality. Control over MMP and/or tissue inhibitor of metalloproteinases (TIMP) activity in vivo occurs at different levels and involves factors such as regulation of gene expression, activation of zymogens and inhibition of active enzymes by specific inhibitors. Whilst these enzymes and inhibitors have clear roles in physiological tissue turnover and homeostasis, if control of their expression or activity is lost, they contribute to a number of pathologies including e.g. cancer, arthritis and cardiovascular disease. The expression of many MMPs and TIMPs is regulated at the level of transcription by a variety of growth factors, cytokines and chemokines, though post-transcriptional pathways may contribute to this regulation in specific cases. The contribution of epigenetic modifications has also been uncovered in recent years. The promoter regions of many of these genes have been, at least partly, characterised including the role of identified single nucleotide polymorphisms. This article aims to review current knowledge across these gene families and use a bioinformatic approach to fill the gaps where no functional data are available

Randomised trials in the South African Medical Journal, 1948- 1997

Objective. To describe randomised controlled trials (RCTs) published in the South African Medical Journal (SAMJ) over a 50-year period from 1948 to 1997 with regard to number, topic and quality.Methods. We hand searched all issues of the SAMJ published during the study period to identify all published RCTs.Outcome measures. Number, topic and quality of RCTs published from 1948 to 1997.Results. Eight hundred and fifty-eight clinical trials were published during the period reviewed. Eighty-four per cent of RCTs were published as full articles. During the 1980s the number of RCTs published increased rapidly,  with a peak of 35 in 1985, but then declined to only 5 in 1997. The majority (92%) of RCTs were conducted in a hospital setting. A varied range of subjects was covered, with gastroenterology taking the lead and no trials in public health. The sample size in more than 50% of RCTs was smaller than 50 patients. Fifty-one per cent (435 trials) used random allocation and 49% (423) quasi-random methods of allocation. Concealment of treatment allocation was judged to be adequate in 46% of studies (N == 200), blinding of observers assessing outcomes was adequate in 28% (123), and all the allocated test subjects were included in the primary analysis in 28% (123). The follow-up period was more than 1 year in 4% (17) and less than 6 days in 16% (71).Conclusions. Compared with other international journals the SAMJ is highly regarded in terms of the number of trials published. There are, however, a number of deficiencies in the quality of the trials

Superoxide dismutase downregulation in osteoarthritis progression and end-stage disease

Oxidative stress is proposed as an important factor in osteoarthritis (OA). To investigate the expression of the three superoxide dismutase (SOD) antioxidant enzymes in OA. SOD expression was determined by real-time PCR and immunohistochemistry using human femoral head cartilage. SOD2 expression in Dunkin–Hartley guinea pig knee articular cartilage was determined by immunohistochemistry. The DNA methylation status of the SOD2 promoter was determined using bisulphite sequencing. RNA interference was used to determine the consequence of SOD2 depletion on the levels of reactive oxygen species (ROS) using MitoSOX and collagenases, matrix metalloproteinase 1 (MMP-1) and MMP-13, gene expression. All three SOD were abundantly expressed in human cartilage but were markedly downregulated in end-stage OA cartilage, especially SOD2. In the Dunkin–Hartley guinea pig spontaneous OA model, SOD2 expression was decreased in the medial tibial condyle cartilage before, and after, the development of OA-like lesions. The SOD2 promoter had significant DNA methylation alterations in OA cartilage. Depletion of SOD2 in chondrocytes increased ROS but decreased collagenase expression. This is the first comprehensive expression profile of all SOD genes in cartilage and, importantly, using an animal model, it has been shown that a reduction in SOD2 is associated with the earliest stages of OA. A decrease in SOD2 was found to be associated with an increase in ROS but a reduction of collagenase gene expression, demonstrating the complexities of ROS function

Structure Discovery in Mixed Order Hyper Networks

Background  Mixed Order Hyper Networks (MOHNs) are a type of neural network in which the interactions between inputs are modelled explicitly by weights that can connect any number of neurons. Such networks have a human readability that networks with hidden units lack. They can be used for regression, classification or as content addressable memories and have been shown to be useful as fitness function models in constraint satisfaction tasks. They are fast to train and, when their structure is fixed, do not suffer from local minima in the cost function during training. However, their main drawback is that the correct structure (which neurons to connect with weights) must be discovered from data and an exhaustive search is not possible for networks of over around 30 inputs.  Results  This paper presents an algorithm designed to discover a set of weights that satisfy the joint constraints of low training error and a parsimonious model. The combined structure discovery and weight learning process was found to be faster, more accurate and have less variance than training an MLP.  Conclusions  There are a number of advantages to using higher order weights rather than hidden units in a neural network but discovering the correct structure for those weights can be challenging. With the method proposed in this paper, the use of high order networks becomes tractable

Using fiberless, wearable fNIRS to monitor brain activity in real-world cognitive tasks

Functional Near Infrared Spectroscopy (fNIRS) is a neuroimaging technique that uses near-infrared light to monitor brain activity. Based on neurovascular coupling, fNIRS is able to measure the haemoglobin concentration changes secondary to neuronal activity. Compared to other neuroimaging techniques, fNIRS represents a good compromise in terms of spatial and temporal resolution. Moreover, it is portable, lightweight, less sensitive to motion artifacts and does not impose significant physical restraints. It is therefore appropriate to monitor a wide range of cognitive tasks (e.g., auditory, gait analysis, social interaction) and different age populations (e.g., new-borns, adults, elderly people). The recent development of fiberless fNIRS devices has opened the way to new applications in neuroscience research. This represents a unique opportunity to study functional activity during real-world tests, which can be more sensitive and accurate in assessing cognitive function and dysfunction than lab-based tests. This study explored the use of fiberless fNIRS to monitor brain activity during a real-world prospective memory task. This protocol is performed outside the lab and brain haemoglobin concentration changes are continuously measured over the prefrontal cortex while the subject walks around in order to accomplish several different tasks

A novel GLM-based method for the Automatic IDentification of functional Events (AIDE) in fNIRS data recorded in naturalistic environments.

Recent technological advances have allowed the development of portable functional Near-Infrared Spectroscopy (fNIRS) devices that can be used to perform neuroimaging in the real-world. However, as real-world experiments are designed to mimic everyday life situations, the identification of event onsets can be extremely challenging and time-consuming. Here, we present a novel analysis method based on the general linear model (GLM) least square fit analysis for the Automatic IDentification of functional Events (or AIDE) directly from real-world fNIRS neuroimaging data. In order to investigate the accuracy and feasibility of this method, as a proof-of-principle we applied the algorithm to (i) synthetic fNIRS data simulating both block-, event-related and mixed-design experiments and (ii) experimental fNIRS data recorded during a conventional lab-based task (involving maths). AIDE was able to recover functional events from simulated fNIRS data with an accuracy of 89%, 97% and 91% for the simulated block-, event-related and mixed-design experiments respectively. For the lab-based experiment, AIDE recovered more than the 66.7% of the functional events from the fNIRS experimental measured data. To illustrate the strength of this method, we then applied AIDE to fNIRS data recorded by a wearable system on one participant during a complex real-world prospective memory experiment conducted outside the lab. As part of the experiment, there were four and six events (actions where participants had to interact with a target) for the two different conditions respectively (condition 1: social-interact with a person; condition 2: non-social-interact with an object). AIDE managed to recover 3/4 events and 3/6 events for conditions 1 and 2 respectively. The identified functional events were then corresponded to behavioural data from the video recordings of the movements and actions of the participant. Our results suggest that "brain-first" rather than "behaviour-first" analysis is possible and that the present method can provide a novel solution to analyse real-world fNIRS data, filling the gap between real-life testing and functional neuroimaging

The microRNA-455 null mouse has memory deficit and increased anxiety, targeting key genes involved in Alzheimer’s disease

The complete molecular mechanisms underlying the pathophysiology of Alzheimer’s disease (AD) remain to be elucidated. Recently, microRNA-455-3p has been identified as a cir-culating biomarker of early AD, with increased expression in post-mortem brain tissue of AD patients. MicroRNA-455-3p also directly targets and down-regulates APP, with the overexpres-sion of miR-455-3p suppressing its toxic effects. Here, we show that miR-455-3p expression de-creases with age in the brains of wild-type mice. We generated a miR-455 null mouse utilising CRISPR-Cas9 to explore its function further. Loss of miR-455 resulted in increased weight gain, potentially indicative of metabolic disturbances. Furthermore, performance on the novel object recognition task diminished significantly in miR-455 null mice (p = 0.004), indicating deficits in recognition memory. A slight increase in anxiety was also captured on the open field test. BACE1 and TAU were identified as new direct targets for miR-455-3p, with overexpression of miR-455-3p leading to a reduction in the expression of APP, BACE1 and TAU in neuroblastoma cells. In the hippocampus of miR-455 null mice at 14 months of age, the levels of protein for APP, BACE1 and TAU were all increased. Such findings reinforce the involvement of miR-455 in AD progression and demonstrate its action on cognitive performance

The microRNA-29 family in cartilage homeostasis and osteoarthritis

MicroRNAs have been shown to function in cartilage development and homeostasis, as well as in progression of osteoarthritis. The objective of the current study was to identify microRNAs involved in the onset or early progression of osteoarthritis and characterise their function in chondrocytes. MicroRNA expression in mouse knee joints post-DMM surgery was measured over 7 days. Expression of miR-29b-3p was increased at day 1 and regulated in the opposite direction to its potential targets. In a mouse model of cartilage injury and in end-stage human OA cartilage, the miR-29 family were also regulated. SOX9 repressed expression of miR-29a-3p and miR-29b-3p via the 29a/b1 promoter. TGFβ1 decreased expression of miR-29a, b and c (3p) in primary chondrocytes, whilst IL-1β increased (but LPS decreased) their expression. The miR-29 family negatively regulated Smad, NFκB and canonical WNT signalling pathways. Expression profiles revealed regulation of new WNT-related genes. Amongst these, FZD3, FZD5, DVL3, FRAT2, CK2A2 were validated as direct targets of the miR-29 family. These data identify the miR-29 family as microRNAs acting across development and progression of OA. They are regulated by factors which are important in OA and impact on relevant signalling pathways