Characterisation of ADAMTS-4 endocytosis by chondrosarcoma cells and chondrocytes

Aggrecan is one of the most abundant components of the articular cartilage matrix and its degradation by aggrecanases is considered to be a key early event in the development of osteoarthritis. This study investigates whether the extracellular level of ADAMTS-4 (a disintegrin and metalloproteinase with thrombospondin type 1 motifs-4), one of the most studied aggrecanases, can be regulated by receptor-mediated endocytosis. Exogenously-added ADAMTS-4 disappeared from the medium of HTB94 cells and TCA-soluble degradation products of ADAMTS-4 increased in the medium over time. Fluorescent-labeled ADAMTS-4 could be detected within the cell by confocal microscopy. ADAMTS-4 clearance by HTB94 cells and chondrocytes could be inhibited by more than 70 % by heparin and another sulfated glycan, calcium pentosan polysulfate, suggesting that the cellular uptake of ADAMTS-4 was via a mechanism involving cell surface heparan sulfate proteoglycans (HSPGs). GM6001 also inhibited ADAMTS-4 clearance by 50 %, suggesting that cell surface metalloprotease-mediated degradation played a contributory role. However, ADAMTS-4 clearance was reduced by 50 % in a HSPG-deficient cell line compared to wild-type cells, further supporting a HSPG-dependent mechanism of ADAMTS-4 cellular uptake and preliminary studies using Timp-3-null fibroblasts suggest that ADAMTS-4 may be endocytosed in a complex with TIMP-3. In HTB94 cells and chondrocytes, the appearance of TCA-soluble degradation products was also inhibited by at least 50 % by receptor-associated protein (RAP), an antagonist for members of the low-density lipoprotein receptor (LDL-R) family. However, siRNA knockdown of LDL-receptor-related protein (LRP-1), a member of the LDL-R family, in HTB94 cells and the use of an LRP-1-deficient cell line had no affect on the clearance of ADAMTS-4. These results suggest that another member of the LDL-R family may be involved. Taken together, this research has revealed a novel RAP-sensitive and/or HSPG-sensitive mechanism of ADAMTS-4 regulation which may have a role in the degradation of the cartilage matrix

EXAMINING RACISM AND WHITE ALLYSHIP AMONG COUNSELING PSYCHOLOGISTS

Historically, research has focused on White individuals’ initial responses to learning about White privilege and other indicators of early stages of racial awareness and identity development. However, the literature is relatively sparse regarding understanding the experiences of racial identity development in White individuals who are beyond initial introductions to racial awareness, such as Counseling Psychologists (CPs). The assumption is that Counseling Psychology professionals are adequately trained to provide efficacious mental health services and engage in culturally sensitive work activities; however, research indicates that Black clients, colleagues, and graduate students experience racism, such as microaggressions, when interacting with White CPs. The current study seeks to address the overarching question: how do White Counseling Psychology faculty members understand their experiences with racism towards Black Americans? Ten White Counseling Psychologists were interviewed, and their interview data were analyzed with Interpretive Phenomenological Analysis (IPA). IPA explored the unique perspectives and meaning-making processes that White Counseling Psychologists employed when discussing their experiences with racism against Black Americans. Findings elucidated how racism and allyship manifested variably among White CPs. Participants ranged from individuals engaged in advocacy work to individuals who actively defend the academy as a White space. Findings were organized into five overarching themes, including: White Privilege to Emotionally Distance Self from the Realities of Racism, Struggles to Engaging in Allyship, Honest Self-Awareness and Reflection, Intentional Advocacy, and Perceives Racism in their Environments. Recommendations were proffered to inform imperative training and allyship opportunities for White Counseling Psychologists in academia

Emerging nanomedicine applications and manufacturing: progress and challenges

APS 6th International PharmSci Conference 2015 7–9 September 2015 East Midlands Conference Centre, University of Nottingham, Nottingham, UK As part of the 6th APS International PharmSci Conference, a nanomedicine session was organised to address challenges and share experiences in this field. Topics ranged from the reporting on latest results and advances in the development of targeted therapeutics to the needs that the community faces in how to progress these exciting proof of concept results into products. Here we provide an overview of the discussion and highlight some of the initiatives that have recently been established to support the translation of nanomedicines into the clinic. </jats:p

Investigating Temporal Features of Carotid Intima-Media Thickness from Ultrasound Imaging with Recurrent Neural Networks

Measuring carotid intima-media thickness (cIMT) of the Common Carotid Artery (CCA) via B-mode ultrasound imaging is a non-invasive yet effective way to monitor and assess cardiovascular risk. Recent studies using Convolutional Neural Networks (CNNs) to automate the process have mainly focused on the detection of regions of interest (ROI) in single frame images collected at fixed timepoints and have not exploited the temporal information captured in ultrasound imaging. This paper presents a novel framework to investigate the temporal features of cIMT, in which Recurrent Neural Networks (RNN) were deployed for ROI detection using consecutive frames from ultrasound imaging. The cIMT time series can be formed from estimates of cIMT in each frame of an ultrasound scan, from which additional information (such as min, max, mean, and frequency) on cIMT time series can be extracted. Results from evaluation show the best performance for ROI detection improved 4.75% by RNN compared to CNN-based methods. Furthermore, the heart rate estimated from the cIMT time series for seven patients was highly correlated with the patient’s clinical records, which suggests the potential application of the cIMT time series and related features for clinical studies in the future.<br/

Reduced physical activity and increased sedentary behaviour: The damage on young people during the COVID-19 pandemic

Health childhood development is fostered through movement behaviours, including sufficient physical activity (Moore et al. 2020). This article reviews some of the recently published global studies that have examined the impact of COVID-19 on children’s physical activity and sedentary behaviours, the majority of which have indicated that children’s physical activity behaviours have lessened significantly during these times, while their sedentary behaviours have risen significantly. The authors then go on to make some suggestions of ways in which to encourage and foster physical activity for both children and their families, for example by showing people different ways of staying active, and offering other opportunities for physical activity, as well as ensuring the feeling of staying safe and protected

MRI of Suspected Appendicitis During Pregnancy: Interradiologist Agreement, Indeterminate Interpretation and the Meaning of Non-Visualization of the Appendix

Objective: To determine the degree of interradiologist agreement between the MRI features of appendicitis during pregnancy, the outcomes associated with an indeterminate interpretation and the negative predictive value of non-visualization of the appendix. Methods: Our study was approved by the institutional review board at the Washington University in St. Louis, Missouri (WUStL) and was HIPAA (Health Insurance Portability and Accountability Act of 1996)-compliant. The informed consent requirement was waived. Cases of suspected appendicitis during pregnancy evaluated using MRI were retrospectively identified using search queries. Scans were re-reviewed by two radiologists (7 and 9 years experience, respectively) to evaluate the interradiologist agreement of different MRI features of appendicitis during pregnancy (visualization of the appendix, appendiceal diameter, appendiceal wall thickening, periappendiceal fat stranding, fluid-filled appendix and periappendiceal fluid). The radiologists were blinded to patient outcome, patient intervention, laboratory data, demographic data and the original MRI reports. Clinical outcomes were documented by surgical pathology or clinical observation. Interradiologist agreement was analysed using Cohen’s κ, while patient demographic and clinical data was analysed using Student\u27s t-testing. Results: 233 females with suspected appendicitis during pregnancy were evaluated using MRI over a 13-year period (mean age, 28.4 years; range, 17–38 years). There were 14 (6%) positive examinations for appendicitis during pregnancy, including 1 patient whose MRI was interpreted as negative, proven by surgical pathology. The presence of periappendiceal soft-tissue stranding and the final overall impression had the most interradiologist agreement (к = 0.81–1). There were no pregnant patients found to have acute appendicitis who had an indeterminate MR interpretation or when the appendix could not be visualized. Conclusion: The final impression by the two retrospectively reviewing radiologists of MR examinations performed for suspected appendicitis during pregnancy had near-perfect agreement. In patients where the appendix could not be visualized or in patients that were interpreted as indeterminate, no patients had acute appendicitis. Advances in Knowledge: MR impression for suspected appendicitis in the pregnant patient has high interradiologist agreement, and a non-visualized appendix or lack of inflammatory findings at the time of MR, reliably excludes surgical appendicitis

FAK Deletion Promotes p53-Mediated Induction of p21, DNA-Damage Responses and Radio-Resistance in Advanced Squamous Cancer Cells

Focal adhesion kinase (FAK) is a cytoplasmic tyrosine kinase that is elevated in a variety of human cancers. While FAK is implicated in many cellular processes that are perturbed in cancer, including proliferation, actin and adhesion dynamics, polarisation and invasion, there is only some limited information regarding the role of FAK in radiation survival. We have evaluated whether FAK is a general radio-sensitising target, as has been suggested by previous reports. We used a clean genetic system in which FAK was deleted from mouse squamous cell carcinoma (SCC) cells (FAK −/−), and reconstituted with exogenous FAK wild type (wt). Surprisingly, the absence of FAK was associated with increased radio-resistance in advanced SCC cells. FAK re-expression inhibited p53-mediated transcriptional up-regulation of p21, and a sub-set of other p53 target genes involved in DNA repair, after treatment with ionizing radiation. Moreover, p21 depletion promoted radio-sensitisation, implying that FAK-mediated inhibition of p21 induction is responsible for the relative radio-sensitivity of FAK-proficient SCC cells. Our work adds to a growing body of evidence that there is a close functional relationship between integrin/FAK signalling and the p53/p21 pathway, but demonstrates that FAK's role in survival after stress is context-dependent, at least in cancer cells. We suggest that there should be caution when considering inhibiting FAK in combination with radiation, as this may not always be clinically advantageous

A review of psychiatric co-morbidity described in genetic and immune mediated movement disorders

Psychiatric symptoms are an increasingly recognised feature of movement disorders. Recent identification of causative genes and autoantibodies has allowed detailed analysis of aetiologically homogenous subgroups, thereby enabling determination of the spectrum of psychiatric symptoms in these disorders. This review evaluates the incidence and type of psychiatric symptoms encountered in patients with movement disorders. A broad spectrum of psychiatric symptoms was identified across all subtypes of movement disorder, with depression, generalised anxiety disorder and obsessive-compulsive disorder being most common. Psychosis, schizophrenia and attention deficit hyperactivity disorder were also identified, with the psychiatric symptoms often predating onset of the motor disorder. The high incidence of psychiatric symptoms across such a wide range of movement disorders suggests a degree of common or overlapping pathogenic mechanisms. Our review demonstrates the need for increased clinical awareness of such co-morbidities, which should facilitate early neuropsychiatric intervention and allied specialist treatment for patients

Refractive and corneal astigmatism in white school children in Northern Ireland

To study the prevalence of and relation between refractive and corneal astigmatism in white school children in Northern Ireland and to describe the association between refractive astigmatism and refractive error