Harnessing the purinergic receptor pathway to develop functional engineered cartilage constructs

Objective: Mechanical stimulation is a widely used method to enhance the formation and properties of tissue-engineered cartilage. While this approach can be highly successful, it may be more efficient and effective to harness the known underlying mechanotransduction pathways responsible. With this aim, the purpose of this study was to assess the effect of directly stimulating the purinergic receptor pathway through exogenous adenosine 5\u27-triphosphate (ATP) in absence of externally applied forces. Methods: Isolated bovine articular chondrocytes were seeded in high density, 3D culture and supplemented with varying doses of ATP for up to 4 weeks. The effects on biosynthesis, extracellular matrix accumulation and mechanical properties were then evaluated. Experiments were also conducted to assess whether exogenous ATP elicited any undesirable effects, such as: inflammatory mediator release, matrix turn-over and mineralization. Results: Supplementation with ATP had a profound effect on the growth and maturation of the developed tissue. Exogenous ATP (62.5-250. μM) increased biosynthesis by 80-120%, and when stimulated for a period of 4 weeks resulted in increased matrix accumulation (80% increase in collagen and 60% increase in proteoglycans) and improved mechanical properties (6.5-fold increase in indentation modulus). While exogenous ATP did not stimulate the release of inflammatory mediators or induce mineralization, high doses of ATP (250μM) elicited a 2-fold increase in matrix metalloproteinase-13 expression suggesting the emergence of a catabolic response. Conclusions: Harnessing the ATP-purinergic receptor pathway is a highly effective approach to improve tissue formation and impart functional mechanical properties. However, the dose of ATP needs to be controlled as not to elicit a catabolic response. © 2010 Osteoarthritis Research Society International

Embedded library services : beyond chance encounters for students from low SES backgrounds

This paper reports research that examined how the embedding of library services through the learning management system contributed to the experience of students from low socio-economic status (SES) backgrounds. To evaluate the embedded practice, the researchers used a mixed-method approach involving surveys with students and interviews with library and academic staff. Survey results showed gains in students\u27 awareness of library resources and in their confidence and satisfaction using them. Staff participants reported benefits to students from the improved visibility of the library and involvement of students in conversations about information literacy. The teacher derived personal benefits in learning more about digital information resources while library staff benefitted from the research-driven nature of the practice which strengthened their collaborative partnership with academic staff. Based on the evaluation, an embedded approach has been adopted at the university in additional courses which have similar student profiles. The outcomes are relevant more widely in demonstrating both the potential benefits of embedded practice for supporting diverse student populations and how libraries can target their activities more effectively to national and university agendas for improving student outcomes

Quantitative magnetisation transfer imaging in relapsing-remitting multiple sclerosis: a systematic review and meta-analysis

Myelin-sensitive MRI such as magnetization transfer imaging has been widely used in multiple sclerosis. The influence of methodology and differences in disease subtype on imaging findings is, however, not well established. Here, we systematically review magnetization transfer brain imaging findings in relapsing-remitting multiple sclerosis. We examine how methodological differences, disease effects and their interaction influence magnetization transfer imaging measures. Articles published before 06/01/2021 were retrieved from online databases (PubMed, EMBASE and Web of Science) with search terms including ‘magnetization transfer’ and ‘brain’ for systematic review, according to a pre-defined protocol. Only studies that used human in vivo quantitative magnetization transfer imaging in adults with relapsing-remitting multiple sclerosis (with or without healthy controls) were included. Additional data from relapsing-remitting multiple sclerosis subjects acquired in other studies comprising mixed disease subtypes were included in meta-analyses. Data including sample size, MRI acquisition protocol parameters, treatments and clinical findings were extracted and qualitatively synthesized. Where possible, effect sizes were calculated for meta-analyses to determine magnetization transfer (i) differences between patients and healthy controls; (ii) longitudinal change and (iii) relationships with clinical disability in relapsing-remitting multiple sclerosis. Eighty-six studies met inclusion criteria. MRI acquisition parameters varied widely, and were also underreported. The majority of studies examined the magnetization transfer ratio in white matter, but magnetization transfer metrics, brain regions examined and results were heterogeneous. The analysis demonstrated a risk of bias due to selective reporting and small sample sizes. The pooled random-effects meta-analysis across all brain compartments revealed magnetization transfer ratio was 1.17 per cent units (95% CI −1.42 to −0.91) lower in relapsing-remitting multiple sclerosis than healthy controls (z-value: −8.99, P < 0.001, 46 studies). Linear mixed-model analysis did not show a significant longitudinal change in magnetization transfer ratio across all brain regions [β = 0.12 (−0.56 to 0.80), t-value = 0.35, P = 0.724, 14 studies] or normal-appearing white matter alone [β = 0.037 (−0.14 to 0.22), t-value = 0.41, P = 0.68, eight studies]. There was a significant negative association between the magnetization transfer ratio and clinical disability, as assessed by the Expanded Disability Status Scale [r = −0.32 (95% CI −0.46 to −0.17); z-value = −4.33, P < 0.001, 13 studies]. Evidence suggests that magnetization transfer imaging metrics are sensitive to pathological brain changes in relapsing-remitting multiple sclerosis, although effect sizes were small in comparison to inter-study variability. Recommendations include: better harmonized magnetization transfer acquisition protocols with detailed methodological reporting standards; larger, well-phenotyped cohorts, including healthy controls; and, further exploration of techniques such as magnetization transfer saturation or inhomogeneous magnetization transfer ratio

The GUCY2C Tumor Suppressor is the Nexus of a Paracrine Hormone Axis Preventing Radiotherapy-Induced Gastrointestinal (GI) Toxicity

Purpose/Objective: Radiation-induced GI toxicity is the primary dose limitation compromising therapy in cancer patients treated with radiation therapy. GUCY2C is the intestinal receptor for diarrheagenic bacterial enterotoxins and the endogenous paracrine hormones guanylin and uroguanylin. Following genomic insult, cyclic (c)GMP produced by ligand activation of GUCY2C enhances DNA damage sensing and repair in intestinal cells. Here, we show that the GUCY2C-cGMP axis mediates p53-dependent radioprotection of intestinal epithelial cells. American Society for Therapeutic Radiation Oncology (ASTRO) 52nd Annual Meeting October 31 - November 4, San Diego, C

Sports Hernia/Athletic Pubalgia Among Women

© The Author(s) 2018. Background: “Athletic pubalgia,” a term that has gained acceptance over “sports hernia,” is more common in men than women; however, it represents a significant source of morbidity for patients of both sexes. Inconsistent terminology surrounding this entity poses a diagnostic challenge and makes studying the populations at risk difficult. Purpose: To review a case series of women with athletic pubalgia by analyzing their presentations, concomitant pathologies, and surgical outcomes. Study Design: Case series; Level of evidence, 4. Methods: Between 2013 and 2016, 197 patients were seen and evaluated for the diagnosis of athletic pubalgia. Eighteen patients seen during this time were women. All patients received “pubalgia protocol” magnetic resonance imaging and subsequent surgical intervention for their pathologies. Outcomes among 17 women were assessed with a patient questionnaire \u3e1 year after surgery. Results: Of the 17 women, 9 had rectus aponeurotic plate injury only, or pure athletic pubalgia; the remaining 8 had athletic pubalgia in combination with ≥1 inguinal, obturator, and femoral hernias. Regarding female patients in both groups, 88.2% reported that the surgery was a success at follow-up. Conclusion: Surgical repair of athletic pubalgia among women is successful in dramatically reducing pain levels in this important subset of patients

Label-free, live optical imaging of reprogrammed bipolar disorder patient-derived cells reveals a functional correlate of lithium responsiveness

Development of novel treatments and diagnostic tools for psychiatric illness has been hindered by the absence of cellular models of disease. With the advent of cellular reprogramming, it may be possible to recapitulate the disease biology of psychiatric disorders using patient skin cells transdifferentiated to neurons. However, efficiently identifying and characterizing relevant neuronal phenotypes in the absence of well-defined pathophysiology remains a challenge. In this study, we collected fibroblast samples from patients with bipolar 1 disorder, characterized by their lithium response (n=12), and healthy control subjects (n=6). We identified a cellular phenotype in reprogrammed neurons using a label-free imaging assay based on a nanostructured photonic crystal biosensor and found that an optical measure of cell adhesion was associated with clinical response to lithium treatment. This cellular phenotype may represent a useful biomarker to evaluate drug response and screen for novel therapeutics

dc readout experiment at the Caltech 40m prototype interferometer

The Laser Interferometer Gravitational Wave Observatory (LIGO) operates a 40m prototype interferometer on the Caltech campus. The primary mission of the prototype is to serve as an experimental testbed for upgrades to the LIGO interferometers and for gaining experience with advanced interferometric techniques, including detuned resonant sideband extraction (i.e. signal recycling) and dc readout (optical homodyne detection). The former technique will be employed in Advanced LIGO, and the latter in both Enhanced and Advanced LIGO. Using dc readout for gravitational wave signal extraction has several technical advantages, including reduced laser and oscillator noise couplings as well as reduced shot noise, when compared to the traditional rf readout technique (optical heterodyne detection) currently in use in large-scale ground-based interferometric gravitational wave detectors. The Caltech 40m laboratory is currently prototyping a dc readout system for a fully suspended interferometric gravitational wave detector. The system includes an optical filter cavity at the interferometer's output port, and the associated controls and optics to ensure that the filter cavity is optimally coupled to the interferometer. We present the results of measurements to characterize noise couplings in rf and dc readout using this system