Neurofilament Proteins as Body Fluid Biomarkers of Neurodegeneration in Multiple Sclerosis

Biomarkers of axonal degeneration have the potential to improve our capacity to predict and monitor neurological outcome in multiple sclerosis (MS) patients. Neurofilament proteins, one of the major proteins expressed within neurons and axons, have been detected in cerebrospinal fluid and blood samples from MS patients and are now being actively investigated for their utility as prognostic indicators of disease progression in MS. In this paper, we summarize the current literature on neurofilament structure, assembly, and degeneration and discuss their potential utility as biomarkers for monitoring neurological decline in MS. We also discuss the need to further develop sensitive methods for assaying neurofilaments in blood to improve clinical applicability

A Podcast of One’s Own

In this short Essay, we discuss the lack of racial and gender diversity on and around the Supreme Court. As we note, the ranks of the Court’s Justices and its clerks historically have been dominated by white men. But this homogeneity is not limited to the Court’s members or its clerks. As we explain, much of the Court’s broader ecosystem suffers from this same lack of diversity. The advocates who argue before the Court are primarily white men; the experts cited in the Court’s opinions, as well as the experts on whom Court commentators rely in interpreting those opinions, are often white men; and the commentators who translate the Court’s work for the public are also largely white men. We suggest this lack of diversity has consequences both for the Court’s work and for the public’s understanding of the Court. We also identify some of the factors that contribute to the lack of diversity in the Court’s ecosystem, including unduly narrow conceptions of expertise and a rigid insistence on particular notions of neutrality. We also note and discuss our own modest efforts to disrupt these dynamics with Strict Scrutiny, our podcast about the Supreme Court and the legal culture that surrounds it. To be sure, a podcast, by itself, will not dismantle the institutional factors that we have identified in this Essay. Nevertheless, we maintain that our efforts to use the podcast as a platform for surfacing these institutional dynamics, while simultaneously cultivating a more diverse cadre of Supreme Court experts and commentators, is a step in the right direction

Self-selecting peer groups formed within the laboratory environment have a lasting effect on individual student attainment and working practices.

Within the present study, we investigate the lasting effect of laboratory peer group interactions on the end of year attainment of bioscience and chemistry students. By asking students to identify who they primarily work with within the laboratory environment and evaluating the interactions through cluster analysis, we identified two main categories of laboratory peer groups. The first long-lived well-established pairings of two students, "swans", who work together for all or the majority of the laboratory sessions and the second dynamic fluid groups, "dolphins", of between three to nine students who work with each other interchangeably. Statistical analysis is presented, which demonstrates that individuals within each lab peer group were likely to achieve a similar average mark at the end of the first year of study on the course. We identified the driving factors for the formation of these groups as friendship and perceived work ethic. There is a preference for high achieving students to work with other high achieving students and lower-achieving to group around a shared social background. Targeted interventions, in which pairings were selected by the tutor at the onset of the study, altered the ratio from long-lived pairs to more dynamic groups and increased students willingness to work with others outside of their group but did not change the drivers of group formation or resulting pattern of achievement. We conclude with recommendations around group working within the laboratory environment

Accelerated Calvarial Healing in Mice Lacking Toll-Like Receptor 4

The bone and immune systems are closely interconnected. The immediate inflammatory response after fracture is known to trigger a healing cascade which plays an important role in bone repair. Toll-like receptor 4 (TLR4) is a member of a highly conserved receptor family and is a critical activator of the innate immune response after tissue injury. TLR4 signaling has been shown to regulate the systemic inflammatory response induced by exposed bone components during long-bone fracture. Here we tested the hypothesis that TLR4 activation affects the healing of calvarial defects. A 1.8 mm diameter calvarial defect was created in wild-type (WT) and TLR4 knockout (TLR4-/-) mice. Bone healing was tested using radiographic, histologic and gene expression analyses. Radiographic and histomorphometric analyses revealed that calvarial healing was accelerated in TLR4-/- mice. More bone was observed in TLR4-/- mice compared to WT mice at postoperative days 7 and 14, although comparable healing was achieved in both groups by day 21. Bone remodeling was detected in both groups on postoperative day 28. In TLR4-/- mice compared to WT mice, gene expression analysis revealed that higher expression levels of IL-1β, IL-6, TNF-α,TGF-β1, TGF-β3, PDGF and RANKL and lower expression level of RANK were detected at earlier time points (≤ postoperative 4 days); while higher expression levels of IL-1β and lower expression levels of VEGF, RANK, RANKL and OPG were detected at late time points (> postoperative 4 days). This study provides evidence of accelerated bone healing in TLR4-/- mice with earlier and higher expression of inflammatory cytokines and with increased osteoclastic activity. Further work is required to determine if this is due to inflammation driven by TLR4 activation. © 2012 Wang et al

Family-focused campus-based university event increases perceived knowledge, science capital and aspirations across a wide demographic

Creative ways of delivering informal science events in community settings are viewed as key to engaging new audiences and participants whom scientists find hard to reach, however, the impact of ‘formal’ setting events is often overlooked. Here, through a mixed-methods approach, we analyse a large-scale family-focused public engagement event hosted within a university campus setting. We aimed to explore the profile of visitors attending together with the impact and perceived knowledge gained. Analysis from two consecutive years of data collection found that the university-based event attracted new visitors annually, with almost half having not attended other science events/attractions within the last year. An increase in perceived knowledge was shown amongst all study participants, being significantly amplified in those from low progression to higher education postcode areas. Both immediate and longer-term positive impact was reported by participants with increases in components of science capital observed as well as enhanced positive perception of the university and its students. This data exemplifies the benefit of university-hosted events in widening participation and public understanding of science

Imaging in Suspected Renal Colic: Systematic Review of the Literature and Multispecialty Consensus

Background Renal colic is common, and CT is frequently utilized when the diagnosis of kidney stones is suspected. CT is accurate but exposes patients to ionizing radiation and has not been shown to alter either interventional approaches or hospital admission rates. This multi-organizational transdisciplinary collaboration sought evidence-based, multispecialty consensus on optimal imaging across different clinical scenarios in patients with suspected renal colic in the acute setting. Methods In conjunction with the American College of Emergency Physicians (ACEP) eQual network, we formed a nine-member panel with three physician representatives each from ACEP, the ACR, and the American Urology Association. A systematic literature review was used as the basis for a three-step modified Delphi process to seek consensus on optimal imaging in 29 specific clinical scenarios. Results From an initial search yielding 6,337 records, there were 232 relevant articles of acceptable evidence quality to guide the literature summary. At the completion of the Delphi process consensus, agreement was rated as perfect in 15 (52%), excellent in 8 (28%), good in 3 (10%), and moderate in 3 (10%) of the 29 scenarios. There were no scenarios where at least moderate consensus was not reached. CT was recommended in 7 scenarios (24%), with ultrasound in 9 (31%) and no further imaging needed in 12 (45%). Summary Evidence and multispecialty consensus support ultrasound or no further imaging in specific clinical scenarios, with reduced-radiation dose CT to be employed when CT is needed in patients with suspected renal colic

How students’ inspirations and aspirations impact motivation and engagement in the first year of study

Within this study, we aim to better understand the inspirations and aspirations of first year Biosciences and Chemistry undergraduates, how these change over the first year of study and their impact on motivation and engagement. Participants were asked to write a short reflective piece at the start of Welcome Week in their first year of undergraduate study. Thematic analysis identified four themes surrounding inspirations and aspirations. The most common theme was students naming a specific career as their aspiration (58%), followed by being inspired by work experience, aspiring to undertake further study and finally personal experience of a specific illness. Our findings showed that students’ career aspirations differed depending on ethnicity, with ambitions for medicine and laboratory work showing a marked increase in some ethnically marginalised groups. Focus groups undertaken at the end of the first year of study highlight increased motivation and engagement when students feel their course content aligns with their career aims. Conversely, students are disengaged by course material they feel is irrelevant to their chosen career. Here, we will discuss the impact of these findings on creating an inclusive curriculum and the career readiness of the student body. Conclusions apply to career development modules and how the applied nature of a course can lead to engagement and higher motivation for students as well as curriculum design

A Macaque Model to Study Vaginal HSV-2/Immunodeficiency Virus Co-Infection and the Impact of HSV-2 on Microbicide Efficacy

Herpes simplex virus type-2 (HSV-2) infection enhances the transmission and acquisition of human immunodeficiency virus (HIV). This occurs in symptomatic and asymptomatic stages of HSV-2 infection, suggesting that obvious herpetic lesions are not required to increase HIV spread. An animal model to investigate the underlying causes of the synergistic action of the two viruses and where preventative strategies can be tested under such complex physiological conditions is currently unavailable.We set out to establish a rhesus macaque model in which HSV-2 infection increases the susceptibility to vaginal infection with a model immunodeficiency virus (simian-human immunodeficiency virus, SHIV-RT), and to more stringently test promising microbicides. HSV-2 exposure significantly increased the frequency of vaginal SHIV-RT infection (n = 6). Although cervical lesions were detected in only approximately 10% of the animals, long term HSV-2 DNA shedding was detected (in 50% of animals followed for 2 years). Vaginal HSV-2 exposure elicited local cytokine/chemokine (n = 12) and systemic low-level HSV-2-specific adaptive responses in all animals (n = 8), involving CD4(+) and CD8(+) HSV-specific T cells (n = 5). Local cytokine/chemokine responses were lower in co-infected animals, while simian immunodeficiency virus (SIV)-specific adaptive responses were comparable in naïve and HSV-2-infected animals (n = 6). Despite the increased frequency of SHIV-RT infection, a new generation microbicide gel, comprised of Carraguard(R) and a non-nucleoside reverse transcriptase inhibitor MIV-150 (PC-817), blocked vaginal SHIV-RT infection in HSV-2-exposed animals (n = 8), just as in naïve animals.We established a unique HSV-2 macaque model that will likely facilitate research to define how HSV-2 increases HIV transmission, and enable more rigorous evaluation of candidate anti-viral approaches in vivo

Downregulation of MicroRNA-9 in iPSC-Derived Neurons of FTD/ALS Patients with TDP-43 Mutations

Transactive response DNA-binding protein 43 (TDP-43) is a major pathological protein in frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). There are many disease-associated mutations in TDP-43, and several cellular and animal models with ectopic overexpression of mutant TDP-43 have been established. Here we sought to study altered molecular events in FTD and ALS by using induced pluripotent stem cell (iPSC) derived patient neurons. We generated multiple iPSC lines from an FTD/ALS patient with the TARDBP A90V mutation and from an unaffected family member who lacked the mutation. After extensive characterization, two to three iPSC lines from each subject were selected, differentiated into postmitotic neurons, and screened for relevant cell-autonomous phenotypes. Patient-derived neurons were more sensitive than control neurons to 100 nM straurosporine but not to other inducers of cellular stress. Three disease-relevant cellular phenotypes were revealed under staurosporine-induced stress. First, TDP-43 was localized in the cytoplasm of a higher percentage of patient neurons than control neurons. Second, the total TDP-43 level was lower in patient neurons with the A90V mutation. Third, the levels of microRNA-9 (miR-9) and its precursor pri-miR-9-2 decreased in patient neurons but not in control neurons. The latter is likely because of reduced TDP-43, as shRNA-mediated TDP-43 knockdown in rodent primary neurons also decreased the pri-miR-9-2 level. The reduction in miR-9 expression was confirmed in human neurons derived from iPSC lines containing the more pathogenic TARDBP M337V mutation, suggesting miR-9 downregulation might be a common pathogenic event in FTD/ALS. These results show that iPSC models of FTD/ALS are useful for revealing stress-dependent cellular defects of human patient neurons containing rare TDP-43 mutations in their native genetic contexts