Sport-Specific Differences in Dynamic Visual Acuity and Gaze Stabilization in Division-I Collegiate Athletes

BACKGROUND: The vestibular-ocular reflex (VOR) integrates the vestibular and ocular systems to maintain gaze during head motion. This reflex is often negatively affected following sport-related concussion. Objective measures of gaze stability, a function mediated by the VOR, such as the computerized dynamic visual acuity test (DVAT) and gaze stabilization test (GST), may have utility in concussion management. However, normative data specific to sport, sex, or concussion history have not been established in collegiate athletes. OBJECTIVE: The objective of this study was to establish normative values for the DVAT and GST in collegiate athletes and explore the effect of sport, sex, and concussion history on VOR assessments. METHODS: The DVAT and GST were completed by 124 collegiate athletes (72 male, 52 female, mean±SD, age: 19.71±1.74 years, height: 173.99±13.97 cm, weight: 80.06±26.52 kg) recruited from Division-I athletic teams (football, soccer and cheerleading). The DVAT and GST were performed in the rightward and leftward directions during a single session in a standardized environment. Normative values for DVAT and GST measures were expressed as percentiles. Non-parametric statistics were used to compare differences between groups based on sex, sport, and concussion history. Alpha was set a-priori at 0.05. RESULTS: Overall, the median LogMAR unit for 124 athletes completing the DVAT was 0 (IQR = 0.17) for both leftward and rightward. The median velocities achieved on the GST were 145 °/sec and 150 °/sec (IQR = 45 and 40) for the leftward and rightward directions respectively. Significant differences were observed between sports (p = 0.001-0.17) for the GST with cheerleading demonstrating higher velocities than the other sports. However, no significant differences were identified based on sex (p≥0.09) or history of concussion (p≥0.15). CONCLUSIONS: Normative estimates for the DVAT and GST may assist in the clinical interpretation of outcomes when used in post-concussion evaluation for collegiate athletes. Although sex and previous concussion history had no effect on the DVAT or GST, performance on these measures may be influenced by type of sport. Sport-related differences in the GST may reflect VOR adaptations based on individual sport-specific demands

Generalised Cantor sets and the dimension of products

In this paper we consider the relationship between the Assouad and box-counting dimension and how both behave under the operation of taking products. We introduce the notion of ‘equi-homogeneity’ of a set, which requires a uniformity in the cardinality of local covers at all length-scales and at all points, and we show that a large class of homogeneous Moran sets have this property. We prove that the Assouad and box-counting dimensions coincide for sets that have equal upper and lower box-counting dimensions provided that the set ‘attains’ these dimensions (analogous to ‘s-sets’ when considering the Hausdorff dimension), and the set is equi-homogeneous. Using this fact we show that for any α ∈ (0, 1) and any β, γ ∈ (0, 1) such that β + γ ≥ 1 we can construct two generalised Cantor sets C and D such that dimBC = αβ, dimBD = α γ, and dimAC = dimAD = dimA (C × D) = dimB (C × D) = α

Activation of the p53 Transcriptional Program Sensitizes Cancer Cells to Cdk7 Inhibitors

Cdk7, the CDK-activating kinase and transcription factor IIH component, is a target of inhibitors that kill cancer cells by exploiting tumor-specific transcriptional dependencies. However, whereas selective inhibition of analog-sensitive (AS) Cdk7 in colon cancer-derived cells arrests division and disrupts transcription, it does not by itself trigger apoptosis efficiently. Here, we show that p53 activation by 5-fluorouracil or nutlin-3 synergizes with a reversible Cdk7asinhibitor to induce cell death. Synthetic lethality was recapitulated with covalent inhibitors of wild-type Cdk7, THZ1, or the more selective YKL-1-116. The effects were allele specific; a CDK7asmutation conferred both sensitivity to bulky adenine analogs and resistance to covalent inhibitors. Non-transformed colon epithelial cells were resistant to these combinations, as were cancer-derived cells with p53-inactivating mutations. Apoptosis was dependent on death receptor DR5, a p53 transcriptional target whose expression was refractory to Cdk7 inhibition. Therefore, p53 activation induces transcriptional dependency to sensitize cancer cells to Cdk7 inhibition. Kalan et al. find that activation of the p53 tumor suppressor protein in human colon cancer-derived cells can induce transcriptional dependency on Cdk7, analogous to constitutive dependencies described in other tumors driven by oncogenic transcription factors. This work provides a proof of concept for combining p53-activating agents with Cdk7 inhibitors to elicit synthetic lethality. Keywords: Cdk7; p53; colon cancer; synthetic lethality; transcription; 5-fluorouracil; nutlin-3; apoptosis; chemical genetics; CDK inhibitorNational Institutes of Health (U.S.) (Grant HG002668

Paediatric extracranial germ-cell tumours.

Management of paediatric extracranial germ-cell tumours carries a unique set of challenges. Germ-cell tumours are a heterogeneous group of neoplasms that present across a wide age range and vary in site, histology, and clinical behaviour. Patients with germ-cell tumours are managed by a diverse array of specialists. Thus, staging, risk stratification, and treatment approaches for germ-cell tumours have evolved disparately along several trajectories. Paediatric germ-cell tumours differ from the adolescent and adult disease in many ways, leading to complexities in applying age-appropriate, evidence-based care. Suboptimal outcomes remain for several groups of patients, including adolescents, and patients with extragonadal tumours, high tumour markers at diagnosis, or platinum-resistant disease. Survivors have significant long-term toxicities. The challenge moving forward will be to translate new insights from molecular studies and collaborative clinical data into improved patient outcomes. Future trials will be characterised by improved risk-stratification systems, biomarkers for response and toxic effects, rational reduction of therapy for low-risk patients and novel approaches for poor-risk patients, and improved international collaboration across paediatric and adult cooperative research groups.This is the author accepted manuscript. The final version is available from Elsevier via http://dx.doi.org/10.1016/S1470-2045(15)00545-

Liberal market economies, business, and political finance: Britain under New Labour

The extent and nature of business financing of parties is an important feature of political finance. Britain’s transparent and permissive regulatory system provides an excellent opportunity to study business financing of parties. Business donations have been very important to the Conservative party over the last decade, and of only marginal importance to Labour. Unlike other Conservative contributors, business donors are more likely to contribute when the party is popular. In contrast to the previous period of Conservative government, the biggest British businesses tended to abstain from political finance under New Labour. However, their bias towards the Conservatives is affected by the party’s popularity and the closeness of an election. Britain shares the political importance of business financing of parties and its mixture of ideological and pragmatic motivations with other liberal market economies. However, in Britain the bias towards the right is much stronger and the role of big business more marginal

Market-Driven Innovation

A new method for starting the iterative innovation process from the market side based on a sociological trend has been developed. It eliminates the traditional difference between the innovators and the sociological group that carries this trend, which can only be achieved by combining real-world innovation with innovation education. The method for market need discovery is presented as a step-by-step process with detailed reasoning, followed by a real-world example that details the outcomes at every step along the way. The example concludes with a detailed description of the outcome after the first innovation iteration cycle. The richness of the resulting concept demonstrates that an innovation process can be successfully started from the market side via the proposed method

Covalent targeting of remote cysteine residues to develop CDK12 and CDK13 inhibitors

Cyclin-dependent kinases 12 and 13 (CDK12 and CDK13) play critical roles in the regulation of gene transcription. However, the absence of CDK12 and CDK13 inhibitors has hindered the ability to investigate the consequences of their inhibition in healthy cells and cancer cells. Here we describe the rational design of a first-in-class CDK12 and CDK13 covalent inhibitor, THZ531. Co-crystallization of THZ531 with CDK12–cyclin K indicates that THZ531 irreversibly targets a cysteine located outside the kinase domain. THZ531 causes a loss of gene expression with concurrent loss of elongating and hyperphosphorylated RNA polymerase II. In particular, THZ531 substantially decreases the expression of DNA damage response genes and key super-enhancer-associated transcription factor genes. Coincident with transcriptional perturbation, THZ531 dramatically induced apoptotic cell death. Small molecules capable of specifically targeting CDK12 and CDK13 may thus help identify cancer subtypes that are particularly dependent on their kinase activities.United States. National Institutes of Health (HG002668)United States. National Institutes of Health (CA109901